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Vol. 37, No. 2 INFECTION AND IMMUNITY, Aug. 1982, p. 609-616 0019-9567/82/080609-08$02.00/0 Specificity of Immunoglobulin E in Coccidioidomycosis and Correlation with Disease Involvement REBECCA A. COX,'* BARBARA S. BAKER,1 AND DAVID A. STEVENS2'3 Department of Research Immunology, San Antonio State Chest Hospital, San Antonio, Texas 78223'; Santa Clara Valley Medical Center and Institute for Medical Research, San Jose, California 951282; and Department of Medicine, Stanford University, Stanford, California 943053 Received 16 February 1982/Accepted 8 April 1982 Serum immunoglobulin E (IgE) antibodies were quantitated in 26 patients with active pulmonary coccidioidomycosis, 59 patients with active disseminated disease, 12 patients in clinical remission, and 91 healthy subjects. Significant differences were obtained in IgE serum levels of patients with active disease versus healthy subjects (P < 0.0001). Patients with pulmonary coccidioidomyco- sis did not differ in their IgE levels when compared with patients with disseminat- ed disease. However, serum IgE levels were significantly increased in patients with disease involving two or more organ systems when compared with patients with pulmonary disease or extrapulmonary disease involving a single organ system (P < 0.02). Total serum IgE correlated with anti-Coccidioides IgE (P < 0.001), but with only six exceptions, patients with anti-Coccidioides IgE also exhibited IgE antibodies to 1 or more of 12 common allergens. The correlation between hyperproduction of IgE and disease severity coupled with the depressed cell-mediated immune status of patients with this disease suggests a defect(s) in the T-lymphocyte population which functions to regulate IgE synthesis. Coccidioidomycosis is a mycotic disease caused by the dimorphic fungus Coccidioides immitis. Humans acquire the infection by inhala- tion of mycelial-phase arthroconidia which con- vert in host tissue to endosporulating spherules. The disease presents a diverse clinical spectrum that includes inapparent infection, primary res- piratory disease usually with uncomplicated res- olution, chronic pulmonary disease either stabi- lized or progressive, and extrapulmonary dissemination either acute, chronic, or progres- sive. The degree of severity varies considerably within each category. Accumulated evidence in humans (6, 9, 10, 29, 39) and in experimentally infected animals (2, 3) suggests that cell-mediated immunity is critical for host defense in coccidioidomycosis. Typical- ly, persons with primary, asymptomatic disease manifest strong cell-mediated immune responses to C. immitis antigens. Conversely, patients with chronic or progressive coccidioidomycosis have depressed cellular immune functions. The anergy is, in most patients, specific for C. immi- tis in that T-cell responses to non-coccidioidal antigens remain intact (6, 10). In contrast to a T- lymphocyte hyporeactivity, patients with this disease characteristically show a B-cell hyper- reactivity with increased serum levels of immunoglobulin G (IgG), IgA, and IgE antibod- ies (7, 31, 32, 36). Hyperproduction of IgE in atopic disorders such as allergic asthma, hay fever, and atopic dermatitis is well documented (18, 19, 22). In addition, markedly elevated serum IgE has been reported in bronchopulmonary aspergillosis (11, 33), chronic dermatophyte infections (21), candi- diasis (24, 27), histoplasmosis (8), leprosy (35), parasitic infections (12, 15, 20, 34), Wiskott- Aldrich syndrome (42), DiGeorge's syndrome (23), and Hodgkin's disease (41). Each of these diseases is associated with a cellular immune defect(s), although the defect(s) varies in sever- ity. This, coupled with the finding that IgE antibody production is regulated by T lympho- cytes (17, 25, 28, 30, 43), suggests that prolifera- tive IgE responses are attributed to a defective T-suppressor cell population(s). Relevant to this is the finding that there are two types of T suppressor cells that regulate IgE synthesis (17, 28, 43). One type regulates antigen-specific IgE responses (18). The other type is antigen non- specific and regulates IgE synthesis in general (28, 43). Both are phenotypically distinct and under separate control. Thus, a defect in anti- gen-specific IgE regulatory T lymphocytes would result in hyperproduction of IgE to a specific antigen. A defect in antigen-nonspecific regulatory T lymphocytes would give rise to a generalized IgE hyperproduction with antibod- ies directed against a variety of allergens. 609 on February 29, 2020 by guest http://iai.asm.org/ Downloaded from

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Page 1: Specificity Immunoglobulin E Coccidioidomycosis ...diseases is associated with a cellular immune defect(s), althoughthe defect(s) varies in sever-ity. This, coupled with the finding

Vol. 37, No. 2INFECTION AND IMMUNITY, Aug. 1982, p. 609-6160019-9567/82/080609-08$02.00/0

Specificity of Immunoglobulin E in Coccidioidomycosis andCorrelation with Disease Involvement

REBECCA A. COX,'* BARBARA S. BAKER,1 AND DAVID A. STEVENS2'3Department ofResearch Immunology, San Antonio State Chest Hospital, San Antonio, Texas 78223'; Santa

Clara Valley Medical Center and Institute for Medical Research, San Jose, California 951282; andDepartment of Medicine, Stanford University, Stanford, California 943053

Received 16 February 1982/Accepted 8 April 1982

Serum immunoglobulin E (IgE) antibodies were quantitated in 26 patients withactive pulmonary coccidioidomycosis, 59 patients with active disseminateddisease, 12 patients in clinical remission, and 91 healthy subjects. Significantdifferences were obtained in IgE serum levels of patients with active diseaseversus healthy subjects (P < 0.0001). Patients with pulmonary coccidioidomyco-sis did not differ in their IgE levels when compared with patients with disseminat-ed disease. However, serum IgE levels were significantly increased in patientswith disease involving two or more organ systems when compared with patientswith pulmonary disease or extrapulmonary disease involving a single organsystem (P < 0.02). Total serum IgE correlated with anti-Coccidioides IgE (P <0.001), but with only six exceptions, patients with anti-Coccidioides IgE alsoexhibited IgE antibodies to 1 or more of 12 common allergens. The correlationbetween hyperproduction of IgE and disease severity coupled with the depressedcell-mediated immune status of patients with this disease suggests a defect(s) inthe T-lymphocyte population which functions to regulate IgE synthesis.

Coccidioidomycosis is a mycotic diseasecaused by the dimorphic fungus Coccidioidesimmitis. Humans acquire the infection by inhala-tion of mycelial-phase arthroconidia which con-vert in host tissue to endosporulating spherules.The disease presents a diverse clinical spectrumthat includes inapparent infection, primary res-piratory disease usually with uncomplicated res-olution, chronic pulmonary disease either stabi-lized or progressive, and extrapulmonarydissemination either acute, chronic, or progres-sive. The degree of severity varies considerablywithin each category.Accumulated evidence in humans (6, 9, 10, 29,

39) and in experimentally infected animals (2, 3)suggests that cell-mediated immunity is criticalfor host defense in coccidioidomycosis. Typical-ly, persons with primary, asymptomatic diseasemanifest strong cell-mediated immune responsesto C. immitis antigens. Conversely, patientswith chronic or progressive coccidioidomycosishave depressed cellular immune functions. Theanergy is, in most patients, specific for C. immi-tis in that T-cell responses to non-coccidioidalantigens remain intact (6, 10). In contrast to a T-lymphocyte hyporeactivity, patients with thisdisease characteristically show a B-cell hyper-reactivity with increased serum levels ofimmunoglobulin G (IgG), IgA, and IgE antibod-ies (7, 31, 32, 36).

Hyperproduction of IgE in atopic disorderssuch as allergic asthma, hay fever, and atopicdermatitis is well documented (18, 19, 22). Inaddition, markedly elevated serum IgE has beenreported in bronchopulmonary aspergillosis (11,33), chronic dermatophyte infections (21), candi-diasis (24, 27), histoplasmosis (8), leprosy (35),parasitic infections (12, 15, 20, 34), Wiskott-Aldrich syndrome (42), DiGeorge's syndrome(23), and Hodgkin's disease (41). Each of thesediseases is associated with a cellular immunedefect(s), although the defect(s) varies in sever-ity. This, coupled with the finding that IgEantibody production is regulated by T lympho-cytes (17, 25, 28, 30, 43), suggests that prolifera-tive IgE responses are attributed to a defectiveT-suppressor cell population(s). Relevant to thisis the finding that there are two types of Tsuppressor cells that regulate IgE synthesis (17,28, 43). One type regulates antigen-specific IgEresponses (18). The other type is antigen non-specific and regulates IgE synthesis in general(28, 43). Both are phenotypically distinct andunder separate control. Thus, a defect in anti-gen-specific IgE regulatory T lymphocyteswould result in hyperproduction of IgE to aspecific antigen. A defect in antigen-nonspecificregulatory T lymphocytes would give rise to ageneralized IgE hyperproduction with antibod-ies directed against a variety of allergens.

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610 COX, BAKER, AND STEVENS

In a previous study of IgE in coccidioidomy-cosis (7), we reported that IgE serum levels wereelevated in 13 (59%) of 22 patients with activedisease. Serum IgE levels correlated with anti-Coccidioides IgE which, in turn, correlated withimmediate wheal and flare responses to coccidi-oidin (CDN). The present study was undertakento further evaluate hyperproduction of IgE inthis disease. Two significant new findings wererevealed. First, IgE antibody production corre-lated with disease severity; i.e., serum IgE lev-els were significantly increased in patients withCoccidioides involvement of multiple organ sys-tems when compared with patients having dis-ease of a single organ system. Second, IgEantibody production to C. immitis was accompa-nied by IgE antibody production to non-cocci-dioidal allergens, a finding that suggests a dys-function in antigen-nonspecific regulatory Tlymphocytes.

MATERIALS AND METHODS

Study groups. The 97 patients comprising this studywere divided into 26 patients with active pulmonarycoccidioidomycosis, 59 patients with active dissemi-nated disease, and 12 patients who had been in clinicalremission (culture negative) for at least 1 year beforethe study (Table 1). Of the patients with pulmonarydisease, 4 had an acute, primary infection; the remain-ing 22 patients had chronic pulmonary coccidioidomy-cosis. Of the 59 patients with disseminated disease, 46had disease of one organ system, i.e., skin and/or softtissue, bone and/or joint, central nervous system,lymph nodes, genitourinary system, or eye; 13 hadextrapulmonary disease of two or more organ systems.Coccidioidal involvement of an organ system wasdefined as a symptomatic lesion and a culture orbiopsy positive for C. immitis. The exceptions to thiswere meningitis and endophthalmitis. The former wasdefined as neurological symptoms and an abnormalcerebrospinal fluid with anti-Coccidioides comple-ment-fixing antibody. Endophthalmitis was defined aschanging lesions consistent with granulomatous dis-ease upon direct and indirect funduscopic examinationafter dilation of the pupil plus complement-fixing anti-body in serum and documented evidence of coccidioi-dal infection elsewhere. To rule out coccidioidal organsystem involvement, a complete history was taken anda physical examination, including funduscopy andchest roentgenograms, was performed in all patients.In addition, most patients had lumbar punctures, bonescans, and urine cultures (with prostatic massage inmale patients) performed although the patients wereasymptomatic with respect to these systems.Of the 91 healthy subjects included, 23 were skin

test positive (-5-mm induration at 24 or 48 h) to CDN(1:100; Cutter Laboratories, Berkeley, Calif.) orspherulin (usual test strength; Berkeley Biologicals,Berkeley, Calif.), and 68 were skin test negative.

Aseptically drawn blood specimens were allowed toclot at room temperature. Sera were separated bycentrifugation and stored at -70°C until assayed.

IgE antibody assays. Total serum IgE levels werequantitated with the paper radioimmunosorbent test(Phadebas PRIST) purchased from Pharmacia FineChemicals, Inc., Piscataway, N.J. Reference IgE wasincluded in each assay.

Specific IgE levels to common allergens were mea-sured with the radioallergensorbent test (PhadebasRAST). Briefly, this assay consists of incubating se-rum with allergen-coated paper disks. Radiolabeledrabbit anti-human IgE is then added, and after incuba-tion and washing, the amount of bound radioactivity isdetermined. Allergens included Bermuda grass, com-mon ragweed, Dermatophagoides farinae (dust mite),dog epithelia, egg white, milk, mountain cedar, whiteoak, wormwood sagebrush, Alternaria tenuis, Asper-gillus sp., and Cladosporium sp.

C. immitis-specific IgE levels were determined withthe RAST test described above except that the paperdisks were coated with C. immitis antigens. The threeantigens were: CDN, prepared as a toluene-inducedmycelial-phase lysate, provided by M. Huppert, Vet-erans Administration Hospital, San Antonio, Tex.;spherulin, an aqueous extract of spherules of C. immi-tis, obtained from Berkeley Biologicals; and the alkali-soluble, water-soluble cell wall extract of mycelia ofC. immitis (9). The antigens (350 ,ug) were coupled tothe paper disks by cyanogen bromide activation (1).

Statistical analyses. Differences in the frequency ofelevated serum IgE levels among study groups wereanalyzed by chi-square analyses (14). Correlation anal-yses were performed with Spearman's rank-sum cor-relation (14).

RESULTSTotal serum IgE levels. A total of 7 (27%) of 26

patients with active pulmonary coccidioidomy-cosis and 23 (39%) of 59 patients with dissemi-nated disease had elevated serum IgE levels(.185 U/ml) as compared with 2 (17%) of 12patients in clinical remission and 2 (9%) of 23healthy, CDN skin test-positive persons (Fig. 1).Only 3 (4%) of 68 healthy, CDN skin test-negative subjects exhibited elevated serum IgE.Statistical analyses of these data establishedsignificant differences in the frequency of elevat-ed serum IgE levels in patients with activedisease versus healthy, skin test-positive (P <0.025) and -negative (P < 0.0001) subjects. Se-rum IgE levels of patients in clinical remissionwere intermediate (P > 0.05) between those ofpatients with active disease and those ofhealthy, CDN skin test-positive persons.Among the 26 patients with pulmonary coc-

cidioidomycosis, serum IgE levels were elevat-ed in 7 (32%) of 22 patients with chronic diseaseand 0 of 4 patients with acute, primary disease.Among the 59 patients with extrapulmonarydisease, serum IgE levels were elevated in 14(30%) of 46 patients with involvement of a singleorgan system as compared with 9 (69%) of 13patients with extrapulmonary disease involvingtwo or more organ systems (P < 0.02).The highest serum IgE level (45,000 U/ml) was

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IgE IN COCCIDIOIDOMYCOSIS 611

obtained in a patient with cutaneous coccidioi-domycosis. This finding was identical to thatobtained in our previous study (7). There wasnot, however, a significant relationship betweencutaneous disease and elevated serum IgE levelswhen compared with other clinical manifesta-tions; i.e., among the 46 patients with extrapul-monary disease involving one organ system,serum IgE levels were elevated in 5 (45%) of 11patients with cutaneous disease, 4 (25%) of 16patients with bone or joint disease, 3 (21%) of 14patients with coccidioidal meningitis, 2 (50%) of4 patients with lymph node involvement, and 0of 1 patient with genitourinary involvement.The correlation between serum IgE level and

seruri anti-CDN complement-fixing antibodywas low but statistically significant (r = 0.28; P< 0.01), as was the correlation between serumIgE and IgG concentrations (r = 0.29; P < 0.01).

In examining the relationship between IgEand the ethnic distribution of patients with ac-tive disease, we observed elevated serum IgElevels in 12 (34%) of 35 Caucasians, 7 (27%) of26 Hispanics, 5 (36%) of 14 blacks, 2 (40%) of 5Filipinos, 0 of 2 American Indians, and 2 (33%)of 3 persons with mixed ancestry. These distri-butions are not significantly different.

Coccidioidal IgE. IgE antibody to CDN wasdemonstrable in 6 (23%) of 26 patients withpulmonary coccidioidomycosis, 18 (31%) of 59patients with disseminated disease, and 2 (17%)of 12 patients with inactive disease (Fig. 2). Aswith total serum IgE levels, anti-CoccidioidesIgE levels correlated with disease severity interms of organ system involvement; i.e., 7 (54%)of 13 patients with Coccidioides involvement oftwo or more organ systems had IgE antibody toCDN as compared with 17 (24%) of 72 patientswith involvement of a single organ system (pul-monary or extrapulmonary) (P < 0.05).The correlation between total serum IgE lev-

els and C. immitis-specific IgE levels was statis-tically significant (Fig. 3; P < 0.001). Of 32patients with an elevated serum IgE (.185PRIST units per ml), 21 (66%) exhibited CDN-specific IgE (-0.35 RAST units per ml). Only 5(8%) of 65 patients with a normal serum IgElevel showed IgE reactivity to CDN. Reactivityto CDN correlated with IgE responses to spher-ulin (r = 0.80; P < 0.0001) and to the alkali-soluble, water-soluble cell wall extract of C.immitis mycelia (r = 0.76; P < 0.001).The specificity of the IgE responses to CDN

was assessed in RAST assays of 25 atopicpersons not infected with C. immitis. Only two(8%) reacted to CDN-coated disks. This fre-quency of reactivity is significantly lower (P <0.005) than that obtained in C. immitis-infectedpersons and establishes the specificity of CDNin RAST assays.

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EXTRAPULMONARY DISEASE DSASEFIG. 1. Total serum IgE levels in 23 healthy, CDN skin test-positive subjects, 26 patients with active

pulmonary coccidioidomycosis, 59 patients with active disseminated disease, and 12 patients with inactivedisease. For convenience, the term "organ" is used to denote organ system involvement. The horizontal linedenotes the upper limits of the 95% confidence level obtained in assays of 65 healthy, skin test-negative persons.

Longitudinal studies of two patients with ac-tive coccidioidomycosis and three patients withinactive disease over a course of 22 to 48 monthsare depicted in Fig. 4. Although individual pa-tient anti-CDN IgE concentrations fluctuated,the concentrations remained relatively constantin four of five patients. Of the three patients inclinical remission, two continued to producehigh levels of anti-CDN IgE (and non-coccidioi-dal IgE) even though they have been culturenegative for C. immitis and have not had demon-strable anti-CDN complement-fixing antibodyfor the past 5 years. On the other hand, the thirdpatient with inactive disease showed a signifi-cant decrease in anti-CDN IgE levels (from aRAST score of 2 to a score of 0) and a decreasein anti-CDN complement-fixing antibody levels(from a titer of 32 to a titer of 8), but has nowconverted her sputum culture and shows radio-logical evidence of reactivated pulmonary dis-ease. Of interest, this patient has maintained anelevated total serum IgE level of 750 to 900 U/mlthroughout the past 4 years.

Non-coccidioidal IgE. Table 2 summarizesnon-coccidioidal IgE responses in the 32 pa-tients who had elevated serum IgE. Twelvepatients failed to exhibit reactivity to any of theallergens. Of these, six had IgE reactivity toCDN; six did not. Only 4 (6%) of the 65 patientswith normal serum IgE levels reacted to 1 ormore of the 12 non-coccidioidal allergens.

Among the panel of allergens, the highestfrequency of reactivity was obtained with Ber-muda grass extract, with 15 (47%) of 32 patientshaving demonstrable levels of anti-Bermudagrass IgE. The correlation between total serumIgE levels and Bermuda grass IgE levels (Fig. 5)was only slightly less (r = 0.51; P < 0.01) thanthat obtained with CDN IgE levels (Fig. 3; r =

0.68; P < 0.001). Moreover, there existed asignificant correlation between anti-CDN IgElevels and Bermuda grass IgE levels (r = 0.43; P< 0.05). Results obtained with this allergen andwith the remaining 11 non-coccidioidal allergensprovide conclusive evidence that IgE antibodiesin coccidioidomycosis are directed against bothcoccidioidal and non-coccidioidal antigens.These responses were not attributed to the pres-ence of atopic disorders commonly associatedwith elevated serum IgE, i.e., asthma, atopicdermatitis, and hay fever.

DISCUSSIONThe results of the present study extend our

earlier findings (7) that a significant number ofpatients with active coccidioidomycosis haveelevated serum IgE levels and that total IgEconcentrations correlate with anti-CDN IgE lev-els. In our earlier report of 22 patients, we wereunable to demonstrate a significant correlationbetween elevated serum IgE (or anti-CDN IgE)

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levels and disease severity. Inclusion of an addi-tional 85 patients with active coccidioidomyco-sis has now established that hyperproduction ofIgE correlates with disease severity in terms oforgan system involvement. In a total of 107patients with active disease examined to date, 13(65%) of 20 patients with multiple organ systeminvolvement had elevated serum IgE levels as

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with active coccidioidomycosis (-) and three pa-tients in clinical remission (----) over a course of 22 to48 months. Arrow denotes conversion of sputum cul-ture in one patient.

VOL. 37, 1982 613

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IgE IN COCCIDIOIDOMYCOSIS 615

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of IgE in vitro and that ongoing IgE synthesis ismarkedly reduced in the presence of mononucle-ar cells (or T lymphocytes) of healthy, nonatopicpersons. The latter finding supports the hypoth-esis that hyperproduction of IgE in atopic dis-

* eases is attributed to a regulatory T-lymphocytedefect and provides the methodology for exam-

* ining suppressor cell dysfunction in patientswith coccidioidomycosis who have increasedserum IgE levels.

ACKNOWLEDGMENTSr. -°0. 51 This work was supported by Public Health Service grant AI-

16095 from the National Institute of Allergy and InfectiousDiseases.

* We thank Ilda DeFilippi of Pharmacia Fine Chemicals andClaude Anderson and Joyce McBride of South Texas Immu-nology Laboratory, Inc., for supplying serum samples from

I---- atopic persons.35 175

ANTI -BERMUDA GRASS Ig E (RAST units)FIG. 5. Correlation between total serum IgE levels

and anti-Bermuda grass IgE levels in 32 patients withserum IgE levels 2 185 U/ml.

correlate with disease severity in terms of singleor multiple organ system involvement.Hyperproduction of IgE was not limited to

anti-C. immitis IgE. Of 32 patients with elevatedserum IgE, 21 (66%) had demonstrable anti-C.immitis IgE. All but six of these had IgE anti-bodies to 1 or more of 12 allergens. Our findingthat excessive production of IgE occurs withboth coccidioidal and non-coccidioidal antigensis the first occurrence in our studies in which theimmunological abnormality is not specific for C.immitis, at least in the majority of patients.These results suggest that a defect exists in thelymphocyte population which functions to regu-late antigen-specific IgE and in the populationwhich functions to regulate IgE synthesis ingeneral. Whether this defect is acquired or ispreexisting is not known. The possibility that thedefect is acquired is supported by the low fre-quency of elevated IgE in patients with inactivecoccidioidomycosis. On the other hand, ourfinding that significant levels of anti-CDN IgE ornon-coccidioidal IgE or both can persist longafter the disease becomes inactive is more con-sistent with a preexisting defect, or a predisposi-tion to the defect. Support for the latter isderived from the finding that atopy is geneticallylinked (26) and that T suppressor cells are en-coded by the major histocompatibility complex(4, 40).

Studies by Buckley and Becker (5), Fiser andBuckley (13), and Saxon et al. (37, 38) haveshown that mononuclear cells of persons withatopic disorders synthesize significant amounts

LITERATURE CITED1. Axen, R., J. Porath, and S. Ernback. 1967. Chemical

coupling of peptides and proteins to polysaccharides bymeans of cyanogen halides. Nature (London) 214:1320-1324.

2. Beaman, L., D. Pappagianis, and E. Benjsamini. 1977.Significance of T cells in resistance to experimental mu-rine coccidioidomycosis. Infect. Immun. 17:580-585.

3. Beaman, L., D. Pappagianis, and E. Benjamini. 1979.Mechanisms of resistance to infection with Coccidioidesimmitis in mice. Infect. Immun. 23:681-85.

4. Brondz, B. D., A. V. Karaulov, I. F. Abronina, and Z. K.Blandova. 1980. Biological, immunological and geneticcharacterization of specific suppressor T cells and theirreceptors to antigens of the H-2 complex. Mol. Immunol.17:833-849.

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