0022-202X/79/7306-0515$02.00 THE JOURNAL OF INVESTIGATIVE DERMATOLOGY, 73:515-520,1979

Reprinted from

Vol. 73, No.6 Printed in U.S.A.

REVIEW ARTICLE

Progress in Dermatology a bulletin published by the DERMATOLOGY FOUNDATION

Co-Editors: Robert A. Briggaman, M .D. North Carolina Memorial Hospital Chapel Hill, North Carolina 27515

Lowell A. Goldsmith, M.D . Box 3030, Duke Medical Center Durham, North Carolina 27710

Phagocyte Chemotaxis

W. RAY GAMMON, M.D.

The inflammatory response depends on the co-ordinated interaction of humoral factors and cells, particularly phagocytes which must leave the circulation, migrate to a site of injury or invasion by micro-organisms and there either phagocytose for­eign material or release their lysosomal enzymes for digestion of tissue!! and foreign substances.

Migration from the circulation to the focus of injury requires activation of phagocytes presumably by soluble humoral sub­stances emanating from the site of injury. Activated phagocytes become "sticky," adhere to the capillary wall and migrate into the tissue_ Movement to the injured site then occurs in a directed fashion. The cells approach the site and collect not by a passive mechanism but by an active cell function.

Chemotaxis (syn. cytotaxis) , is the directed migration of a cell toward a concentration gradient of a chemotactic factor (syn_ chemotaxin, chemoattractant, cytotaxin). The process includes 3 major components, a cell capable of directed migra­tion, a stimulus (chemotactic factor) and a signal mechanism whereby the chemotactic factor activates directed movement.

THE CELLULAR MECHANISMS OF DIRECTED MOTION

Phagocyte movement, whether random or directed, requires adherence to a substrate, formation of pseudopods of cell mem­brane called lamellipodia and a poorly understood process called cytoplasmic flow. The direction of cytoplasmic flow rather than the direction of pseudopod formation determines the course of cell movement [1]. Adherence to a solid surface results from a charge interaction between the cell and the surface. Many biological surfaces such as blood vessels are negatively charged. The phagocyte membrane is also negatively charged, but forces that repel the cell may be minimized by a reduction of cell membrane charge to a less negative state. Cheznotactic factors cause a rapid neutralization of phagocyte surface charge and drugs which block this effect block chemo­taxis [2].

The formation of lamellipodia and flow of cytoplasm are controlled by the cytoskeletal system which is composed of 2 types of contractile proteins, microtubules and microftlaments. Both function cooperatively in cell movement. MicrofIlaments are polymers of actin and myosin and provide the propulsive forces to move membrane and cytoplasm. Microtubules, com­posed of a protein called tubulin, influence the direction of movement by a poorly understood process of asymmetric po­lyznerization and depolymerization. Changes in tubulin polym-

erization influence the orientation of cytoplasm and presumably the direction cytoplasm takes when acted upon by the propul­sive forces generated by microfilaments. Though microtubule function seems essential for directed migration, it is less impor­tant in random movement [3,4].

Chemotactic factors may influence cells to move in a specific direction by an indirect effect on tubulin mediated by changes in the cytoplasmic level of calcium ions. When chemotactic factors interact with the cell membrane, calcium moves from the intracellular to the extracellular space [5]. Lowering of the intracellular calcium concentration favors the polymerization of tubulin. If the effect, as some investigators suspect, is greatest in the portion of the cell in contact with the highest concentra­tion of chemotactic factor, the result might be a polarization of tubulin polyme.rization resulting in the flow of cytoplasm to­ward the source of chemotactic factor.

Evidence that microtubules are essential for directed move­ment comes from several sources. It is well established that drugs which inhibit tubulin aggregation, antitubulins, inhibit directed migration without significantly affecting random mo­tion [6]. Furthermore, patients with defective microtubular assembly as seen in the Chediak-Higashi syndrome (CHS) have faulty directed migration of their phagocytes, but relatively normal random migration.

Evidence supporting a role for microfilaments in cell move­ment comes from studies using an inhibitor of microfilament function, cytochalasin B [9] and from a patient with defective cell movement associated with abnormal polymerization of neutrophil actin [10].

THE INTERACTION OF CHEMOTACTIC FACTORS WITH PHAGOCYTES

The response of phagocytes to chemotactic factors is influ­enced by changes in cell surface enzymes, cyclic nucleotide levels, ion transport mechanisms and energy-producing path­ways. These changes and how they contribute to cell movement help us understand the basic physiology of chemotaxis.

Chemoattractants probably initiate cell responses by inter­acting fIrst at the cell membrane. Initial ihteraction at this site is inferred from the rapidity of the cellular response to chemo­taxins, the fact that many chemotaxins are too large to pass easily through the membrane and from recent evidence that membrane receptors exist for at. least some synthetic chemoat­tractants.

To date, membrane receptors have been demonstrated only

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516 GAMMON

for the synthetic chemotactins, N-formyl di- and tri-peptides [11,12). None of the biologically derived factors interact com­petitively suggesting that either there are other receptors with different specificities or chemotactic factors may stimulate cells without binding to a specific surface molecule. Several factors including kallikrein and plasminogen activator are chemotactic but only if their enzymatic functions are intact [13).

Two serine esterases in the neutrophil have been identified as necessary in the mediation of the chemotactic stimulus [14). One of these, pro esterase I, is present in an inactive form until chemotactic stimulation. After stimulation, the proenzyme is converted to esterase I. A second esterase is present in an activated form prior to exposure to chemotactic factor. This enzyme, unlike the proenzyme, can be inhibited before chemo­tactic factors interact with the cell. Inhibition of either esterase blocks the chemotactic response but it remains unknown how these enzymes function to relay the chemotactic signal.

A role for membrane bound ATPase-dependent active trans­port systems is suggested by studies showing that ATPase inhibitors are able to block the chemotactic response [15]. Transport systems are required for electrolyte transfer across the cell membrane and probably play a role in the shift of calcium and other ions necessary for cell motion. The shift of calcium ions, as previously noted, appears necessary for optimal microtubular aggregation and may be required for microfJla­ment contraction as well. It has been postulated that the efflux of calcium to an extracellqlar location may be responsible for the neutralization of the cell surface charge required for adher­ence [2).

Considerable circumstantial evidence suggests an important role for the cyclic nucleotides, cyclic adenosine monophosphate (cAMP) and guanosine monophosphate (cGMP) in regulating the cellular response to chemotactic factors [16,17]. In general, an increase in the intracellular levels of cAMP or a decrease in cGMP causes a decrease in responsiveness. Conversely, a de­crease in cAMP and increase in cGMP causes an increased response. Increased cGMP and decreased cAMP are known to favor tubulin aggregation and is a possible mechanism whereby cyclic nucleotides influence directed migration [18].

Changes in the levels of cyclic nucleotides are linked to stimulation of surface receptors on phagocytes and may offer a mechanism for humoral control over the chemotactic response. Beta adrenergic drugs such as isoproterenol and epinephrine increase intracellular levels of cAMP and have been reported to inhibit chemotaxis. Cholinergic agents acting on different receptors increase cGMP and increase chemotactic responsive­ness. Histamine may inhibit neutrophil chemotaxis by stimu­lating the H2 receptor' and increasing intracellular cAMP [19).

A clinical example of the importance of cyclic nucleotides in chemotaxis is supplied by patients with CHS. They have neu­trophil cAMP levels 8 times normal. It has been postulated that such elevated levels may be associated with faulty tubulin aggregation, which might explain not only the presence of giant lysosomal granules but the defective chemotaxis of CHS phag­ocytes. In vivo and in vitro treatment of CHS phagocytes with ascorbic acid, a compound known to decrease cAMP and in­crease cGMP results in substantial improvement in chemotaxis [20).

Chemotaxis is an energy-dependent cell function. Chemotac­tic stimulation of neutrophils produces a rapid increase in both aerobic glycolysis and hexose monophophate shunt activity [21]. These pathways presumably furnish sufficient high energy phosphates for the metabolic requirement of chemotaxis.

How the above factors are integrated to produce directed motion has not been worked out, but one can speculate what may happen when a phagocyte comes in contact with a che­motactic gradient. There is an initial reaction between che­moattractant and cell membrane receptors or esterases which may then activate the hexose monophosphate shunt and aero­bic glycolytic pathways for the production of ATP. The high energy phosphates are the energy source for membrane-asso-

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cia ted ion transport mechanisms, for microftlament contraction, and possibly microtubular assembly. Activated ion transport mechanisms facilitate the transfer of divalent actions such as Ca++ to extracellular sites favoring cell adherence, microftla­ment contraction and the aggregation of tubulin . An increase in cGMP and a decrease in cAMP promote tubulin aggregation. Directed motion appears to result from the intergration of these and perhaps other undefined processes.

PHAGOCYTE CHEMOT ACnC FACTORS, ORIGIN AND MECHANISMS OF GENERATION

A growing number of chemotactic factors and substances capable of generating chemo-attractants are present in mam­malian tissues and microorganisms. The structures, chemical and biological properties and tissues of origin vary greatly. Little information is available on the relative importance of specific factors in different types of inflammation. It is probable that in any inflammed tissue, multiple factors of varying po­tency are active and different factors are important at various stages of inflammation.

The "endogenous" chemo-attractants which originate from host tissues include the complement-derived proteins, C3a, C5a and C567 complex substances from the kinin-generating and coagulation-fibrinolytic pathways, kallikrein, plasminogen ac­tivator and fibrin-split products; factors generated from the proteolytic dewadation of collagen and immunoglobulins and soluble substances. released from granulocytes and activated lymphocytes.

The complement derived factors are especially important due to their potency and the variety of pathways that lead to their formation [22). Supporting a major in vivo role for these factors are studies which show depressed neutrophil chemotaxis in animals and man deficient in key complement components [23-25], and animals artificially depleted of complement [24]; and reports of isolation of chemotactically-active complement fac­tors from inflammed tissues [26,27).

C5a is the most active of the complement factors [28). C5a can be generated by several mechanisms including the classical and alternative complement pathways and by a mechanism of direct activation that requires neither pathway. The latter mechanism is due to the activity of C5 cleaving proteases [29], called chemotaxigens. These enzymes have been definitely dem­onstrated in leukocytes, platelets, myocardium and human ep­idermis [30, 31] but may be present in all tissues. Micro-orga­nisms too may produce C5-cleaving enzymes. Chemotaxigens may be very important in complement-associated inflammatory reactions where classical or alternative pathways of comple­ment activation are not readily demonstrable. Activation of the kinin-generating and coagulation-fibrinolytic pathways are fre­quent if not invariable accompaniments of inflammation and may be another important source of chemotactic factors. Many stimuli including crystals (pyrophosphate, uric acid), endotoxin, basement membranes, and exposed native collagen activate Hagemen factor (clotting factor #12). Activated Hagemen fac­tor subsequently converts pre kallikrein to kallikrein and plas­minogen proactivator to plasminogen activator. Both conver­sion products are chemotactic in vitro [32].

Leukocytes produce chemotactic factors which may serve to augment inflammatory responses. Mast cells release a neutro­phil chemotactic factor during degranulation [33] and lympho­cytes stimulated by specific antigen release chemotactic factors for both macrophages and neutrophils [34].

Additional chemotactic factors have been produced in vitro by the enzymatic degradation of collagen and immunoglobulins [35,36). Though an in vivo role for these substances has not been demonstrated, they offer a ubiquitous substrate for che­motactic factor production.

Exogenous chemotactins and chemotaxigens have been dem­onstrated in a variety of micro-organisms [37]. Bacteria produce chemotaxins during the rapid phase of culture growth. Some organisms possess surface molecules that may activate the

Dec. 1979

alternative complement pathway [38], and chemotaxigens ca­pable of directly cleaving C5 to C5a [39]. Virus-infected cells have been shown to produce chemotactins and activate com­plement components [40].

Of particular interest to dermatologists is recent work show­ing that yeast, Candida species activate the complement sys­tem to produce neutrophil chemotactic factors. It is assumed that these factors are responsible for the characteristic pustules seen in cutaneous candidiasis and the limited invasiveness of these organisms in normal hosts [41].

It is apparent that there are numerous ways phagocyte che­motactic factors can be generated. This is not surprising in view of the necessity of an efficient chemotactic response for host survival. Multiple factors acting in any instance of infection or inflammation may be an important "safety" mechanism against serious infection when a single chemotactic system fails.

REGULATION OF THE CHEMOTACTIC RESPONSE

Regulation of phagocyte chemotaxis is necessary presumably to focus and confine cells to sites of inflammation and limit the undesirable consequences of unrestrained or inappropriately generalized inflammation. Control of the chemotactic response may occur at the level of the chemotactic factor .by blocking its production or inhibiting its activity, or at the cellular level by rendering phagocytes unresponsive to chemotactins.

At the cellular level, phagocyte deactivation .may play a regu latory role. Deactivation occurs follQwing El"xposure ofphag­ocytes to a chemo-attractant in the absence of a concentration gradient. Cells permanently lose their ability to respond to any and all chemotactins regardless of the one causing deactivation [14]. One consequence of deactivation is the confinement of cells to sites of inflammation. Another may be reduction in both chemotactic responsiveness and "self-destructive" inflam­mation in patients with circulating immune complex diseases and widespread complement activation. Patients with SLE and rheumatoid arthritis often show a diminished phagocyte che­motactic response [42,43].

Cell-directed inhibitors of chemotaxis are produced by in­flammatory effector cells including neutrophils, monocytes [44], and lymphocytes [34]. Two of the best known are the le ukocyte migration inhibitory factor and macrophage migra­tion inhibitory factor. Both are Iymphokines released from activated lymphocytes. In addition to the cell-derived factors, the serum proteins, alpha 1 antitrypsin and alpha 2 macroglob­ulin, inhibit chemotaxis at the cellular level [44].

Several serum proteins may act directly to inactivate che­motactic factors. The complement derived chemotactins C3a and C5a are inactivated by at least 2 serum proteins, anaphy­latoxin inactivator and chemotactic factor inactivator. The latter protease(s) has activity against kallikrein and plasmino­gen activator as well as complement-derived factors. P lasmin­ogen activator and kallikrein are also inhibited by alpha 2 macroglobulin and kallikrein is inhibited by Cl esterase inhib­itor [45,46].

Regulation of phagocyte chemotaxis is not completely under­stood but is a very important area. Greater knowledge of controlling factors might lead to ways of augmenting or dimin­ishing the response and decreasing t he chemotactic response may prove to be an important means of controlling inflamma­tion.

DRUG INHIBITION OF NEUTROPHIL CHEMOTAXIS

Some patients with inflammatory diseases, Behcet's syn­drome [47], pyoderma gangrenosum [48], and possibly psoriasis [49,50], have unusually brisk neutrophil chemotactic responses which has led to speculation that supranormal chemotaxis may be related to the lesions in these and perhaps other inflamma­tory skin diseases. Whether supranormal or normal, pharma­cologic inhibition of the chemotactic response has obvious clinical implications for patients with inflammatory disease.

Though still of questionable therapeutic value, some work

PHAGOCYTE CHEMOTAXIS 517

has been done on drug inhibition of phagocyte chemotaxis. Drugs which have been reported to be inhibitory are vincristine, vinblastine, 6 mercaptopurine, methotrexate, colchicine, gluco­corticosteroids, chloroquine and the antibiotics griseofulvin, erythromycin, tetracycline and clindamycin. In all but a few cases, drug inhibition of chemotaxis has been demonstrated only in vitro by incubating cells with drugs during or prior to measurement of chemotaxis. In practically no cases have cells or serum taken from patients receiving the drug been used to assess the chemotactic response.

Colchicine has long been used to treat acute gouty arthritis and recently has been reported effective in the treatment of Behcet's syndrome [47]. In vitro pharmacologic concentrations of colchicine inhibit neutrophil chemotaxis and lysosomal en­zyme release. Colchicine may inhibit these functions by binding to tubulin, and inhibiting microtubular assembly. The vincaal­kaloids, vincrinstine and vinblastine, are thought to inhibit neutrophil chemotaxis by a similar mechanism [3].

Griseofulvin is an antitubulin drug but binds to a receptor on t.ubulin distinct from colchicine. In vitro griseofulvin inhibits neutrophil chemotaxis at concentrations below those reported

-in patients taking the drug for fungal infection [6]. Griseofulvin like colchicine has been reported effective in the treatment of gout.

Other antibiotics, tetracycline HCI, erythromycin base and clindamycin HCl will inhibit neutrophil cheinotaxis in vitro and at concentrations easily attainable in vivo [52]. Serum from patients taking. tetracycline has also been shown to inhibit neutrophil chemotaxis [53]. Interestingly, it has been suggested that perhaps part of the effectiveness of these agents applied topically or systemically in the treatment of acne is due to inhibition of phagocyte chemotaxis.

Several studies have examined the effect of glucocorticoste­roids on neutrophil chemotaxis in vitro [54-56]. All have re­ported inhibition but always at suprapharmacologic concentra­tions. Monocytes appear to be more sensitive to the inhibitory effects of steroids but neither monocytes nor neutrophils taken from patients on high dose steroids have demonstrated defec­tive chemotaxis [57,58]. It would appear that inhibition of chemotaxis does not offer an explanation for the anti-inflam­matory effects of glucocorticosteroids. Chloroquine does sup­press chemotaxis in vitro at pharmacologic concentrations and this may be one of its mechanisms for anti-inflammatory activ­ity [55, 56]. Chloroquine, like steroids, has many other effects on the inflammatory response which undoubtedly contribute to its therapeutic effectiveness.

ABNORMAL NEUTROPHIL CHEMOTAXIS

A number of clinical syndromes and diseases are associated with defective phagocyte chemotaxis. Some are of interest to dermatologists because affected patients present with severe recurrent or intractable skin or subcutaneous infections. Fur­thermore, many patients have noninfectious cutaneous signs which may suggest the possibility of deficient phagocyte che­motaxis and altered susceptibility to infection.

Deficiencies of phagocyte chemotaxis can be divided into several categories. One group of patients have intrinsic cellular defects which prevent the phagocyte from responding normally to a chemotactic factor. In another group, the chemotactic response may be blocked by cell-directed soluble inhibitors of chemotaxis. A third group are deficient in the generation of chemotactic factors due to either insufficient production or excessive inhibition. In some cases, the defect has not been determined.

INTRINSIC PHAGOCYTE DYSFUNCTION

Neutrophils and/or monocytes from patients with Chediak­H igashi syndrome [7] , lazy leukocyte syndrome [59], familial chemotactic defect [60] and neutrophil actin dysfunction [10] show abnormal chemotaxis presumably due to an intrinsic defect in cellular machinery necessary for directed motion. The

518 GAMMON

defect is present in the absence of circulating inhibitors of chemotaxis a nd cannot be restored by incubation of cells in normal serum. Random motility of cells in these patients may or may not be affected.

The Chediak-Higashi syndrome is characterized by recurrent pyogenic infection, granulocytopenia, pigment dilution affecting the skin, hair and eyes and giant lysosomal granules in mela­nocytes and phagocytes. It is suggested that defective assembly of microtubules is responsible for the large lysosomal granules seen in these cells. Microtubular assembly is activated by cGMP and inhibited by cAMP. Although no data is available on leukocyte cGMP levels in these patients, cAMP levels are greatly elevated. Ascorbic acid which decreases cAMP, im­proves leukocyte function of CHS leukocytes in vitro. Treat­ment of CHS patients with ascorbic acid may reduce the incidence of infection [20]. If so, this represents one of the few treatable defects in phagocyte chemotaxis.

The lazy leukocyte syndrome is manifested by recurrent low­grade fever, gingivo-stomatitis and otitis media. These patients have defective chemotaxis, random movement and moderately severe neutropenia but a normal bone marrow [59]. Defective demargination of neutrophils with epinephrine or endotoxin is present. A primary defect in neutrophil movement has been postulated.

Two families have been reported with an inherited defect in chemotaxis termed familial chemotactic defect. Random move­ment of neutrophils from patients and family members is nor­mal, but the neutrophils fail to respond to chemotactic stimuli. Cutaneous manifestations of the disease include congenital ichthyosis vulgaris and recurrent T. rubrum infection [60]. The cause of the defect is unknown.

A single infant has been described with defective in vitro and in vivo chemotaxis and recurrent superficial and deep pyogenic infections since birth. Neutrophils from this patient were found to have defective actin protein which showed abnormal polym­erization in vitro. The defect has been called "defective actin polymerization" and may represent a specific abnormality of microftlament function [10].

Acrodermatitis enteropathica (AE) is associated with an ac­quired intrinsic abnormality of both monocyte and neutrophil chemotaxis. The defect is presumably due to zinc deficiency since normal motility of phagocytes is restored in patients treated with zinc. Zinc added to abnormal AE phagocytes in vitro also restores chemotaxis in a dose-dependent fashion. The effect of zinc in restoring chemotaxis is not known but some observations suggest an effect on the cell membrane [61).

DISEASES ASSOCIATED WITH CELL-DIRECTED INHIBITORS OF CHEMOTAXIS

In some diseases, chemotaxis of phagocytes may be inhibited by soluble serum factors. Included among these conditions are the Wiskott-Aldrich syndrome, some collagen vascular diseases and allergic reactions associated with hypocomplementemi'a, and possibly the hyperirnmunoglobulinemia E (hyper IgE) syn­drome.

In recent years, a number of children and adults have been described with severe and recurrent bacterial skin infections and increased serum immunoglobulin E. levels [62-68). Most patients have had defective neutrophil chemotaxis as well. Although not a homogeneous patient population, the term hyper IgE syndrome has been applied to denote its most consistent feature. Patients have recurrent bacterial skin infec­tions from infancy including nonspecific pyoderma, cellulitis, deep and superficial abscesses, erysipelis and impetigo. Staph· ylococcus aureus and Streptococcus pyogenes are the most common organism isolated but gram-negative bacteria have been recovered. Some patients have had recurrent or chronic mucocutaneous candidiasis [64] and a few have had chronic T. rubrum infection [68). In addition to skin infections, many patients have chronic bacterial lymphadenitis, otitis media,

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dental, retropharyngeal and lymph node abscesses, bronchitis, pneumonia, pulmonary empyema and septic arthritis. So called "cold abscesses" which lack pain and heat occur typically in patients with Job's syndrome, a variant of the hyper IgE syndrome. Other features of Job's syndrome in addition to increased serum IgE levels and defective neutrophil chemotaxis are red hair, atrophic nails and hyperextensible joints [69,70).

Nearly all patients with hyper IgE syndrome have noninfec­tious skin manifestations particularly eczema. The eczema is often indistinguishable from atopic dermatitis with flexural lichenification, pruritus and Denny Morgan lines [71). Neutro­phil chemotaxis has been observed to approach or return to normal as skin infections clear [72). A recent study showed that atopic patients with elevated serum IgE but without a previous history of severe infection had normal chemotaxis [73). It is not known if chemotaxis becomes abnormal in atopies during epi­sodes of infection. Additional noninfectious skin signs in the hyper IgE syndrome include urticaria, congenital ichthyosis and incontinentia pigmenti [68,73-75).

It has been postulated that defective chemotaxis in the hyper IgE syndrome is due to circulating histamine acting on the neutrophil H2 receptor to increase levels of intracellular cAMP. As discussed previously, a number of substances which in­creased cAMP inhibit chemotaxis. In vitro histamine causes a dose-related suppression of neutrophil chemotaxis which can be blocked by an H2 blocker such as metiamide. Though elevated histamine levels have not been demonstrated in these patients, histaminemia has been inferred from the elevated serum levels of IgE, the frequent presence of a pruritic skin rash and eosinophilia and the appearance of urticaria in some pa­tients during periods of active infection [19).

In the Wiskott-Aldrich syndrome (WAS), patients have atopic-like eczema, thrombocytopenic purpura, recurrent infec­tions and a variety of humoral and cellular immunologic dis­turbances. Many have defective monocyte chemotaxis which correlates with high levels of circulating lymphocyte-derived chemotactic factor. It is thought that elevated levels of this Iymphokine inactivate circulating monocytes. Evidence for in­activation comes from the observation that normal monocytes incubated in WAS serum develop defective chemotaxis [76). In SLE, rheumatoid arthritis and other immune complex diseases impaired phagocyte chemotaxis has been reported [42,43], and may explain in part the increased incidence of infections seen in these patients. There are at least 2 possible mechanisms for abnormal phagocyte chemotaxis in immune complex diseases. One is deactivation of cells by circulating chemotactic factors which could be released by the interaction of complement with immune complexes. Exposure of cells to C3a or C5a renders neutrophils unresponsive to further chemotactic stimulation [14]: A second mechanism may be a refractory state induced in neutrophils which have phagocytized immune complexes. Cells which have been incubated with rheumatoid serum, rheumatoid complexes purified from serum or iron dextran particles ex­hibited impaired chemotaxis [43). Similar mechanisms may explain the defective neutrophil chemotaxis observed in pa­tients with dl'Ug reactions associated with severe hypocomple­mentemia [77].

ABNORMAL GENERATION AND INACTIVATION OF CHEMOTACTIC FACTORS

A delay in the generation of sufficient chemotactic factor activity can result in a faulty inflammatory response and in­creased susceptibility to infection. Clinically, these situations may arise when chemotactic factors such as these derived from complement are absent or severely depressed or when chemo­tactic factor inhibitory activity is excessive.

The best studied examples of deficient chemotactic factor production are the relatively rare syndromes associated with inherited or acquired complement deficiency. These include Cl r, C2, C3, and C5 deficiency and Leiner's disease associated

Dec. 1979

with C5 dysfunction. Obviously since complement components play m a ny roles in defe nse against infection, faulty chemotactic factor generation is but one cause of abnormal inflammatory responses in these patients.

Patients with a homozygous deficie ncy of Clr or C2 have delayed production of ch e motactic factors in sera activated by the classical complem ent pathway, but normal production when the alternative pathway is activated. It has bee n suggested that s u c h a d elay in the generat ion of chemotactic factor may be responsible for the moderate increase in pyogenic infection seen in these patients [78].

As expected, more frequent and severe infections may be seen in patients with C3 and C5 deficiency since both alternative and classical pa thways of activation are a ffected . Patients with C5 deficiency al'e unusually susceptible to infection supporting t h e view that C5 is an important ch emotactic factor in host defense [79-81]'

Leiner's syndJ'ome is associated with C5 dysfunction. Though total he molytic complement levels are normal in these patients, C5-mediated phagocytosis of yeast particles and generation of C5a ch emotactic factor is abnormal [81].

Patients with C5 d eficiency and C5 dysfunction have on occasion benefited from the infusion of fresh normal human plasma a nd r e present additional examples of therapy for defec­t ive chemotaxis.

A larger group of patie nts with a variety of illnesses including sarcoidosis, Hodgkins disease, hepatic cirrhosis and nonspecific acute illnesses associated with leukocytosis h ave had elevated serum levels of chemotactic factors inactivator activity [82,83]. Serum from these patients has demonstrated supranormal sup­pression of both complement and noncomplement derived che­motactic factors.

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PHAGOCYTE CHEMOTAXIS 519

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