cutaneous defenses against dermatophytes and yeasts

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CLINICAL MICROBIOLOGY REVIEWS, July 1995, p. 317–335 Vol. 8, No. 30893-8512/95/$04.00ϩ0Copyright ᭧ 1995, American Society for Microbiology

Cutaneous Defenses against Dermatophytes and YeastsDAVID K. WAGNER AND PETER G. SOHNLE*

Division of Infectious Diseases, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, and Medical and Research Services,

VA Medical Center, Milwaukee, Wisconsin 53295

OVERVIEW .................................................................................................................................................................318TYPES OF CUTANEOUS FUNGAL INFECTIONS .............................................................................................318

Cutaneous Candidiasis...........................................................................................................................................318Dermatophytosis .....................................................................................................................................................319Tinea (Pityriasis) Versicolor .................................................................................................................................320Malassezia Folliculitis............................................................................................................................................320Miscellaneous Superficial Fungal Infections ......................................................................................................320

FACTORS PREDISPOSING TO CUTANEOUS FUNGAL INFECTIONS........................................................321Cutaneous Candidiasis...........................................................................................................................................321Dermatophytosis .....................................................................................................................................................321Tinea Versicolor ......................................................................................................................................................321Other Cutaneous Fungal Infections.....................................................................................................................321

NONIMMUNOLOGIC CUTANEOUS DEFENSES ..............................................................................................321Structure of the Skin..............................................................................................................................................321Keratinization and Epidermal Proliferation.......................................................................................................321

Antifungal Substances............................................................................................................................................321Unsaturated Transferrin........................................................................................................................................322

THE INFLAMMATORY RESPONSE .....................................................................................................................322Relationship between Inflammation and Chronicity .........................................................................................322Chemotactic Mechanisms ......................................................................................................................................322

Antifungal Mechanisms of Phagocytic Cells.......................................................................................................322THE CUTANEOUS IMMUNE SYSTEM ................................................................................................................322

Potential Role in Superficial Fungal Infections .................................................................................................322Cells with Immunologic Potential in the Skin....................................................................................................323

Epidermal Langerhans cells..............................................................................................................................323Dermal dendritic cells........................................................................................................................................323Epidermal T lymphocytes ..................................................................................................................................323Keratinocytes .......................................................................................................................................................324

Microvascular endothelial cells ........................................................................................................................324Interactions between Cutaneous Cells .................................................................................................................324

Langerhans cells and lymphocytes...................................................................................................................324Keratinocytes and Langerhans cells ................................................................................................................325Keratinocytes and lymphocytes.........................................................................................................................325Keratinocytes and inflammatory cells..............................................................................................................325Microvascular endothelial cells and lymphocytes..........................................................................................326

Initiation and Expression of Cutaneous Immune Responses...........................................................................326IMMUNE RESPONSES TO FUNGAL ANTIGENS..............................................................................................326

Cutaneous Candidiasis...........................................................................................................................................326Dermatophytosis .....................................................................................................................................................327Tinea Versicolor and Other Superficial Fungal Infections...............................................................................328

MECHANISMS OF IMMUNOLOGIC DEFECTS ................................................................................................328Cutaneous Candidiasis...........................................................................................................................................328Dermatophytosis .....................................................................................................................................................329

Tinea Versicolor ......................................................................................................................................................329IMMUNOLOGIC THERAPY....................................................................................................................................329Cutaneous Candidiasis...........................................................................................................................................329Dermatophytosis .....................................................................................................................................................329Tinea Versicolor ......................................................................................................................................................330

SUMMARY AND CONCLUSIONS..........................................................................................................................330REFERENCES ............................................................................................................................................................330

* Corresponding author. Phone: (414) 384-2000, ext. 2878. Fax:(414) 383-8010.

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OVERVIEW

This review will cover mechanisms of cutaneous defenseagainst superficial mycoses such as cutaneous candidiasis, der-matophytosis, tinea (pityriasis) versicolor, and some relatedinfections. The various individual infections and the organismscausing them are shown in Table 1. In addition, the anatomy of the normal skin is provided in Fig. 1 in order to show the mostimportant cell types and the epidermal cell layers where theinfections usually occur. These infections are generally con-fined to the stratum corneum and cutaneous appendages, incontrast to the subcutaneous mycoses and cutaneous infectionsassociated with deep mycoses. The discussion of defensesagainst the organisms causing superficial mycoses will be or-ganized to describe the individual infections and predisposi-tions to them, immunologic and nonimmunologic cutaneousdefenses, mechanisms of host defense defects in patients withchronic superficial fungal infections, and possibilities for im-munologic therapy to correct these defects.

TYPES OF CUTANEOUS FUNGAL INFECTIONS

Cutaneous Candidiasis

Cutaneous candidiasis is an infection of the skin that isgenerally caused by the yeast Candida albicans and which canbe either acute or chronic in nature. Cases of cutaneous can-didiasis caused by other Candida species such as C. parapsilosisor C. tropicalis are sometimes seen, but these are rare. C.

albicans is part of the normal flora of the gastrointestinal tractrather than of the skin, although it can be found on the skin onoccasion. This organism can grow as either yeast cells or fila-mentous forms, with mixtures of the two phases generally seenin tissue infections. The virulence of C. albicans has beenattributed variously to its ability to grow at particular temper-atures, its ability to produce filamentous forms, its adherencecapabilities, and the activity of its different enzymes.

Acute cutaneous candidiasis may present as intertrigo, pro-ducing intense erythema, edema, creamy exudate, and satellitepustules within folds of the skin. Other infections may be morechronic, as in the feet where there can be a thick, white layerof infected stratum corneum overlaying the epidermis of theinterdigital spaces. Candida paronychia is marked by infectionsof the periungual skin and the nail itself, resulting in the typical

swelling and redness of this type of candida infection.In some cases superficial C. albicans infections may be par-ticularly severe and recalcitrant to treatment, producing theuncommon disorder known as chronic mucocutaneous candi-diasis. This condition consists of persistent and recurrent in-fections of the mucous membranes, skin, and nails, along witha variety of other manifestations. The superficial infections lastfor years in the affected patients unless they are properly treat-ed; however, deep candida infections are very rare in thissituation (141). Oral thrush and candida vaginitis are fairlycommon in patients with chronic mucocutaneous candidiasis.There is often infection of the esophagus, although furtherextension into the viscera is unusual. The typical skin lesionsare generally red, raised, and hyperkeratotic but usually arenot painful. Epidermal neutrophilic microabscesses, which are

common in acute cutaneous candidiasis, are rare in the lesionsof chronic mucocutaneous candidiasis. Nail involvement canbe severe in this condition, producing marked thickening, dis-tortion, and fragmentation of the nails, with chronic swelling of the distal phalanx. The oral thrush and vaginitis in chronicmucocutaneous candidiasis closely resemble the acute mucousmembrane infections in other patients, except that they are

FIG. 1. Anatomy of the normal skin.

TABLE 1. Types of cutaneous mycoses and the commonresponsible pathogens

Type of infection Responsible path ogen(s)

Cutaneous candidiasis Candida albicansDermatophytosis Trichophyton, Microsporum, Epidermophyton

spp.Tinea pedis T. rubrum, T. mentagrophytes, E. floccosum

Tinea cruris E. floccosum, T. rubrum, T. mentagrophytesTinea barbae T. rubrum, T. verrucosum, T. mentagrophytesTinea unguium

(onychomycosis)T. rubrum, T. mentagrophytes, E. floccosum

Tinea capitis T. tonsurans, T. schoenleini (favus), T. viola- ceum, M. canis

Tinea corporis T. rubrum, T. mentagrophytes, T. concentri- cum, T. verrucosum, T. tonsurans, M. canis, M. gypseum, E. floccosum

Tinea versicolor Malassezia furfur ( Pityrosporum orbiculare)Malassezia folliculitis Malassezia furfur Tinea nigra Phaeoannellomyces werneckii ( Exophialia

werneckii)White piedra Trichosporon beigeliiBlack piedra Piedraia hortae

318 WAGNER AND SOHNLE CLIN. MICROBIOL . REV.



more chronic in nature. The oral lesions are generally tenderand painful.

There are a number of other disorders that are associated with the syndrome of chronic mucocutaneous candidiasis (reviewed in references 76 and 147). Especially prominent arecertain types of endocrine dysfunction, such as hypoadrenal-ism, hypoparathyroidism, hypothyroidism, ovarian insufficiency,pernicious anemia, and diabetes mellitus. The combination of

chronic superficial candidiasis and endocrine hypofunction hasbeen termed the ‘‘candida endocrinopathy’’ syndrome. Alsofound in these patients are alopecia totalis, vitiligo, malabsorp-tion, chronic hepatitis, dysplasia of the dental enamel, congen-ital thymic dysplasia, thymomas, and other infections. Amongthe latter, chronic dermatophytosis, recurrent bacterial infec-tions, and occasional opportunistic infections such as crypto-coccosis, histoplasmosis, and Pneumocystis carinii pneumoniaare the most common. In these patients dermatophytosis maycause extensive skin lesions that may be misidentified as cuta-neous candidiasis and then perhaps not treated optimally (44).Chronic mucocutaneous candidiasis no doubt represents agroup of syndromes with a variety of predisposing or secondaryabnormalities in host defense function. Therefore, it may bedifficult to describe an immunologic pattern that includes all

patients. The most common deficiency appears to be one of cell-mediated immune responses against candida antigens, asdiscussed below, although abnormalities in chemotaxis orphagocytic cell function have also been reported (176, 222, 235,276, 282). Other host defense mechanisms, such as humoralimmunity and the complement system, have generally beenfound to be normal in these patients (76, 144, 145, 147, 275).

Although the superficial infections of chronic mucocutane-ous candidiasis are generally not life-threatening, they can be

very disfiguring. Before ketoconazole and other azole antifun-gal agents became available, the treatment of this condition

was quite difficult. Whereas amphotericin B produced promptclearance of the cutaneous lesions, relapses usually occurred,presumably because of the underlying immunodeficiency state.

At present, long-term treatment with azole antifungal drugs

can produce good results in chronic mucocutaneous candidia-sis, although occasional failures have occurred due to the development of resistant strains of C. albicans. Also, endocrinedysfunction, including life-threatening adrenal crises, can de-

velop after presentation of the candidiasis, so these patientsneed to be followed for this possibility. Patients who present

with chronic mucocutaneous candidiasis should also be evalu-ated for the presence of infection with the human immunode-ficiency virus and, if presenting as adults, for the possibility of thymoma.

Dermatophytosis

Dermatophytoses are infections of keratinized structures,such as the nails, hair shafts, and stratum corneum of the skin,by organisms of three genera of fungi termed the dermato-phytes. Although they are not part of the normal human skinflora (50), these organisms are particularly well adapted toinfecting this location because they can use keratin as a sourceof nutrients, unlike most other fungal pathogens. The differenttypes of dermatophytosis are classified according to body site,using the word, ‘‘tinea,’’ followed by a term for the particularbody site. The major types of dermatophytosis and the mostfrequent organisms associated with them are listed in Table 1.The word tinea itself comes from the Roman word for theclothes moth because of the similarity of its effect on woolgarments to the shape of the fungal skin infections (2). Thedegree of inflammation produced in the lesions appears to

depend primarily on the particular organism and perhaps alsoto some extent on the immunological competence of the pa-tient. In any event, the more chronic forms of dermatophytosisare generally associated with less inflammation and tend to beproduced most often by organisms usually associated with hu-mans (anthropophilic). Those associated with animals (zoo-philic) or the soil (geophilic) usually cause much more inflam-matory infections.

Tinea pedis (athlete’s foot) is probably the most commonform of dermatophytosis. This condition is a chronic toe webinfection that can be scaly, vesicular, or ulcerative in form and

which can sometimes produce hyperkeratosis of the sole of thefoot. Secondary gram-negative and mixed bacterial infectionsmay complicate tinea pedis, producing more exudative lesions.Tinea cruris is an expanding dermatophyte infection in theflexural areas of the groin and occurs much more frequently inmales than in females. Dermatophytosis of the major surfaceareas of the body is termed tinea corporis. These infectionsfrequently take the classical annular, or ‘‘ringworm,’’ shape.This type of infection can sometimes be extensive, particularlyin patients with some kind of preexisting immunological defi-ciency. In these immunodeficient patients the patches are usu-ally nummular instead of annular and are studded with small

papules or pustules where the organism has descended intohair follicles.

Involvement of the beard area in men, a condition known astinea barbae, is often caused by zoophilic organisms such asTrichophyton verrucosum. These infections can be highly in-flammatory because of the organism involved and may also besecondarily infected with bacteria. Tinea unguium is a form of onychomycosis, or fungal infection of the nails, and is mostfrequently caused by Trichophyton rubrum. Nail infections, par-ticularly of the toenails, are among the most difficult type of dermatophytosis to treat. Infection of the hair and skin on thescalp is called tinea capitis and is more common in childrenthan adults. In some cases a raised, tender mass of inflamedtissue, called a kerion, may occur. This situation generallyindicates that a spontaneous cure will result. In other cases

(black dot ringworm) there may be minimal inflammation, buthair loss may occur, with the scattered stumps of broken hairsbeing left behind in the infected area. Favus (or tinea favosum)is a distinctive type of tinea capitis that lasts for many years andis characterized by the development of extensive, cup-shapedcrusts called scutula. The description of the fungal origin of favus in 1837 marked the first time that a microorganism hadbeen incriminated as causing a human disease (2).

Some patients with dermatophytosis develop secondary cu-taneous eruptions known as dermatophytids or id reactions.These reactions generally occur at a site distant from the pri-mary dermatophyte infection and may be elicited by skin test-ing with fungal antigens. They are generally vesicular but canalso be papular, eczematous, or urticarial or have the appear-ance of erythema multiforme. Vesicular dermatophytids aremost commonly associated with inflammatory dermatophyteinfections. It is a characteristic of dermatophytids that theorganism can usually not be cultured from them, although it iseasily recoverable from the original site of dermatophytosis.Most patients with vesicular dermatophytids can be shown tohave delayed hypersensitivity to dermatophyte antigens (96),and some have also been demonstrated to have vigorous lym-phocyte transformation responses to these antigens (257).Most patients with urticarial dermatophytids have immediate

wheal reactions to dermatophyte antigens. In the past, der-matophytids have been treated effectively with topical cortico-steroids (96), but elimination of the infecting fungus is thetreatment of choice.

VOL . 8, 1995 CUTANEOUS DEFENSES AGAINST DERMATOPHYTES AND YEASTS 319



Dermatophytes rarely invade the deep tissues or producesystemic infections, even in severely immunocompromised pa-tients. Infrequently, however, granulomas, draining sinuses, oractual abscesses can be produced by these organisms (72). Asdiscussed below, competition for iron by serum proteins suchas transferrin or activation of complement may preclude thedermatophytic fungi from invading deep tissues in most pa-tients, even if they are immunosuppressed.

There are two opportunistic fungal organisms, Scytalidium dimidiatum ( Hendersonula toruloidea) and Scytalidium hyalinum, that can produce conditions clinically mimicking thosecaused by the usual dermatophyte species (67). These twoorganisms appear to be antigenically distinct from the der-matophytes (181). Some cases have apparently been acquired

within the United States, but most come from areas in otherparts of the world where the organisms are endemic. Becausethese infections do not respond to conventional antifungaltherapy, it is important to identify these pathogens by cultureof the infected skin.

The treatment of dermatophytosis has improved markedly inrecent years with the development of new antifungal agents fortopical application or oral administration. The initial approachto most cases of dermatophytosis is to try topical therapy with

creams or powders containing specific antifungal agents, in-cluding tolnaftate, chlorphenesin, undecylenate, cyclopiroxol-amine, and naftafine, or an imadozole such as clotrimazole,miconazole, econazole, or ketoconazole. However, certainkinds of dermatophytosis, including widespread infections andthose of hair and nails, will often respond poorly to topicaltherapy and will require prolonged courses of an oral antifun-gal agent, such as griseofulvin, ketoconazole, itraconazole, flu-conazole, or terbinafine.

Tinea (Pityriasis) Versicolor

Tinea (pityriasis) versicolor is a chronic superficial fungalinfection of the skin, generally affecting the trunk or proximalparts of the extremities, caused by the yeast Malassezia furfur or

Pityrosporum orbiculare (81). The organism is lipid requiringand will not grow on most laboratory media unless they areenriched with an appropriate lipid source such as olive oil. Thelesions resulting from infection with M. furfur are macules thatmay coalesce into large, irregular patches characterized by fine(pityriasiform) scaling. Hypopigmentation in the lesions maybe due to dicarboxylic acids, such as azelaic acid, that areproduced by the fungus and inhibit the tyrosinase that is in-

volved in melanin production (187). Hyperpigmentation mayalso result, usually stimulated by low-grade inflammation.These infections can persist for years unless treated appropri-ately, although the major symptoms associated with them arecosmetic. On the other hand, pruritus is occasionally producedby the lesions and can be bothersome for some patients. Po-tassium hydroxide preparations of skin scrapings reveal thetypical grapelike clusters of yeast and tangled webs of hyphaeof the causative fungus so that a diagnosis of tinea versicolorcan be made.

By electron microscopy, the organisms of tinea versicolorhave been demonstrated to be actually invading the cornifiedcells of the superficial skin layer, producing a true intracellularinfection (178). In some individuals tinea versicolor may befound in unusual patterns. For example, the infection mayoccasionally be located in sites such as the scalp, genitalia, orflexural areas (a condition termed inverse tinea versicolor).Infection on the face has been reported in immunosuppressedpatients (121), and in other patients without obvious underly-ing conditions it may present as intertrigo (140). Tinea versi-

color is more common in adults than in children (71) perhapsbecause of the greater activity of the sebaceous glands inadults. M. furfur has also been postulated to play a role incertain other diseases, including atopic dermatitis, seborrheicdermatitis, psoriasis, and reticulate papillomatosis (40, 74, 191,231).

Tinea versicolor can be treated topically with lotions orcreams containing selenium or sodium thiosulfate or with spe-

cific antifungal agents. Sulfur-salicyclic acid shampoo can alsobe used. Topical treatment is generally successful, althoughrelapses are frequent, either because the patient’s predisposi-tion to the infection has not been reversed or because theorganisms may persist within hair follicles (152). Oral ketocon-azole, fluconazole, and itraconazole have also been shown tobe effective in treating tinea versicolor, although relapses mayalso occur after these systemic treatments.

Malassezia Folliculitis

Malassezia folliculitis resembles several other cutaneous in-fections, including acne vulgaris, the macronodular lesions of disseminated candidiasis in immunosuppressed patients, andthe candidal papular folliculitis of heroin addicts (152). It may

also be confused with graft-versus-host disease in bone marrowtransplant recipients (33). Malassezia folliculitis is caused by

M. furfur and tends to infect the same areas as does tinea versicolor: the upper shoulders, back, and chest. As opposed toacne, pustules extend down the arms and down the back to the

waist. There are no comedones and the lesions are monoto-nously monomorphic. The papules begin as an inflammation of the hair follicles, instead of the macules typical of tinea versi-color, and may progress to frank pustules. These lesions aregenerally quite pruritic. The contents of the infected hair fol-licles include keratinaceous material, amorphous cellular de-bris, inflammatory cells, and the yeast forms (but not the hy-phal forms) of the infecting organisms (153, 206).

Malassezia folliculitis can be treated with topical antifungalagents and may also respond to 50% propylene glycol in water

applied twice a day for 3 weeks (9). If topical therapy fails,malassezia folliculitis can be treated with an oral azole anti-fungal drug for 2 to 3 weeks.

Miscellaneous Superficial Fungal Infections

Tinea nigra is a superficial mycosis of the palms that is mostoften caused by Phaeoannellomyces werneckii ( Exophiala wer-

neckii). The lesions are generally dark colored, nonscalingmacules that are usually asymptomatic but can be confused

with melanomas and perhaps result in unnecessary surgery(195). Tinea nigra is most often seen in tropical or semitropicalareas of Central and South America, Africa, and Asia, al-though some cases do occur in North America. This conditioncan be treated effectively with either keratinolytic agents ortopical imadazoles. White piedra is an asymptomatic fungalinfection of the hair shafts that is caused by Trichosporon

beigelii. This infection produces light-colored, soft nodules onthe hair shafts and may cause the involved hairs to break.Otherwise, this condition appears to be asymptomatic, al-though the causative fungus can produce serious infections inimmunocompromised patients. Cutaneous trichosporonosisand trichosporon onychomycosis have also been reported (82,138). Black piedra is similar to white piedra in that it is anodular, generally asymptomatic fungal infection of the hairshafts. It is caused by Piedraia hortae and most commonlyaffects the scalp hair. Black and white piedra are generallytreated by clipping off the affected hairs.




FACTORS PREDISPOSING TO CUTANEOUSFUNGAL INFECTIONS


A variety of local and systemic factors predispose to super-ficial fungal infections. Cutaneous candidiasis most frequentlyoccurs when there are warm, moist conditions such as in skin

folds, under the diapers of newborns, and in tropical climatesor during the summer months. Otherwise, treatment with cor-ticosteroids, cytotoxic agents, broad-spectrum antibiotics, andoral contraceptives all predispose to various forms of candidi-asis. Diabetes mellitus (179) and infection with human immu-nodeficiency virus (52, 164, 208) are both strongly associated

with superficial candidiasis, although disseminated candidiasisis unusual in these conditions. Genetic predisposition may beimportant in chronic mucocutaneous candidiasis in that ap-proximately 25% of these patients have relatives with this dis-ease (116, 117).

Dermatophytosis

Local cutaneous factors appear to be very important in de-termining whether or not infection will occur after an exposure

to the dermatophytic fungi. For example, the warm and moistconditions in the swampy areas of Vietnam were thought to berelated to the high incidence of dermatophytosis in combattroops there (28). Also, occlusion over the site appears toenhance susceptibility to experimental dermatophyte infec-tions in humans and other animals (10, 28, 105, 154, 254, 264).Occlusion has been postulated to increase hydration of theunderlying skin and emission from the skin of carbon dioxide,

which could favor dermatophyte growth (142). A number of medical conditions also appear to predispose

patients to chronic dermatophytosis. Most cases of dermato-phytosis that persist for long periods in relatively normal per-sons are caused by Trichophyton rubrum. However, other der-matophytes can cause chronic infections in patients with someunderlying disease, such as collagen vascular disease, systemic

corticosteroid therapy or Cushing’s disease, hematologic ma-lignancy, chronic mucocutaneous candidiasis, diabetes melli-tus, or atopy (41, 77, 113, 189). Advanced age has also beenrelated to an increased incidence of dermatophytosis (90, 199),and these infections are often asymptomatic (273). Underlyingperipheral vascular disease and disorders of keratinizationhave also been found to be associated with chronic dermato-phytosis (113). As discussed below, the chronic infections seemto be related to a higher than expected rate of atopy in theaffected individuals. In addition, there is some evidence thatsusceptibility to chronic dermatophytosis may occur as an in-herited trait (114). The best example is tinea imbricata, in

which predisposition to the infection has been demonstrated tobe transmitted as an autosomal recessive trait (227).

Tinea VersicolorWarm climates are strongly associated with an increased

incidence of tinea versicolor (167). Since some conjugal casesof tinea versicolor do occur (215), there may be some degree of infectivity of the responsible organism for normal persons. Thisinfection has been reported to be more frequent in steroid-treated patients, those with Cushing’s disease, those undergo-ing immunosuppression for renal transplantation, and persons

who are severely malnourished (29, 46, 77, 156). Genetic sus-ceptibility has also been postulated for tinea versicolor in thatinfections in relatives occur at a higher than expected rate (35,108, 215).

Other Cutaneous Fungal Infections

Malassezia folliculitis may develop in immunosuppressedpatients (33, 152, 153, 283), although it can also occur inpatients with presumably normal immunologic function (9).Experimental infections with Malassezia spp. suggest that cer-tain patients, such as those with seborrheic dermatitis, have apredisposition to this condition (91). Therefore, other host

factors, in addition to obvious immunosuppression, may berelated to the pathogenesis of this condition.

Tinea nigra and both black and white piedra are caused byfungi that are frequently found in the environment. Theseconditions all seem to be more frequent in warm climates,perhaps because the organisms may be more common there. Inaddition, Trichosporon beigelii, the cause of white piedra, col-onizes a relatively small proportion of hospitalized patients(219). Severely immunocompromised patients may developlife-threatening systemic infections with this organism.

NONIMMUNOLOGIC CUTANEOUS DEFENSES

Structure of the Skin

The physical and chemical structure of the skin represents aform of defense against fungal pathogens. The skin surface isrelatively inhospitable to fungal growth because of exposure toUV light, low moisture conditions, and competition from thenormal bacterial flora of this site. Therefore, this surface actsas a barrier to the entry of fungi. The stratum corneum is madeup of keratin, which most microorganisms cannot use for nu-trition. However, C. albicans and the dermatophytes producekeratinases, which hydrolyze this substance and facilitate thegrowth of these organisms in the stratum corneum itself (188,266, 284). This very superficial site of infection may protect theinfecting organisms from direct contact with at least some of the effector cells of the immune system. Although neutrophilsand small numbers of lymphocytes may enter the epidermis,the major infiltrates of cell-mediated immune responses aregenerally confined to the dermis.

Keratinization and Epidermal Proliferation

The process by which the stratum corneum is continuallyrenewed through keratinization of the epidermal cells may alsopresent a form of defense against organisms infecting this site.The anatomy of the normal skin is shown in Fig. 1. The basalepidermal cells produce continued growth of the epidermis asthey undergo continued cell divisions that move the resultingdaughter cells (keratinocytes) outward, toward the surface. Asthey mature these cells lose their nuclei and become flattenedto form the keratinized cells. This process results in continuousshedding of the stratum corneum, which also may removeinfecting fungal microorganisms residing there. Keratinocytesin the periphery of annular dermatophytosis have been found

to divide at an increased rate (20). Inflammation, includingthat produced by cell-mediated immune reactions, appears toenhance epidermal proliferation so that rates of transit of epidermal cells towards the stratum corneum are increased(163). A number of studies have demonstrated that epidermalproliferation is important in the defense against superficialmycoses (20, 131, 149, 163, 245).

Antifungal Substances

Lipids of adult hair contain saturated fatty acids that arefungistatic against Microsporum audouini, formerly a commoncause of hair and scalp infections (220). In particular, various




types of sphingosines have recently been found to be activeagainst certain dermatophytes and C. albicans (22). Whereasthe sebum of adults may not be significantly more fungistaticthan that from children on a weight-per-weight basis, olderindividuals appear to produce quantitatively more of this ma-terial than do children (151). In addition, fungicidal proteinshave been isolated from normal epidermis and could play somerole in the defense against cutaneous fungal infections (139).

Unsaturated Transferrin

In contrast to other fungal pathogens such as C. albicans, M. furfur , and Trichosporun beigelii, the dermatophytic fungi ap-pear to be relatively incapable of causing disseminated disease,except for occasional local abscesses or granulomas in severelyimmunosuppressed patients. Thus, infections with dermato-phytes are generally confined to the keratinized stratum cor-neum and the cutaneous appendages like the hair and nails.This phenomenon has been related to the presence in thedermis of unsaturated transferrin, which may prevent growthof the organisms in the deeper layers of the skin by competitionfor iron (143).

THE INFLAMMATORY RESPONSE

Relationship between Inflammation and Chronicity

With various kinds of superficial fungal infections there ap-pears to be an inverse relationship between the degree of inflammation produced by a particular fungal pathogen andthe chronicity of that infection. M. furfur and the anthropo-philic dermatophytes, Trichophyton rubrum and Epidermophy-ton floccosum, generally produce little inflammation in theircutaneous lesions and frequently cause infections that persistfor long periods. On the other hand, many of the geophilic orzoophilic dermatophytes, e.g., Trichophyton verrucosum, pro-duce highly inflammatory infections that are usually self-lim-ited. Thus, the local inflammatory processes may indeed beinvolved in the defense against this group of pathogens.

Chemotactic Mechanisms

Although superficial fungal infections are generally limitedto the most superficial layers of the skin or its appendages,some of these infections are highly inflammatory. One canobserve in the infected skin a variety of gross changes includingscaling, vesicles, pustules, annular dermatitis, and severe in-flammatory reactions (kerions). Microscopically, the lesionsare characterized by an accumulation of neutrophils in theinfected skin of acute infections or a mononuclear cell infil-trate in the dermis of the more chronic ones. The acute in-flammatory responses may be manifested as epidermal micro-abscesses. Evidence of epidermal proliferation may also beseen in the chronic infections as hyperkeratosis and paraker-atosis.

A variety of mechanisms by which inflammatory cells areattracted to the sites of cutaneous fungal infections have beendescribed. Trichophyton rubrum and Trichophyton mentagro-

phytes have both been shown to be capable of activating com-plement by the alternative pathway to produce chemotacticactivity for neutrophils (59, 258). Likewise, C. albicans and M.

furfur have been found to activate complement by this pathway(211, 239). Trichophyton mentagrophytes and C. albicans pro-duce low-molecular-weight chemotactic factors analogous tothe ones made by growing bacteria (56, 263). On the otherhand, Trichophyton rubrum extracts have been shown to de-stroy chemotactic activity generated from serum (58), perhaps

explaining the minimal degree of inflammation usually seen inthe lesions produced by this organism. Finally, as discussedmore fully below, keratinocytes can generate chemotactic cy-tokines that could also be responsible for some of the inflam-mation in the lesions of cutaneous fungal infections.

Antifungal Mechanisms of Phagocytic Cells

Neutrophils and monocytes/macrophages appear to be im-portant in the defense against fungi, including those involvedin the cutaneous mycoses. Neutrophils can directly attackpathogens by a variety of microbicidal processes (reviewed inreferences 218 and 272). Some of these processes depend onmicrobicidal oxidants, including superoxide, hydrogen perox-ide, hypochlorous acid, and monochloramine (106, 269). Al-ternatively, the neutrophil killing mechanisms may involvenonoxidative granule microbicidal substances, such as cathep-sins (62), the defensins (85, 226), bactericidal/permeability-increasing protein (279), lactoferrin (5), lysozyme (48), elas-tase (192), azuricidin (40, 83), and a number of other proteins(118, 177, 234). Most of these substances have been studiedprimarily for their ability to kill the organisms, although lacto-ferrin may have both microbistatic and microbicidal effects (6).

The neutrophil oxidative mechanisms are capable of killingTrichophyton sp. in vitro (38), suggesting that they could havea role in the defense against dermatophytosis. Macrophageshave an additional antimicrobial mechanism by which they canuse production of nitric oxide to inhibit growth of ingestedfungal pathogens, such as Cryptococcus neoformans (4). Thismechanism might be active against the organisms causing su-perficial fungal infections also.

Neutrophils also appear to have significant growth inhibitoryactivity in addition to their microbicidal processes. These cellscontain large amounts of a calcium and zinc binding protein,called calprotectin, that has potent microbistatic activityagainst C. albicans and other fungi (174, 185, 250). This proteinis released into inflammatory exudates as neutrophils die atsites of infection (242) and could supplement other host de-fenses in the infected skin by controlling growth of C. albicansor other fungi there (174).

THE CUTANEOUS IMMUNE SYSTEM

Potential Role in Superficial Fungal Infections

Since cutaneous fungal infections are more frequent andmore severe in patients with immunologic defects, immuneresponses to fungal antigens would seem to play an importantrole in the host defense against these infections. Immunologichost defense mechanisms in normal hosts seem to be effectiveeven when the infections are limited to superficial locationssuch as the stratum corneum (277). A number of studies sug-gest that the epidermis of the skin represents more than apassive barrier against entry of infecting organisms: i.e., that italso acts as an immunologic organ with some unique elements.In 1983, a hypothesis regarding the skin-associated lymphoidtissue concept, in which the skin acted as an immune surveil-lance unit (255), was advanced. A variety of cell types arebelieved to be involved in this cutaneous immune system and

will be reviewed below. The mechanisms employed are com-plex, involving a network of fixed or mobile cells interactingeither by trafficking of the cells themselves from one site toanother or by producing cytokines that influence the functionof other cells. Such skin-initiated immune responses act againsta broad spectrum of foreign antigens, including contact aller-gens, tumors, and transplants, and it is likely that they are also




active against the fungal pathogens of interest here. Therefore,this system is probably responsible for initiating immune re-sponses that work to eliminate the infecting organisms in theimmune host. In addition, such responses may also producesome of the inflammation that results in much of the symp-tomatology of these infections.

Cells with Immunologic Potential in the Skin

Epidermal Langerhans cells. Langerhans cells, first discov-ered by Paul Langerhans in 1868 (252), develop as dendriticcells from bone marrow stem cells and home in to selectedtissues. At least five distinct subsets of dendritic cells have beenrecognized, including Langerhans cells in epithelial tissues,dendritic cells in peripheral blood or lymph, interdigitatingdendritic cells in T-cell-dependent areas of lymphoid tissues,follicular dendritic cells in B-cell-dependent areas, and dermaldendritic cells (19). The bone marrow stem cells are defined asdendritic-Langerhans cell CFU and appear to be a commonorigin of both macrophages and dendritic cells (155, 212).Peripheral blood dendritic cells account for up to 2% of cir-culating mononuclear cells and have been shown by transmis-sion electron microscopy to be of three different types (155).

Of the three types, the type 2 peripheral blood dendritic cellhas an appearance and functional similarity to Langerhanscells, indicating that these cells are precursors of Langerhanscells. Signals for movement into epidermal tissues are notentirely clear but could involve adhesion molecules and lym-phokines such as tumor necrosis factor ␣ (TNF-␣) and gran-ulocyte-macrophage colony-stimulating factor (GM-CSF) (43,155).

Epidermal Langerhans cells make up approximately 2 to 5%of the total epidermal cell population (197) and vary in densitydepending on anatomic location. For example, Langerhans celldensity is higher in the epidermis of the head, face, neck, trunk,and limbs than in that of the palms, soles, and genital region(252). These cells have a pronounced dendritic shape andcontain rod-shaped organelles of varying length and position,

called Birbeck granules, which were first described in 1961(26). Birbeck granules are not specific for epidermal Langer-hans cells, however, and have been detected in other tis-sues, including lymph node, thymus, and dermis (252). Freshlyisolated Langerhans cells display nonspecific esterase and

ATPase activity. They also express a variety of antigenic mark-ers on their surface (reviewed in references 251 and 252).Langerhans cells are the only cells within the normal epidermisto express cluster of differentiation antigen 1a (CD1a), Fcimmunoglobulin G (IgG) receptor type II (Fc␥RII/CD32), FcIgE receptor type I (FcεRI), C3bi receptors (CD11b to CD18),and major histocompatibility complex (MHC)-encoded class IIantigens. Among these markers, the anti-CD1a labeling ap-pears to be the most reliable one for distinguishing epidermalLangerhans cells. The major products produced by Langerhanscells are summarized in Table 2.

The functional significance of Langerhans cells was first elu-cidated in the early 1970s with the observation of the apposi-tion of Langerhans cells and T lymphocytes and the proposalthat Langerhans cells might function as antigen-presentingcells (232). Since that time, numerous studies have furtherelucidated the function of these cells. As antigen-presentingcells, the Langerhans cell would be required to process andpresent antigens for T-lymphocyte activation. In this regard,there have been a number of observations that support thisconcept. Similar to other types of antigen-presenting cells,phagocytosis of antigens by Langerhans cells has been demon-strated (248). The Birbeck granules may have an important

role in the processing of antigens in that there is loss of anti-gen-processing capacity during culture of these cells, and thisloss appears to be associated with the disappearance of Bir-beck granules (253). Also, the aspartic proteinase, cathepsin E,appears to play a crucial role in other antigen-processing cellsby cleaving proteins and releasing smaller peptides (15), andthis enzyme has recently been demonstrated by immunocyto-chemical stains in the cytoplasmic vesicles (including Birbeckgranules) of Langerhans cells (246).

Dermal dendritic cells. The dermis contains a population of

antigen-presenting cells that constitute one of the five subsetsdescribed above. These cells have dentritic processes, are mo-tile, and express a variety of markers, as shown in Table 3.These include high levels of class II MHC antigen as well ascertain proteins involved in adherence of one cell type toanother, including intercellular adhesion molecule-1 (ICAM-1), leukocyte function antigen-1 (LFA-1), and adhesion mole-cule B7. All dermal dendritic cells, but not epidermal Langer-hans cells, express factor XIIIa in addition to CD1a, althoughthe expression of the latter is weaker than on Langerhans cells.In addition to the above observations, dermal dendritic cellshave recently been phenotypically and functionally character-ized into three distinct subsets (190). Subset 1 (65 to 70% of total) expresses neither CD1a nor CD14, subset 2 (15 to 20%of total) expresses CD1a but not CD14, and subset 3 (10 to

15% of total) expresses CD14 but not CD1a. The CD14-neg-ative subsets (subsets 1 and 2) are more potent antigen-pre-senting cells than subset 3 and are as potent as Langerhanscells or blood-derived dendritic cells in allogeneic mixed lym-phocyte reactions. These cells may be different from Langer-hans cells or they may represent an immature form of thesecells (190). In either case, they probably are important in theinitiation of immunologic responses in the skin, particularlythose involving antigens in the dermis. In this regard it hasbeen shown that in UV B-damaged skin dermal dendritic cellsare able to provide an antigen-presenting function and mayalso confer tolerance (158). However, their role in the afferentphase of immune responses against antigens in the epidermis isunclear at this time.

Epidermal T lymphocytes. As discussed above, the lymphoid

infiltrates characteristic of cutaneous cell-mediated immuneresponses are generally confined to the dermis of the skin. A

TABLE 2. Major products of Langerhans cells

Product class Products a

Surface markers CD1a, Fc␥RII/CD32, FcεRI, εBP, FcεRII/ CD23, CD11b-CD18, CD25, CD40, CD54,CD58, MHC class I, MHC class II

Adhesion molecules LFA-3, ICAM-1, B7Cytokines IL-1␤, IL-6, TNF-␣

a Fc␥RII/CD32, Fc IgG receptor type II; FcεRI, high-affinity receptor for IgEreceptor; εBP, IgE binding protein; FcεRII/CD23, low-affinity receptor for IgE;B7, cell surface molecule B7.

TABLE 3. Major products of dermal dendritic cells


Surface markers MHC class II, factor XIIIa, subset 1(CD1aϪ, CD14Ϫ), subset 2 (CD1aϩ,CD14Ϫ), subset 3 (CD1aϪ, CD14ϩ)

Adhesion molecules ICAM-1, LFA-1, B7

a B7, cell surface molecule B7.




majority of the T lymphocytes of normal human skin are lo-cated around postcapillary venules beneath the dermal-epider-mal junction, whereas less than 5% are present within theepidermis (31). There may be some differences between thetwo populations of cells. T-lymphocyte antigen receptors are of two types, with most being of the ␣␤ heterodimer phenotypeand a small population expressing the ␥␦ heterodimer. In the

papillary dermis, up to 80% of T lymphocytes are ␣␤ positiveand approximately 7% are ␥␦ positive. In contrast, only 60% of the T lymphocytes in the epidermis are ␣␤ positive, with 18 to29% being ␥␦ positive. Although these numbers could repre-sent differences in patterns of migration into the epidermis,there does not appear to be a preferential pattern of immigra-tion of the lymphocyte subtypes into the epidermis (31). Sen-sitized T lymphocytes can be found in the epidermis, with twopossibilities accounting for their presence there: (i) throughantigenic stimulation of resting T lymphocytes at this site, and(ii) attraction of already sensitized T lymphocytes by chemo-tactic cytokines. The latter could include members of the in-terleukin-8 (IL-8) family produced by keratinocytes.

Keratinocytes. Keratinocytes not only have an importantstructural role in forming a physical barrier to foreign antigens

and microorganisms but also are important functionally inmediating cutaneous immune reactions. These cells are by farthe most numerous in the epidermis, although other cellstypes, including melanocytes, neuroendocrine Merkel cells,and Langerhans cells, are also found there. The interfollicularepidermis is divided into a series of proliferating units, knownas epidermal proliferative units (165, 205). Within an epider-mal proliferative unit, there are slow- and fast-cycling basalkeratinocytes, which are distinct populations (182, 198) thatcould possibly have different functions. Other neighboringcells, Langerhans cells, and cells in the dermis appear to havea regulatory effect on keratinocytes and may lead to cellulardiversity within the basal layer (198).

Keratinocytes secrete a number of soluble factors that arecapable of up-regulating and down-regulating immune re-sponses. The major products of these cells are shown in Table4. Cytokines produced by keratinocytes include a number of growth factors, interleukins, and CSFs (12, 13, 159, 168, 169,172, 251, 252). The major growth factors produced includebasic fibroblast growth factor, platelet-derived growth factors

AA and B, transforming growth factor alpha, transforminggrowth factor beta, and TNF-␣. These cells also produce sev-eral interleukins, including II-1, IL-3 (also called multi-CSF),IL-6, IL-7, and IL-8, and a number of CSFs, such as GM-CSF,granulocyte CSF, and macrophage CSF. Most of these medi-ators are not constitutively produced, but their gene expressionis up-regulated after a variety of stimuli (251, 252).

In addition to the production of soluble factors, keratino-

cytes also express important cell surface molecules, such asMHC and adhesion molecules, suggesting that they may func-tion as immunologic targets. Class I MHC molecules are ex-pressed constitutively on keratinocytes and may represent atarget for CD8ϩ cytotoxic T lymphocytes (252). Such a role hasbeen suggested for contact hypersensitivity (267), herpes sim-plex virus infection (55), graft-versus-host disease and otherskin disorders with a lichenoid infiltrate, and keratinocyte ne-crosis (252). Class II MHC molecules are not expressed con-stitutively but can be induced by gamma interferon (IFN-␥)

(186). Production of the latter is attributed to infiltrating Tlymphocytes (252). Whereas keratinocytes can express func-tional peptide-class II complexes, they are apparently unableto process exogenous protein antigens (86).

Microvascular endothelial cells. Microvascular endothelialcells are located near the microenvironment where the impor-tant cutaneous immunologic reactions occur. Endothelial cellsare known to be active participants in a variety of functions,including wound healing, angiogenesis, production of clottingfactors, and maintenance of vascular tone. Their role in epi-dermal immunologic events is not entirely clear, althoughthere is increasing evidence for their participation in this area.Like the keratinocytes, microvascular endothelial cells secretea number of soluble factors capable of inducing inflammationand recruiting leukocytes and express a variety of adhesion

molecules. The major products of microvascular endothelialcells are shown in Table 5. The soluble factors include numer-ous cytokines (IL-1, IL-6, and IL-8), CSFs (granulocyte CSF,macrophage CSF, and GM-CSF), and the chemotactic factorsmelanoma growth-stimulating factor and macrophage chemo-tactic and activating factor (193, 260). Adhesion moleculesproduced by microvascular endothelial cells include ICAM-1,

vascular adhesion molecule-1, P-selectin, E-selectin, and oth-ers (260).

Interactions between Cutaneous Cells

Langerhans cells and lymphocytes. After the interaction with a foreign antigen, Langerhans cells migrate to regionallymph nodes, where they interact with T lymphocytes (19). Theeffect of stimulation of Langerhans cells is to produce enlarge-ment and sheetlike processes (or veils) and loss of Birbeckgranules (126). In epidermal cell cultures, ATPase activity andthe expression of certain markers (e.g., Fc␥RII) decrease,along with the loss of Birkbeck granules, whereas the surfacedensity of other markers (MHC class I and II antigens, CD25,CD40, CD54, and CD58) increases (251). These culturedLangerhans resemble other lymphoid tissue dendritic cells

which are stimulators of T-cell responses (175) and are them-selves much better able than resting Langerhans cells to stim-ulate resting T cells (124). This in vitro phenotypic maturation(reviewed in reference 251) is likely comparable to the in vivosituation inasmuch as increased MHC class II expression con-

TABLE 4. Major products of keratinocytes


Surface markers MHC class I, MHC class II Adhesion molecules ICAM-1, LFA-3, B7Eicosanoids PGE2

CytokinesGrowth factors bFGF, PDGF AA and B, TGF-␣, TGF-␤,

TNF-␣Interleukins IL-1, IL-3, IL-6, IL-7, IL-8CSFs GM-CSF, G-CSF, M-CSF

a B7, cell surface molecule B7; bFGF, basic fibroblast growth factor; PDGF,platelet-derived growth factor; PGE2, prostaglandin E2; LTB4, leukotriene B4;G-CSF, granulocyte CSF; M-CSF, macrophage CSF.

TABLE 5. Major products of microvascular endothelial cells


Adhesion molecules ICAM-1, VCAM-1, P-selectin, E-selectinCytokines

Interleukins IL-1, IL-6, IL-8CSFs GM-CSF, G-CSF, M-CSFChemotactic factors gro ␣, MCAF

a VCAM, vascular adhesion molecule; G-CSF, granulocyte CSF; M-CSF, mac-rophage CSF; gro ␣, melanoma growth stimulating factor; MCAF, macrophagechemotactic and activating factor.




sistent with acquisition of active antigen-presenting cell func-tion has been observed in contact-sensitized Langerhans cells(54).

For proper presentation of antigen and subsequent T-lym-phocyte activation and clonal expansion, it is essential to havea proper physical interaction between Langerhans cells and Tlymphocytes. The contact between Langerhans cells and thereceptor for antigen on T lymphocytes is class II MHC depen-

dent (1). The physical interaction has been shown by electronmicroscopy to be of two types (49): (i) a glycocalyx-glycocalyx interaction that occurs in relation to protrusions (microvilli) of both cells and may represent the locus for antigen presenta-tion, and (ii) wide and tight areas of close apposition betweenplasma membranes of both cells. The latter interaction is ap-parently involved in maintaining adhesiveness between the twocell types. The adhesion molecules LFA-3 and ICAM-1 areexpressed on Langerhans cells, whereas the correspondingmolecules CD2 and LFA-1 are expressed on T lymphocytes(270). LFA-1 is a member of the integrin family of adhesion-promoting proteins, while LFA-3, ICAM-1, and CD2 aremembers of the immunoglobulin superfamily. Interaction of LFA-3 with CD2 and ICAM-1 with LFA-1 may enhance T-lymphocyte activation either by providing unique costimula-

tory signals or by augmenting T-lymphocyte–Langerhans cellinteraction (126, 271). Following cellular activation, the ex-pression of all four adhesion molecules has been shown to beincreased (270).

In addition to the antigen-MHC and adhesion interaction, asecond signal, such as IL-1, is required for optimal antigen-specific T-lymphocyte clonal expansion. The second signal islikely delivered to the T lymphocyte through the above-de-scribed adhesion molecules (233, 270). These molecules there-fore serve the purpose of not only physical adhesion but alsodelivery of stimulatory signals. Langerhans cells themselvescan produce IL-1 as well as other cytokines (IL-6 and TNF-␣)(68, 169, 252). Recent studies indicate that the Langerhanscell-derived IL-1␤ may play a critical role as the second signalfor T-lymphocyte activation (68, 202). Evidence also suggests

that the B7/BB-1 (B7) molecule, known to be expressed oncells such as activated monocytes, is a principal costimulator of T lymphocytes. It has also been shown that B7 is expressed onthe cell surface of cultured Langerhans cells and that Langer-hans cell B7 costimulates the proliferation of resting allogeneicCD4ϩ T lymphocytes (261). The interaction of Langerhanscells and naive CD4ϩ T lymphocytes results in the generationof Th1 effector cells. The latter can release the cytokine IL-2,leading to expansion of the T-lymphocyte clone. When acti-

vated hapten-specific CD4ϩ T lymphocytes are stimulated in vitro for several cycles with hapten-modified Langerhans cells,IL-4-secreting Th2 effector cells are produced (111). IL-4 haspreviously been reported to induce the secretion of IgE inactivated B cells (47). Langerhans cells could therefore have arole in atopic reactions when there is constant exposure toantigenic stimulation.

Among the surface receptors described above on Langer-hans cells is the IgE receptor. Actually, three distinct IgE-binding structures of Langerhans cells have been demon-strated, including the low-affinity receptor for IgE (FcεRII/ CD23), the IgE-binding protein (εBP), and the high-affinityreceptor for IgE (FcεRI) (24, 25). IgE molecules play a centralrole in immediate hypersensitivity reactions, and the descrip-tion of IgE receptors on Langerhans cells, a well-known par-ticipant in T-lymphocyte reactions, demonstrates a unique linkbetween these two types of immune response. Although thefunctional role of the IgE receptors on Langerhans cells hasnot been well elucidated, it is possible that they may participate

in defense mechanisms against parasites and/or immune reac-tions to allergens (25).

There is some evidence that Langerhans cells may be involved in the down-regulation of immune responses throughtheir soluble IgG receptors. These cells produce the Fc IgGreceptor type II (Fc␥RII/CD32), which may inhibit the bindingof immune complexes to Fc␥Rϩ cells and therefore participatein suppression of immune responses (7).

The fate of Langerhans cells after they stimulate T lympho-cytes is unclear. They may serve as targets of natural killer cells(or cytotoxic T cells) and be destroyed after stimulating Tlymphocytes. Alternatively, the observation that up to 1% of thoracic duct cells are dendritic would seem to suggest survivaland recirculation of these cells (19).

Keratinocytes and Langerhans cells. Some of the cytokinesproduced by keratinocytes (IL-1, GM-CSF, and TNF-␣) havethe potential to influence the maturation of dendritic cells(217) and therefore could differentially modify the ability of Langerhans cells to respond to antigens. This effect on Langer-hans cells may be different in regard to primary or secondaryimmune responses (94). Therefore, contact hypersensitivitymight require not only antigen uptake by Langerhans cells butalso antigen-induced cytokine expression by keratinocytes. Ke-

ratinocytes have also recently been shown to adhere to Langer-hans cells through the expression of E-cadherin on the latter(268). This adhesion may enhance the functional interactionsbetween these two cell types.

Keratinocytes and lymphocytes. Although the functionalrole of class II-expressing keratinocytes in human epidermis isunclear, there is evidence that they may have a role in devel-oping tolerance to certain antigens. When keratinocytes areused as accessory cells, there is a preferential initial productionof IL-2 and IL-4 from stimulated lymphocytes and a specificlack of IFN-␥ production. Restimulation induces only IL-4,

which is a Th2 cytokine that has been suggested to be impor-tant in the maintenance of tolerance to self-antigens (92).Keratinocytes are able to induce nonresponsiveness (toler-ance) to subsequent antigen-specific stimulation of T-helper

cell clones in vitro (11), and transient hyporesponsiveness tocontact allergens has been demonstrated after injection of these keratinocytes into naive mice (87). The potential exists,therefore, for keratinocytes to be involved in selective hypore-sponsiveness to microbial antigens in certain cases of chroniccutaneous infections when cell-mediated immune reactions tothe infecting organisms appear to be diminished.

Keratinocytes, like Langerhans cells, express cell surfaceadhesion molecules ICAM-1, LFA-3, and B7 (61, 66, 80).ICAM-1 expression is increased by IFN-␥ (66). These adhesionmolecules are important, as described above, for appropriatecontact of Langerhans cells to T lymphocytes and subsequentT-lymphocyte clonal expansion. In a similar way, these mole-cules are probably integral to keratinocyte and lymphocyteinteractions.

Keratinocytes and inflammatory cells. Keratinocytes mayalso enhance inflammation through cytokine effects on variouskinds of inflammatory cells. For instance, macrophage chemo-tactic and activating factor is produced by keratinocytes inresponse to IFN-␥ (13). Other cytokines produced by thesecells, such as IL-8, are chemotactic for both neutrophils andlymphocytes (12, 169), and keratinocyte-derived IL-7 has beendemonstrated to be a growth factor for epidermal T cells (168).In addition to these effects on other cells of the immune sys-tem, keratinocytes can themselves respond to keratinocyte-derived cytokines by dividing and then migrating over a woundsurface to form a new epidermis (172).

Keratinocytes also generate products of arachidonic acid




metabolism, called eicosanoids, which may influence inflam-matory reactions in the skin and whose synthesis appears to beenhanced by IL-1 produced by the keratinocytes themselves(203). One of these products, prostaglandin E

2increases vas-

cular permeability and could promote the influx of inflamma-tory cells into the skin. Prostaglandin E2, however, is primarilyinvolved in down-regulating immune responses, including T-and B-cell proliferation and suppression of IL-1 production by

mononuclear phagocytes (93, 252). Another arachadonic acidmetabolism product, leukotriene B4, is a potent mediator of leukocyte chemotaxis that may be generated by keratinocytesthrough an leukotriene A4 hydrolase found in the cytoplasm of these cells (123).

Microvascular endothelial cells and lymphocytes. Whereasmicrovascular endothelial cells have been shown to producenumerous cytokines and adhesion molecules, their specific rolein inflammatory events is not clear. However, one of the ad-hesion molecules produced, P-selectin, has been shown to me-diate binding of a variety of other cell types, including neutro-phils (88), T lymphocytes (180), and natural killer cells (180).This molecule is not constitutively produced but is induced byhistamine or thrombin (88). Similarly, E-selectin is producedby microvascular endothelial cells only after induction by cy-

tokines (21) and has been shown to bind memory T lympho-cytes (230). ICAM-1 is constitutively expressed on endothelialcells, but the expression can be increased by a number of cytokines, including IL-␣, TNF-␣, and IFN-␥ (65, 259). Thismolecule probably plays a role in binding of lymphocytes to theendothelial cells. The expression of these specific adhesionmolecules and the production of proinflammatory soluble fac-tors suggest that these microvascular endothelial cells are ac-tive participants in cutaneous immunologic trafficking. Theirspecific involvement probably reflects the types of soluble me-diators and/or adhesion molecules produced.

Initiation and Expression of Cutaneous Immune Responses

According to the skin-associated lymphoid tissue concept

described in 1983, the skin contains an immune surveillancesystem consisting of antigen-presenting Langerhans cells, cy-tokine-producing keratinocytes, epidermotropic T lympho-cytes, and draining peripheral lymph nodes. Much work hasbeen done since that time to confirm and expand this concept.In the working hypothesis proposed for mechanisms and path-

ways involved in these cutaneous immune responses (251, 252),foreign antigens entering the epidermis are first ingested andprocessed by Langerhans cells so that the antigenic fragment iscomplexed to MHC-encoded antigens. Concomitantly, there isantigen-induced enhancement of cytokine production of kera-tinocytes, leading to activation of the Langerhans cells. Withina short time, the antigen-processing Langerhans cells leave theepidermis, enter the dermal lymphatics, and migrate as veiledcells to the draining lymph nodes. Here they present the anti-gen-MHC complex on their surface to the proper receptors onresting T lymphocytes and elicit an antigen-specific responsein these cells. Through a second signal (IL-1 and/or B7) pro-duced by the Langerhans cells, there is T-lymphocyte stimula-tion and subsequent clonal expansion. The resulting T-lympho-cyte blasts then migrate back to the dermis and epidermis byhoming to cytokine-activated microvascular endothelial cells inthis area. Once in this location, the T lymphocytes can befurther stimulated by other antigen-presenting cells to undergocontinued clonal expansion and generation of effector cellsthat can help to eliminate the pathogenic microorganisms.Other aspects of this immune surveillance mechanism, whichare continuing to be elucidated, include the dermal dendritic

cells as antigen-presenting cells, keratinocytes as antigen-pre-senting cells, and the role of epidermal T lymphocytes in thecutaneous immune response. Each of these cell types may haveother less well-defined roles in the above-described immunepathway, or they may play a more or less prominent roleagainst a particular type of infection or other antigenic insult tothe skin. The exact role of each cell type in producing immuneresponses against the organisms causing cutaneous mycoses

have not yet been defined, although it is very likely that theimmune surveillance mechanism described above is heavilyinvolved in the defense against this type of infection.

IMMUNE RESPONSES TO FUNGAL ANTIGENS


Inoculation into the skin of viable C. albicans yeast cells inmice has been shown to elicit cell-mediated immune responsesto various antigens of this organism (183). Experimental cuta-neous candidiasis also sensitizes the infected animals so that asecond infection is cleared more rapidly than is the initial onein both guinea pigs (243) and mice (280). Clearance of theorganism in these experimental infections appears to be me-

diated at least in part by a vigorous epidermal proliferativeresponse associated with cell-mediated immune responses tothe antigens of the organisms (243, 245). On the other hand, acertain degree of epidermal proliferation occurs in the infectedskin of immunosuppressed mice, suggesting that other factorsare also involved (244).

Depending on environmental conditions, C. albicans cangrow in either yeast or filamentous forms, with the latter beingpostulated to be more invasive. Therefore, it is possible thatphase-specific immune responses could develop to antigensthat are different between the two phases. Indeed, specificantigens that are not present on yeast cells have been found onthe surface of cultured hyphal forms (256). In addition, it hasbeen found that antibodies in sera from some patients withcandidiasis react only with germinating C. albicans, whereas

those from normal individuals react preferentially with yeastcells (119). Antibody against C. albicans is often found in high titers in

human patients with chronic mucocutaneous candidiasis (8, 57,145, 176, 265, 275). Whereas an occasional patient with thiscondition lacks anti-candida antibodies in either serum (45,117) or saliva (160), most seem to have intact humoral immu-nity to C. albicans (8). Also, the patients who have been re-ported to have abnormal antibody production appear to beindistinguishable from other patients with chronic mucocuta-neous candidiasis, so the significance of these abnormalities isuncertain. More specific tests of B-cell function may showabnormalities in patients with this condition in that Schick testshave been reported to be abnormal in some patients (36), andin vitro antibody production to candida mannan by cells frompatients with active candida infection was found to be deficientin another study (64). Patients with the hyper-IgE syndromeoften have chronic superficial C. albicans infections along withelevated levels of IgE antibodies to this organism (18, 224).

Most noninfected humans have evidence of cell-mediatedimmunity to C. albicans, as demonstrated by skin testing (75,228), in vitro lymphocyte stimulation (23, 89), and lymphokineproduction (23, 241). On the other hand, patients with chronicmucocutaneous candidiasis often demonstrate significant im-munologic defects in cell-mediated immune responses to C.

albicans antigens, as discussed below. Even so, the pattern of immunologic abnormalities does not correlate very well withother manifestations of chronic mucocutaneous candidiasis.




Also, since some uninfected relatives of patients with this con-dition also have diminished responsiveness to Candida anti-gens (221), this abnormality cannot entirely explain why thepatients are susceptible to the fungal infections.

Dermatophytosis

Most of the early animal work with experimental dermato-

phytosis involved guinea pigs and generally demonstrated thatsome kind of immunity, either local or systemic, resulted froma previous infection. In one study generalized immunity wasdemonstrated after experimental dermatophyte infections inthat the course of a second infection was accelerated at adifferent site (104). In contrast, other workers found that theaccelerated response to a second infection was greatest at thesite of the first infection, suggesting some form of local immu-nity (30, 60, 207). Memory cells in the healed skin at the site of a first infection have been demonstrated after experimentalTrichophyton mentagrophytes infectious in guinea pigs (207). Inrats and mice, the success of experimental dermatophyte inoc-ulation appears to be dependent on the stage of hair and skingrowth cycles, so that immunity to reinfection may not be aseasy to demonstrate as it is with guinea pigs (150). In cattle, a

previous infection appears to afford partial immunity to a sec-ond infection at the same site as well as at different sites (161).Because dermatophytosis in cattle is an important economicproblem in some countries, and because these infections rep-resent potential sources of human dermatophytosis, attemptshave been made to produce vaccines against Trichophyton ver-

rucosum for veterinary use. One of these, a live vaccine (LTF-130) based on a less virulent strain of the organism, appears toshow considerable promise for controlling infections with wild-type strains of this organism (225).

The findings concerning immunity to experimental dermato-phytic infections in humans parallel those in animals in thatthere is generally some indication of increased resistance, eventhough it may be only local in nature (60, 104, 130, 149).

Although the results of various studies on experimental der-

matophyte infections in humans have differed somewhat fromone to another, in general it appears that this immunity is notcomplete and is probably less than that found in animals (96,154).

The cell wall of the dermatophytes is made up primarily of chitin and glucan in addition to the glycopeptides which rep-resent the major antigens of these organisms. The dermato-phytes, like other fungi, have a very complicated antigenicmakeup. Antigenic substances of the dermatophytes may beglycopeptides, peptides, or carbohydrates, and the individualtypes of antigens may elicit different types of responses (14,184). In addition, the keratinase of Trichophyton mentagro-

phytes may be an important antigen not only because it elicitsstrong delayed hypersensitivity responses but also because an-tibodies that inhibit the proteolytic activity of this enzyme areproduced (97).

Extracts of various dermatophyte species have usually beenfound to contain a mixture of antigens that are either speciesspecific or broadly cross-reactive with those of other dermato-phytes (98, 101) or those of other fungi (213). This phenome-non may relate to the susceptibility of atopic patients tochronic dermatophytosis because these patients may developimmediate hypersensitivity to airborne molds that cross-reacts

with the dermatophyte antigens, and this immediate hypersen-sitivity may later interfere with the development of delayedresponses to these antigens (127, 133). Cross-reactivity be-tween penicillin and dermatophyte antigens has also been pos-tulated as a possible cause of penicillin hypersensitivity in pa-

tients who have never received this drug before (201). Similarcross-reactivity between the antigens of Trichophyton rubrumand those of epidermal cells could also be a factor in thedevelopment of inflammatory responses in dermatophytosis(120, 200).

Even though dermatophyte infections are very superficial inlocation, they do appear to sensitize the host to the antigens of the infecting organisms. In fact, low levels of antibody againstTrichophyton rubrum have been found in uninfected humans byusing an enzyme-linked immunosorbent assay (ELISA), al-though it is possible that such antibodies represent cross-reac-tivity with other microorganisms (240). Also, rabbits inoculated

with Trichophyton verrucosum have been shown to developprecipitins against extracts of the organisms; however, the ti-ters of these antibodies do not seem to correlate with suscep-tibility to reinfection (51). Complement-fixing antibodies todermatophyte antigens have been found in the sera of exper-imentally infected guinea pigs and naturally infected horses(32).

Humoral immunity has been demonstrated in human der-matophytosis, using a variety of techniques such as ELISAs,complement fixation, immunodiffusion, and agglutination. Al-though precipitins are produced relatively infrequently (99,115), more sensitive methods may show antibody against theinfecting organism in larger numbers of patients with dermato-phytosis (100, 137, 196). However, whereas antibody titers toextracts of the organisms have been shown to generally beelevated in patients with dermatophytosis, some of these pa-tients may have low titers that are not different from those incontrol subjects (99, 137).

Immediate hypersensitivity to dermatophyte antigens hasbeen well documented in dermatophytosis. In fact, this processmay be involved in the pathogenesis of this condition, as sug-gested from evidence that this type of response may interfere

with the development of a protective delayed hypersensitivityresponse. In patients with dermatophytosis, both immediatehypersensitivity to dermatophyte antigens and a higher than

expected incidence of atopy have been found in a number of studies (113, 125, 129). It is not clear if chronic dermatophy-tosis stimulates IgE production or if this condition tends todevelop in persons who are already atopic (127). A frequentpattern seen in these patients is the presence of immediate, butnot delayed, hypersensitivity to trichophytin (110, 112, 122,134). However, many patients with chronic dermatophytosisneither are atopic nor manifest immediate hypersensitivity totrichophytin, indicating that other factors must also be in-

volved in producing susceptibility to this type of infection. Also, in one patient with Cushing’s disease and widespread,chronic dermatophytosis, treatment of the underlying diseaseby adrenalectomy resulted in restoration of a positive delayedtrichophytin skin test and appeared to improve the patient’scutaneous infections, even though the patient continued tomanifest strong immediate hypersensitivity to trichophyton an-tigens (69). Therefore, it would appear in this case that theimmediate hypersensitivity reactions were unrelated to defi-cient host defense in the patient before treatment.

Delayed hypersensitivity responses to intradermal injectionsof trichophytin are fairly common in the normal population(107, 194, 281). Because trichophytin can be obtained commer-cially, it can be used as one of a battery of delayed hypersen-sitivity skin tests to assess immunological competence. How-ever, since only 30% or so of normal subjects will have apositive delayed response to this antigen, it is not particularlyuseful for this purpose. Although these responses are probablydue to prior episodes of self-limited dermatophytosis, it is also




possible that cross-reactivity with another organism is respon-sible.

Experimental dermatophyte infections in animals do appearto result in cell-mediated immunity to the antigens of theinfecting organism (53, 103, 157). In guinea pigs with experi-mental Trichophyton mentagrophytes infections, maximal ery-thema in the infected skin has been demonstrated to occur atthe time the animals developed cell-mediated immunity to

trichophytin, as manifested by delayed hypersensitivity skintest responses and positive in vitro lymphocyte transformationresponses (157). Similar findings have been reported in cattleexperimentally infected with Trichophyton verrucosum (162). Inthe latter system delayed hypersensitivity reactions in the in-fected skin appeared to promote clearance of the infection byincreasing the rate of desquamation of the stratum corneum(163).

In humans, the type and duration of dermatophytosis appearto be important factors in determining whether or not delayedhypersensitivity to trichophytin will be present. Positive de-layed hypersensitivity responses to trichophytin have beenfound to be more frequent in patients with acute dermatophy-tosis caused by Trichophyton mentagrophytes than in patients

with chronic infections caused by Trichophyton rubrum (110,

129, 135). In children with tinea capitis, positive delayed skintests to trichophytin were found in one study to be present in15 of 16 of those with highly inflammatory infections (kerions)but in none of 36 with minimally inflammatory (black dot)infections (210). Patients with chronic dermatophytosis aregenerally fairly healthy and have been found to have only amild depression in their ability to develop delayed hypersensi-tivity skin test responses to antigens unrelated to trichophytin(247). Cell-mediated immunity to trichophytin appears to beimportant in the defense against dermatophytosis in that stud-ies of experimental infections in humans have demonstratedthat patients with positive delayed trichophytin skin tests aremore resistant to inoculation with Trichophyton mentagrophytesthan are those with negative skin tests (132).

Cell-mediated immunity to dermatophyte antigens has been

demonstrated by in vitro lymphocyte transformation assays inboth animals and humans. Guinea pigs with experimentalTrichophyton mentagrophytes infections develop this type of response approximately 9 to 11 days after inoculation with thefungus (103, 157). In human patients with dermatophytosis,positive in vitro lymphocyte transformation to trichophytin hasalso been found in a number of studies (110, 115, 136, 249,257). The in vitro response usually correlates with the presenceof a positive delayed skin test to trichophytin, although a fewpatients with chronic Trichophyton rubrum infections havebeen found to have negative skin tests along with positive in

vitro lymphocyte transformation responses (136). This findingsuggests some kind of local suppression of the skin test re-sponse, as discussed below. The cellular infiltrates of dermato-phytosis have been analyzed, and the majority of infiltratingcells have been found to be helper T lymphocytes (262).

Tinea Versicolor and Other Superficial Fungal Infections

Serum antibody to M. furfur has been found in a large per-centage of normal persons who do not show evidence of infec-tion with this organism (3, 57, 70, 240). This antibody is pre-dominantly of the IgG class, although there are also some IgMand IgA antibodies (240). Titers have been shown to be lowerin children under 5 years of age, perhaps because they are lesslikely to be colonized with M. furfur and therefore not yetsensitized (17). In elderly individuals the titers have also beenfound to be reduced (16, 240), and this decrease can perhaps

be related to decreased numbers of the organism on the skin of older individuals (16). Antibody titers have also been com-pared in homosexual men who were either seropositive orseronegative for the human immunodeficiency virus, but thetiters were not found to be different between the two groups(109).

Humoral responses to M. furfur have been shown to beeither slightly elevated in patients with tinea versicolor com-

pared with controls in one study (57) or approximately equiv-alent in another study (73). In malassezia folliculitis, IgG an-tibodies against this organism were found to be markedlyhigher in the patients than in healthy subjects, although imme-diate hypersensitivity to the antigens of this organism seemedto be lacking when prick tests were done with an M. furfur extract (16).

Antibody to trichosporon antigens has been shown by animmunoblot technique to be present not only in patients withinvasive Trichosporon beigelii infections but also in uninfectedcontrols (170). In addition, both IgG and IgA antibodiesagainst this organism have been demonstrated by an indirectimmunofluorescence technique in the vaginal washings fromthree women with asymptomatic carriage of Trichosporon bei-

geli (209). In that study, washings from women having vaginitis

caused by other organisms generally had low titers againsttrichosporon. Trichosporon also has been shown to share an-tigens with Cryptococcus neoformans, and the latex agglutina-tion tests for cryptococcal antigen may be positive in patients

with disseminated trichosporon infections (173).Cell-mediated immunity to malassezia antigens has been

demonstrated by lymphocyte transformation and lymphokineassays in a majority of uninfected human subjects, whereastinea versicolor patients appear to have deficient lymphokineproduction and weaker lymphocyte transformation responsesto these antigens (236, 238). On the other hand, proportions of B and T lymphocytes, subsets of T lymphocytes, and lympho-cyte transformation responses against nonspecific mitogensand unrelated antigens appear to be normal in tinea versicolorpatients (223, 236).

MECHANISMS OF IMMUNOLOGIC DEFECTS


In human patients with chronic mucocutaneous candidiasisthe most common immunologic abnormalities found are de-fects in cell-mediated immunity (76, 117, 145, 147, 275). Thesedefects fall into three general groups: (i) anergy to all antigenstested, (ii) unresponsiveness to candida antigens only, and (c)normal responses to all antigens, including those from candida.For example, in one study, 10 of 26 patients appeared to havenormal cell-mediated immunity to candida antigens (275).However, other patients appear to have significant abnormal-ities in lymphocyte function, with some having complete an-ergy to a battery of recall antigens and negative in vitro lym-phocyte proliferation responses to mitogens and all antigens(147).

Serum inhibitors appear to account for some of the immu-nologic defects in patients with chronic mucocutaneous candi-diasis (34, 148, 274, 275). Sometimes the defects disappearafter antifungal therapy (63, 146, 274). Parenteral administra-tion of viable C. albicans yeast cells or extracts of this organismto experimental animals can result in suppression of cell-me-diated immunity (42, 214, 216). Carbohydrate antigens from C.

albicans, primarily mannans, have been shown to persist in thesera of patients with chronic mucocutaneous candidiasis andsuppress lymphocyte proliferation responses of cells from con-




trol subjects (78). Defective handling of mannan by monocytesfrom patients with chronic mucocutaneous candidiasis hasbeen postulated as the reason why this substance accumulatesin the sera of these patients (79). Mannan-derived oligosac-charides from C. albicans can inhibit in vitro lymphocyte pro-liferation induced by candida antigens (204). Therefore, catab-olism of mannan in vivo may generate immunoinhibitoryoligosaccharides that cause the defects in cell-mediated immu-

nity in some patients with chronic mucocutaneous candidiasis.However, other patients with this syndrome probably haveimmunologic abnormalities due to other mechanisms, and stillothers have no demonstrable immunologic abnormalities at alland may be susceptible to chronic superficial C. albicans infec-tions for other reasons.

Dermatophytosis

Suppression of lymphocyte blastogenic responses has beenrelated to potentially immunosuppressive serum factors inacute Trichophyton mentagrophytes infections produced exper-imentally in animals (37, 102). Studies with human patientsalso suggest that serum factors may be involved in suppressionof cell-mediated immunity to fungal antigens in chronic der-matophytosis (39, 229, 278). A mannan component of Tricho-

phyton rubrum has been shown to be immunosuppressive of in vitro lymphocyte function (27), perhaps because it preferen-tially binds to monocytes (95). It has also been suggested thatthe lack of inflammation in Trichophyton rubrum infectionsmay be due to dermatophyte-derived lymphocyte inhibitoryfactors acting locally rather than systemically (171).

As discussed above, local antagonism between immediateand delayed hypersensitivity is another possible mechanism of immunosuppression in dermatophytosis (128). Most patients

with chronic dermatophytosis have relatively normal cell-me-diated immunity to nonspecific mitogens and antigens otherthan trichophytin (110, 115, 122, 247), indicating that they arerelatively intact immunologically. Subjects with immediate hy-persensitivity to trichophytin have been found to be more eas-ily infected experimentally with Trichophyton mentagrophytes

than are those without this type of response (132). Also, pro-duction of an immediate skin test response to trichophytin bypassive transfer has been shown to block delayed reactions inpatients who previously had only the delayed response (166).Delayed hypersensitivity reactions to trichophytin could beuncovered in some patients with chronic dermatophytosis bysuppressing immediate reactions to this antigen via injectionsof antihistamines into the site (131). Therefore, it is possiblethat an IgE response in some patients with chronic dermato-phytosis may inhibit the development of protective cell-medi-ated immune responses to dermatophyte antigens.

Tinea Versicolor

Like patients with chronic dermatophytosis, most patients with tinea versicolor have relatively normal immune systemsand respond well against nonspecific mitogens and non-malassezia antigens. The cells infiltrating the infected skin of patients with tinea versicolor and malassezia folliculitis havebeen characterized as predominantly helper-inducer ratherthan suppressor-cytotoxic cells by staining with monoclonalantibodies (73, 223). Tinea versicolor patients have been foundto have weaker lymphokine responses (236) and a statisticallysignificant reduction in lymphocyte transformation responsesto malassezia antigens compared with uninfected subjects(238); the diminished blastogenic response appears to be re-lated to a decrease in the number of cells initially respondingto this antigen (238).

As a possible explanation for the relatively modest degree of inflammation present in the lesions of tinea versicolor, therelative antigenicity of this organism has been compared withthat of C. albicans, which produces highly inflammatory le-sions, and found to be markedly less by a number of assays(237). Therefore, two possible reasons for the minimal inflam-mation in tinea versicolor are a reduction in the responsivenessof lymphokine-producing cells of these patients to malassezia

antigens and a relative lack of antigenic material in the organ-ism itself.

IMMUNOLOGIC THERAPY


A variety of treatments aimed at restoring immune functionhave been tried in patients with chronic mucocutaneous can-didiasis (76, 147); these treatments have involved thymic trans-plantation, thymic hormone replacement, infusion of leuko-cytes from normal donors, bone marrow transplantation, andadministration of transfer factor from candida skin test-posi-tive donors. Of these various therapies, the combination of transfer factor administration with specific antifungal therapy

probably has given the best results (147). However, the mech-anism of action of transfer factor remains undefined, and itsuse in restoring immunologic function is still considered ex-perimental.

At present, antifungal therapy with oral azole agents re-mains the standard therapy for chronic mucocutaneous candi-diasis. Even so, this therapy is unsatisfactory for some patientsbecause of intolerance or the development of resistant C. al-

bicans strains. Therefore, some form of immunological recon-stitution might be beneficial. A variety of immunomodulatoryagents, including interleukins, interferons, CSFs, monoclonalantibodies, and synthetic immunomodulators, have been usedto treat other conditions associated with depressed immuno-logical function (84), and it is possible that in the future someof these agents may prove useful as adjunctive therapy for

patients with chronic mucocutaneous candidiasis or otherchronic superficial fungal infections.

Dermatophytosis

A useful live vaccine (LTF-130) against Trichophyton verrucosum, the major cause of cattle ringworm, has been developedand has been successful in reducing the infections in cattleherds in the Soviet Union and some European countries (225).However, the use of vaccines against this type of infection ismuch more difficult in humans. Dermatophytosis has generallynot been considered a serious enough disease to warrant large-scale immunization programs in children. Therefore, the typesof human patients who have been given vaccine in the pastinclude those with intractable, chronic dermatophytosis andthose with significant dermatophytid reactions. This type of therapy has not been particularly effective and has been sup-planted in recent years by the use of antifungal drugs. Thesituation in patients with chronic dermatophytosis is quite dif-ferent from that in animals that have never been infected witha dermatophyte or sensitized to the antigens of these organ-isms. In the human patients who are infected at the time of treatment, an inadequate immune response is most likely dueto dysfunction of some element of the immune system ratherthan to lack of primary exposure to the antigens involved; thistype of immune dysfunction would generally not be expectedto respond to additional amounts of the antigen. Attemptshave also been made to treat dermatophytid reactions with




trichophytin immunotherapy. Because patients with these re-actions usually have strong delayed hypersensitivity to der-matophyte antigens, attempts to desensitize them by injectionsof trichophytin make some sense immunologically. However,as with therapy of the infection itself, dermatophytid eruptionsare probably best treated with appropriate antifungal therapy.

Other immunomodulatory methods might have some poten-tial in the treatment of patients with chronic and intractable

dermatophytosis. Suppression of immediate reactions to der-matophyte antigens could possibly benefit this type of patient,provided the immediate reactions were indeed suppressing aprotective delayed hypersensitivity response. Treatment withoral cimetidine did partially suppress immediate hypersensitiv-ity to trichophytin in patients with chronic dermatophytosis butdid not restore the delayed hypersensitivity responses (112).

Also, because the infection itself may directly suppress cell-mediated immunity to the antigens of the infecting organism, itis possible that successful antifungal therapy by itself couldrestore the protective immunological responses and perhapsprevent future relapses. Finally, specific immunological ther-apy to restore immune function in patients with chronic der-matophytosis might be beneficial in those in whom antifungaltherapy is either ineffective or not tolerated. However, as with

chronic mucocutaneous candidiasis, such immunological ther-apy is experimental at the present time.

Tinea Versicolor

Because of the lack of serious effects of this infection and thehigh degree of sensitivity of M. furfur to available antifungalagents, it would seem unlikely that immunological therapy

would be of much benefit to patients with this condition.

SUMMARY AND CONCLUSIONS

Predispositions to the superficial mycoses include warmthand moisture, natural or iatrogenic immunosuppression, andperhaps some degree of inherited susceptibility. Some of theseinfections elicit a greater inflammatory response than others,and the noninflammatory ones are generally more chronic. Theimmune system is involved in the defense against these infec-tions, and cell-mediated immunity appears to be particularlyimportant. The mechanisms involved in generating immuno-logic reactions in the skin are complex, with epidermal Langer-hans cells, other dendritic cells, lymphocytes, microvascularendothelial cells, and the keratinocytes themselves all partici-pating in one way or another. A variety of defects in theimmunologic responses to the superficial mycoses have beendescribed. In some cases the defects may be preexistent,

whereas in others the infection itself may interfere with pro-tective cell-mediated immune responses against the organisms.

A number of different mechanisms may underlie these immu-nologic defects and lead to the development of chronic super-ficial fungal infections in individual patients. Although the

immunologic defects appear to be involved in the chronicity of certain types of cutaneous fungal infections, treatment of thesedefects remains experimental at the present time.

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