The Association of Antinuclear Antibodies with the Chronic lridocyclitis of Juvenile Rheumatoid Arthritis (Still s Disease)

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1 The Association of Antinuclear Antibodies with the Chronic lridocyclitis of Juvenile Rheumatoid Arthritis (Still s Disease) Jane Green Schaller, Gerald D. Johnson, Eric J. Holborow, Barbara M. Ansell and W. K. Smiley Positive tests for antinuclear antibodies (ANA) were found in 51 of 58 (88%) patients with chronic iridocyclitis and juvenile rheumatoid arthritis (Still s disease). Antinuclear antibodies were predominantly of the IgG class of immunoglobulins and were generally present in titers of 150 (six ANA units) or more. They were unassociated with disease activity, severity or duration, age of patient at onset or testing, or sex. Neither other autoantibodies nor antibodies reactive with DNA or RNA were associated. In 8 patients tested early in disease, ANA were found prior to the onset of iridocyclitis. The presence of ANA should prove useful in identifying patients with JRA at risk for chronic iridocyclitis. In contrast, negative tests for ANA in patients with childhood-onset arthritis and iridocyclitis were found to be associated with acute iridocyclitis and subsequent ankylosing spondylitis. Iridocyclitis, inflammation of the iris and and signs, persistent ocular inflammation, ciliary body, affects about 10% of children and frequent scarring residua, accounts for with juvenile rheumatoid arthritis (JRA, S070 to 90% of cases (4). Chronic irido- Still s disease) and is a major cause of mor- cyclitis occurs most frequently in children bidity in the disease (1-4). Two types of with pauciarticular JRA, that is children iridocyclitis occur: acute and chronic. who have arthritis limited to only a few Chronic iridocyclitis, characterized by an joints (2-7). Acute iridocyclitis, characterinsidious onset, minimal early symptoms ized by abrupt onset, prominent early symptoms and signs, brief duration of ocu- ~~ ~ From the MRC Rheumatism Unit, Canadian Red Cross Memorial Hospital, Taplow, Maidenhead, Berks, England. Presented at the American Rheumatism Association Meeting, December 8, 1972, Pittsburgh, Penn- sylvania. JANE c SCHALLER, MD: Associate Professor of Pediatrics, University of Washington School of Medicine, Seattle; Clinical Scholar, The Arthritis Foundation, and Visiting Physician, MRC Rheumatism Unit, Taplow ; GERALD D JOHNSON, PhD: Immunologist, MRC Rheumatism Unit, Canadian Red Cross Memorial Hospital, Taplow, Maidenhead, Berks. England; ERIC J HOLBOROW, MD, MC Path: Head Immunology, MRC Rheumatism Unit, Canadian Red Cross Memorial Hospital, Taplow, Maidenhead, Berks: BARBARA M ANSELL, MD, FRCP: Consultant Rheumatologist, MRC Rheumatism Unit, Canadian Red Cross Memorial Hospital, Taplow, Maidenhead, Berks; w K SMILEY, FRCS, DOMS: Consultant Ophthalmic Surgeon, Canadian Red Cross Memorial Hospital, Taplow, Maidenhead, Berks. Address reprint requests to: Jane Schaller, MD, Department of Pediatrics, RD 20. University of Washington School of Medicine, Seattle, Washington Submitted for publication September 5, 1973; accepted January 2, Arthritis and Rheumatism, Vol. 17. No. 4 (July-August 1974) 409

2 lar inflammation, and infrequent scarring residua, occurs much less frequently, accounting for only about 10% of cases (4). Acute iridocyclitis is associated with subsequent radiographic sacroiliac joint changes and ankylosing spondylitis, although affected children may appear to have JRA before characteristic sacroiliac joint and back changes occur (4). In 1968 Schaller and associates noted the occurrence of ANA in 5 of 8 children with the chronic iridocyclitis of JRA, studied in Seattle (2). Similar observations were made in small numbers of patients by Munthe (8) and by Koskiahde and Laaksonen (9). The present study was made to test the hypothesis that ANA occur frequently in association with the chronic iridocyclitis of JRA. MATERIALS AND METHODS Diagnosis of JRA (Still s disease) was made according to the criteria of Ansell and Bywaters (10): all patients had been previously referred to the Rheumatism Unit at Taplow for consultation or care. All JRA patients had had periodic slit-lamp examinations, usualy at yearly or more frequent intervals. Diagnosis of iridocyclitis was made by one observer (WKS) on a basis of slit-lamp examination: the absence of iridocyclitis in the control group was similarly documented by slit-lamp examination. Iridocyclitis was distinguished as acute if associated with prominent early symptoms and signs and brief duration of ocular inflammation, and chronic if associated with insidious onset and persistent inflammation. Diagnosis of ankylosing spondylitis required radiographic changes of ankylosing spondylitis in both sacroiliac joints (1 1) as well as limited back motion or radiographic changes of ankylosing spondylitis in the lumbar spine (11). Seventy-six patients with JRA and iridocyclitis had been seen at Taplow from the opening of the Unit in 1947 until January 1, All patients with iridocyclitis, 69 in number, from whom serum samples had recently been drawn were included in this study. Of these 69 patients, 58 had chronic iridocyclitis and 11 had acute iridocyclitis. Study sera from 62 patients were obtained in SCHALLER ET AL 1972 and from 7 patients, between All stored sera had been frozen at -70 C prior to study. At the time study sera were obtained patients also had complete physical and ophthalmologic examinations, standard laboratory tests (complete blood counts, sedimentation rates, tests for rheumatoid factor by latex agglutination and differential agglutination tests (12), serum immunoglobulins by radial diffusion in agar (13)), and radiographs of the sacroiliac joints. At the time of study the mean disease duration of the disease for patients with iridocyclitis was 12.9 years (median 11 years, range 1 to 34 years), and most patients were between 11 and 30 years of age (mean age 17.4 years, median age 16 years, range 4-37 years. At the time sera were obtained, 24 patients had both active iridocyclitis and active arthritis (22 from the group with chronic iridocyclitis, 2 from the group with acute iridocyclitis), 14 had active iridocyclitis but inactive arthritis (13 chronic iridocyclitis, 1 acute iridocyclitis), 12 had inactive iridocyclitis but active arthritis (7 chronic iridocyclitis, 5 acute iridocyclitis). and 19 had neither active iridocyclitis nor active arthritis (16 chronic iridocyclitis, 3 acute iridocyclitis). Sera from the 69 patients with iridocyclitis were randomized with 189 other sera, making a total of 258 sera for study. Ninety-two sera were from patients with JRA, who were known not to have iridocyclitis. This group was weighted for known ANA-positive sera (44 sera) so that valid observations concerning immunoglobulin class of ANA could be made. Twenty-three sera were from patients with ankylosing spondylitis. Seventy-four sera were from control children from an otolaryngology service, presumably weighted for children with recurrent upper respiratory tract infections. The age distribution of patients with JRA but without iridocyclitis was similar to that of the control children and of patients with iridocyclitis; patients with ankylosing spondylitis were predominantly adults. The prevalence of ANA in patients with JRA but without iridocyclitis was calculated from 133 who did not have iridocyclitis and had been tested consecutively in the same laboratory, using the same methods, during a 16-month period in Tests for ANA were made at a routine serum dilution of 1:lO by standard indirect immunofluorescence technique (14). Cryostat sections of rat liver provided the source of nuclear antigen. Standardized fluorescein conjugates (Burroughs Wellcome, Ltd) reactive with whole immunoglobulin and spe- 410 Arthritis and Rheumatism, Vol. 17, No. 4 (July-August 1974)

3 ANA AND CHRONIC IRIDOCYCLITIS IN JRA cific for A, a, and p chains were used at optimum working dilutions, as determined by chessboard titration. Stained sections were examined with a Reichert microscope equipped with a quartz iodine lamp and appropriate filters. Tests were read by two observers independently US and GJ). Sera positive for ANA were titered by a dilution series of 1:lO. 150, 1:250 and 1:1250. For IgG ANA these titers corresponded to 1. 6, 31 and 158 ANA units, based on an ANA standard.. Other autoantibodies were sought on the same series of 258 randomized sera. Sera were routinely diluted 1:lO and similar indirect immunofluorescence techniques employed. Cryostat sections of rat liver, stomach and kidney were the source of antigen. Standardized fluorescein conjugates specific for A and fi were used. Tests were read by two observers independently US, EJH). Antibodies reactive with smooth muscle, gastric parietal cells, mitochondria and reticulin were specifically sought (15). Selected randomized sera from iridocyclitis, noniridocyclitis, and control children were tested for serum binding of DNA and RNA; approximately one-third of the patients from each group were tested. Double-stranded calf thymus DNA and double-stranded fungal RNAt were externally labeled with tritiated actinomycin D and a modified Farr technique employed (16,17). Based on a series of determinations on adult sera, the thresholds of positivity for these methods in this laboratory had been set at 10% for DNA binding and 35% for RNA binding. RESULTS Positive tests for ANA were found in 52 of 69 patients with iridocyclitis (75%) (Table 1). Of 58 patients with chronic iridocyclitis, 5 1 (880/,). were positive. In comparison, only 1 of 11 patients with acute iridocyclitis was positive ($ = 30.95, P << 0.001), only 2 of 23 patients with ankylosing spondylitis were positive (x2=45.7, P << 0.001, and none of 74 control children was positive (xz = 105.6, P << 0.001). Of *The Standard 66/233 (homogeneous) supplied by the Division of Biological Standards, National Institute for Medical Research, Holly Hill, London. fkindly provided by Dr. D. N. Planterose, Beecham Research Laboratories, Betchworth, Surrey. Table 1. Positive Tests for Antlnuclear Antibodium Group No. of Patients JRA with iridocyclitis 69 Chronic iridocyclitis 58 Acute iridocyclitis 11 Ankylosing spondylitis 23 Control children 74 JRA without iridocyclitis 133 Positive Tests No. % patients with JRA but without iridocyclitis who were tested in the same laboratory by the same method during a 16-month period in , only 40 (30%) were positive &z = 54.2, P <<0.001). These dif- ferences are highly significant. Nuclear staining patterns were overwhelmingly of the homogeneous type regardless of serum dilutions. Antinuclear antibodies were predominantly IgG in class, IgG ANA being present in all,4na positive patients in both the iridocyclitis and ANA positive noniridocyclitis groups. Titers of IgG ANA were 1:50 (6 units) or greater in the majority of both iridocyclitis and noniridocyclitis patients. Three additional patients with chronic iridocyclitis had titers of IgG ANA of less than 1:lO; these patients were counted as negative for purposes of this study. IgM ANA were present in three-fifths of the patients in both groups. Titers of IgM ANA exceeded those of IgG ANA in only 5 patients, 4 of them in the noniridocyclitis group. IgA ANA were present in a minority of patients, but occurred more frequently in the noniridocyclitis than the iridocyclitis group (x2 = 10.5, P < 0.005). Titers of IgA ANA exceeded those of IgG ANA in only 2 patients, both in the noniridocyclitis group (Tables 2 and 3). There was no relationship between ANA positivity and activity of either eye or joint inflammation at the time of testing. In the Arthritlr and Rheumatism, Vol. 17, No. 4 (July-August 1974) 41 1

4 Table 2. Immunoglobulin Class of Antinuclear Antibodies No. of Group Patients IgG IgA IgM lridocyclitis (52 ANA positive) Noniridocyclitis (44 ANA positive) Table 3. Titers of IgG Antinuclear Antibodies Serum dilutions <1:10 1:lO 150 1:250 1:1250 ANA units (<lu) (lu) (6u) (31u) (158u) lridocyclitis 3' (55 patients) Noniridocyclitis lt (44 patients) 'These 3 patients with chronic iridocyclitis had only IgG ANA at titers of <1:10 and were counted as ANA negative in this study.?this patient had IgM ANA in a higher titer and was counted as ANA positive. chronic iridocyclitis group, ANA were found in 31 of 35 patients with active eye inflammation and in 20 of 23 patients with inactive eye disease. In the acute iridocyclitis group, ANA were found in none of 3 patients with active eye inflammation and in only 1 of 8 patients with inactive eye dis ease. Further relationships of ANA positivity were sought; the prevalence of ANA in patients with chronic iridocyclitis could not be correlated with sex, age at disease onset, age at testing, duration of disease, or severity of either joint or eye disease. In most patients with JRA iridocyclitis, the arthritis begins months or a few years before the iridocyclitis (1-5). Most patients in this series were not tested for ANA prior to the onset of iridocyclitis. However of 8 patients who were tested early in disease, 7 had positive tests for ANA before the onset of iridocyclitis. In these patients normal slit-lamp examinations had clearly defined SCHALLER ET AL the absence of iridocyclitis at the time of positive tests for ANA. Available evidence therefore suggests that positive tests for ANA precede rather than result from iridocyclitis. There was no association between positive tests for ANA and other laboratory tests performed. No patient with iridocyclitis had a positive latex or differential agglutination test for rheumatoid factor at the time of this study, and none had been consistently seropositive in the past. Sedimentation rates were normal in 70% of the ANA-positive patients with iridocyclitis and in 50y0 of the ANA-negative patients with iridocyclitis. Serum immunoglobulin levels (IgG, IgA, IgM) were normal in 60% of both ANA-positive and ANA-negative patients with iridocyclitis; no immunoglobulin deficiencies were identified in either group. Several significant observations appeared concerning the 14 ANA-negative patients with iridocyclitis. At the time of follow-up, radiographic sacroiliac joint changes consistent with ankylosing spondylitis were present in 11 of I4 patients and radiographic changes of ankylosing spondylitis were found in the lumbar spine in 6 of 14. Ten of I4 ANA-negative patients had had acute rather than chronic iridocyclitis. It can therefore be seen that negative tests for antinuclear antibodies in children with arthritis and iridocyclitis were associated with acute iridocyclitis and subsequent sacroiliitis and ankylosing spondylitis. In contrast, only 1 of 52 ANA-positive patients with iridocyclitis had sacroiliitis and acute iridocyclitis, and none had definite ankylosing spondylitis at follow-up. Smooth muscle antibodies, predominantly of the IgM class of immunoglobulins, were present in similar proportions (15y0-23%) of patients with JRA and iridocyclitis, JRA 41 2 Arthritis and Rheumatism, Voi. 17, No. 4 (July-August 1974)

5 ANA AND CHRONIC IRIDOCYCLITIS IN JRA Table 4. Serum Binding of DNA and RNA DNA Binding (10% threshold) RNA Binding (35% threshold) Mean Mean Binding (%) f 1 SE Binding (%) f 1 SE JRA iridocyclitis 7.6 * k2.58 ANA positive (17 patients) JRA iridocyclitis 9.3 f f1.93 ANA negative (8 patients) JRA noniridocyclitis 9.3 f k2.29 ANA positive (19 patients) JRA noniridocyclitis 7.6 k f5.29 ANA negative (5 patients) Control children 7.7 f k2.90 without iridocyclitis, and ankylosing spondylitis; and control children. These percentages correspond to those found in various control groups, about 20% of whom may be expected to have some detectable smooth muscle antibody (18). No other autoantibodies were found. The iridocyclitis patients, either ANA positive or ANA negative, did not exhibit increased serum binding of DNA or RNA as compared to patients with JRA but without iridocyclitis, either ANA positive or ANA negative, or this particular group of control children (Table 4). DISCUSSION Antinuclear antibodies are characteristic of systemic lupus erythematosus, but are found also in some patients with rheumatoid arthritis, JRA, and other rheumatic diseases including scleroderma, Sjogren s syndrome, and mixed connective tissue disease (19-24). Antinuclear antibodies are also known to be associated with certain infectious processes (25), malignancies (18), and with the normal aging process (26). The stimulus for the formation of ANA in these conditions remains unknown. Whether native (either altered or unaltered) or cross-reactive substances are acting as antigens, and whether immune incompetence on the part of the host plays a role in allowing the formation of ANA remain unanswered questions. What, if any, role ANA play in the pathogenesis of disease also remains largely unknown, with one important exception. Antibodies to DNA have been clearly identified as instrumental in the immune complex nephritis of systemic lupus erythematosus (27). It has also been suggested that ANA may perpetuate the chronic synovitis of rheumatoid arthritis by an immune complex mechanism (28). Antinuclear antibodies have been reported in % of children with JRA (5,2941). In JRA they have been related to female sex and early childhood onset of disease, but not to disease severity. Antinuclear antibodies have been found in about 25y0 of both children with pauciarticular JRA and polyarticular JRA (5), but rarely if ever in children with sys- Arthritis and Rheumatism, Vol. 17, No. 4 (July-August 1974) 41 3

6 SCHALLER ET AL temic JRA (JRA with high fevers and rheumatoid rash) (53 1). This study clearly relates ANA to the chronic iridocyclitis of JRA. The 88 % prevalence of ANA in patients with JRA and chronic iridocyclitis represents the highest prevalence of positive tests in any described disease group other than SLE. Antinuclear antibodies were predominantly of the IgG immunoglobulin class, with titers of 1:50 (6 units) or more in most patients. Neither rheumatoid factors nor other autoantibodies were associated, nor were antibodies to DNA and RNA demonstrated. The absence of antibodies to RNA differs from a recent report where antibodies to double-stranded RNA were found in 5 of 5 children with JRA and iridocyclitis (32). The consistent homogeneity of the nuclear fluorescence patterns of ANA in this study is in accord with the reactivity of the ANA being directed against desoxyribonucleoprotein (22), although it does not exclude the presence of antibodies to other nuclear antigens. No relationships could be demonstrated between ANA positivity and severity, activity, or duration of either eye or joint disease. The group of ANA-negative iridocyclitis patients proved to contain a heavy preponderance of patients with ankylosing spondylitis rather than JKA. Nost ANA-negative patients had acute (10 of 14 patients) rather than chronic iridocyclitis, and at follow-up had radiographic changes of ankylosing spondylitis in the sacroiliac joints (11 of 14 patients) and the lumbar spine (6 of 14 patients). Ankylosing spondylitis is well known to be associated with acute iridocyclitis. The disease may begin in childhood with peripheral arthritis, masquerading as JRA until characteristic sacroiliac and back changes become manifest (33,34). Twenty-one of 23 control patients with known ankylosing spondylitis in this study were ANA negative; it would appear that ANA are rarely associated with this disease. Evidence of ankylosing spondylitis at follow-up was not found in any patient with chronic iridocyclitis and positive tests for ANA. The explanation for the association of chronic iridocyclitis with JRA, particularly with pauciarticular JRA, is unknown, as is the etiology of both the synovial and anterior uveal tract inflammation. This type of eye disease is notorious for its insidiousness, chronicity, and frequency of scarring residua. The occurrence of ANA in association with this chronic iridocyclitis might be interpreted as evidence of an underlying infectious process or of some immunologic aberration on the part of the host. Both infectious processes and host immune defects have been associated with the formation of ANA and other autoantibodies (25,35-39). Whether the ANA play any role in the causation or perpetuation of the ocular inflammation is open to question. Available evidence suggests that the ANA precede rather than follow the iridocyclitis. Patients with iridocyclitis generally have few other extraarticular symptoms and certainly no evidence of systemic immune complex disease or vasculitis (2,4). The high prevalence of ANA in JRA with chronic iridocyclitis, and their rarity in systemic JRA (high fevers and rheumatoid rash, not associated with iridocyclitis) adds credence to the hypothesis that what we now call JKA may be in fact more than a single disease process (5,40,41). The iridocyclitis of JRA is characteristically unassociated with early symptoms or signs; early diagnosis can be made only if periodic slit-lamp examinations are done. Although explanations for the association of ANA with the chronic iridocyclitis of 41 4 Arthritis and Rheumatism, Vol. 17, No. 4 (July-August 1974)

7 ANA AND CHRONIC IRlDOCYCLlTlS IN JRA JRA remain obscure, positive tests for ANA should prove useful for identifying patients with JRA at risk for chronic iridocycli tis. ACKNOWLEDGMENTS We gratefully acknowledge the assistance of Mr. Arthur Howard (immunoglobulin determinations), Mrs. Mavis Smith, (technical assistance), and Dr. Paula Kanarek (statistical analyses). REFERENCES 1. Smiley WK, May E, Bywaters EGL: Ocular presentations of Still s disease and their treatment. Iridocyclitis in Still s disease; its complications and treatment. Ann Rheum Dis 16: , Schaller J, Kupfer C, Wedgwood RJ: Iridocyditis in juvenile rheumatoid arthritis. Pediatrics 44:92-100, Calabro JJ, Parrino GR, Atchoo PD, et al: Chronic iridocyclitis in juvenile rheumatoid arthritis. Arthritis Rheum 13:406413, Schaller J, Smiley WK, Ansell BM: Iridocyclitis of juvenile rheumatoid arthritis (JRA, Still s disease): A followup study of 76 patients. Arthritis Rheum (abstract) 16: , Schaller J, Wedgwood RJ: Is juvenile rheumatoid arthritis a single disease? A review artide. Pediatrics 50: , Bywaters EGL, Ansell BM: Monarticular arthritis in children. Ann Rheum Dis 24: , Cassidy JT, Brody GL, Martel W: Monarticular juvenile rheumatoid arthritis. J Pediatr 70: , Munthe E: Personal communication 9. Koskiahde V, Laaksonen AL: Juvenil reumatoid artrit och ogat. Den XI1 Nordiska Reumatologkongressen i Otnas, Finland, June Ansell BM, Bywaters EGL: Prognosis in Still s disease. Bull Rheum Dis 9: , McEwen C, DiTata D, Lingg C, et al: Ankylosing spondyli tis accompanying ulcerative colitis, regional enteritis, psoriasis and Reiter s disease. Arthritis Rheum 14: , Bywaters EGL, Carter ME, Scott FET: Differential agglutination titer in juvenile Rheumatoid arthritis. Ann Rheum Dis 18: , Mancini G, Carbonara AO, Heremans JF: Immunochemical quantitation of antigens by single radial immunodiffusion. Immunochemistry , Holborow EJ, Johnson GD: The immunofluorescent test for serum antinuclear factor. Association of Clinical Pathologists: Broadsheet 65, March Johnson GD, Holborow EJ, Glynn LE: Antibody to smooth muscle in patients with liver disease. Lancet , Wold RT, Young FE, Tan EM, et al: Deoxyribonucleic acid antibody: A method to detect its primary interaction with deoxyribonucleic acid. Science 161: , Steinberg AD, Pincus T, Tala1 N: The pathogenesis of autoimmunity in New Zealand mice Factors influencing the formation of anti-nudeic acid antibodies. Immunology 20: , Whitehouse JMA, Holborow EJ: Smooth muscle antibody in malignant disease. Br Med J 4: , Kunkel HG, Tan EM: Autoantibodies and disease. Adv Immunol 4: , Seligmann M, Cannat A, Hamard M: Studies on antinuclear antibodies. Ann NY Acad Sci 124: , Vaughan JH, Barnett EV, Leddy JP: Autosensitivity diseases. N Engl J Med 275: , , Friou GJ: Antinuclear antibodies: Diagnostic significance and methods. Arthritis Rheum 10: , Beck JS: Antinuclear antibodies: Methods of detection and significance. Mayo Clin Proc 44: , Sharp GC, Irvin WS, Tan EM, et al: Mixed connective tissue disease: An apparently distinct rheumatic disease syndrome assod- Arthritis and Rheumatism, Vol. 17, No. 4 (July-August 1974) 41 5

8 SCHALLER ET AL ated with a specific antibody to an extractable nuclear antigen (ENA). Am J Med 52: , Ziff M: Viruses and the connective tissue diseases. Ann Intern Med 75: , Cammarata RJ, Rodman GP, Fennel1 RH: Serum antigammaglobulin and antinuclear factors in the aged. JAMA 199:455458, Koffler D, Agnello V, Thoburn R, et al: Systemic lupus erythematosus: Prototype of immune complex nephritis in man. J Exp Med 134: 169s--179s, Zvaifler NJ, Martinez MM: Antinuclear factors and chronic articular inflammation. Clin Exp Immunol 8: , Kornreich HK. Drexler E, Hanson V: Antinuclear factors in childhood rheumatic diseases. J Pediatr 69: , Miller JJ, Henrich VL, Brandstrup NE: Sex difference in incidence of antinuclear factors in juvenile rheumatoid arthritis. Pediatrics 38: , Petty RE. Storm PB, Cassidy JT, et al: Immunologic correlates of antinuclear antibody in juvenile rheumatoid arthritis. Arthritis Rheum 12: , 1969 (abstr) 32. Epstein WV, Tan M, Easterbrook M: Serum antibody to double-stranded RNA and DNA in patients with idiopathic and secondary uveitis. N Engl J Med 285: , Schaller J, Bitnum S, Wedgwood RJ: Ankylosing spondylitis with childhood onset. J Pediatr 74: , Ansell BM, Bywaters EGL: Diagnosis of probable Still s disease and its outcome. Ann Rheum Dis 21: , Notkins AL, Mergenhagen SE, Howard RJ: Effect of virus infections on the function of the immune system. Ann Rev Microbiol 24: , Fudenberg HH: Genetically determined immune deficiency as the predisposing cause of autoimmunity and lymphoid neoplasia. Am J Med 51: , Ammann AJ, Hong R: Selective IgA deficiency: Presentation of 30 cases and a review of the literature. Medicine 50: , Allison AC, Denman AM, Barnes RD: Cooperation and controlling functions of thymus-derived lymphocytes in relation to autoimmunity. Lancet 2: , Weigel WO: Recent observations and concepts in immunological unresponsiveness and autoimmunity. Clin Exp Immunol 9: , Ansell BM: Still s disease followed into adult life. Proc Roy SOC Med 62: , Schaller J, Wedgwood RJ: Is JRA a single entity? Pediatr Res (abstract) 3: , Arthritis and Rheumatism, Vol. 17, No. 4 (July-August 1974)