Uveitis associated with acute interstitial nephritis (AIN)

Transcription

1 Strong Associations between Specific HLA-DQ and HLA-DR Alleles and the Tubulointerstitial Nephritis and Uveitis Syndrome Ralph D. Levinson, 1,2 Min S. Park, 3 Sarah M. Rikkers, 1,2 Elaine F. Reed, 3 Justine R. Smith, 4,5 Tammy M. Martin, 4,5 James T. Rosenbaum, 4,5 C. Stephen Foster, 6 Mark D. Sherman, 7 and Gary N. Holland 1,2 PURPOSE. To identify genetic markers for the tubulointerstitial nephritis and uveitis (TINU) syndrome by using human leukocyte antigen (HLA) genotyping. METHODS. Eighteen patients who had TINU syndrome were evaluated at three institutions. Typing of class I and II genes was performed by using DNA-based techniques. RESULTS. Significant associations were found with HLA-B14 (6/18 patients, 33.3%; control subjects, 5.5%; P ; relative risk [RR] 8.5), HLA-DQA1*01 (17/18 patients, 94.4%; control subjects, 46.6%, P ; RR 19.5), HLA- DQA1*0101 (14/18 patients, 77.8%; control subjects 22.2%; P ; RR 12.2), HLA-DQB1*05 (14/18 patients, 77.8%; control subjects 17.7%; P ; RR 16.3), HLA- DQB1*0501 (13/18 patients, 72.2%; control subjects 12.9%; P ; RR 17.6), HLA-DRB1*01 (14/18 patients, 77.8%; control subjects, 12.1%; P ; RR 25.5), and HLA- DRB1*0102 (13/18 patients, 72.2%; control subjects, 1.6%; P , RR 167.1). The HLA haplotype most frequently identified in the study patients was HLA-DQA1*01/DQB1*05/ DRB1*01 (13/18 patients, 72.2%). CONCLUSIONS. TINU syndrome is strongly associated with HLA- DQA1*01, HLA-DQB1*05, and HLA-DRB1*01. The association with HLA-DRB1*0102 is one of the highest reported for any disease. Because these genes are in linkage disequilibrium, the role of the individual alleles is difficult to assess. Based on the results of the present study and on previously reported HLA associations in patients with TINU syndrome, the dimer encoded by HLA-DQA1*01/DQB1*05 may be particularly important in conferring risk for development of this disease. From the 1 Ocular Inflammatory Disease Center, Jules Stein Eye Institute and Departments of 2 Ophthalmology and 3 Pathology and Laboratory Medicine, UCLA Immunogenetics Center, University of California Los Angeles School of Medicine, Los Angeles, California; the 4 Casey Eye Institute and 5 Department of Ophthalmology, Oregon Health and Science University, Portland, Oregon; the 6 Ocular Immunology and Uveitis Service, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts; and the 7 Uveitis Referral Service, Southern California Permanente Medical Group, Orange County, California. Supported in part by the MacDonald Family Foundation, Los Angeles, CA (RDL), Research to Prevent Blindness, Inc. (JRS, TMM, JTR, GNH), and the David May II Endowed Professorship (GNH). GNH is a recipient of a Research to Prevent Blindness, Lew R. Wasserman Award. Submitted for publication April 15, 2002; revised July 31, 2002; accepted August 19, Commercial relationships policy: N. The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked advertisement in accordance with 18 U.S.C solely to indicate this fact. Corresponding author: Ralph D. Levinson, Jules Stein Eye Institute, 100 Stein Plaza, UCLA, Los Angeles, CA ; levinson@jsei.ucla.edu. (Invest Ophthalmol Vis Sci. 2003;44: ) DOI: / iovs Uveitis associated with acute interstitial nephritis (AIN) appears to be a distinct clinical entity that has come to be known as the tubulointerstitial nephritis and uveitis (TINU) syndrome. TINU syndrome is rare, with 133 cases identified in a recent review of the world literature, 1 and it accounts for 2% or less of patients in university-based uveitis practices. 2 TINU syndrome is of particular interest, because it has been thought to have an identifiable trigger in many cases, including use of antibiotics in 24% of cases and use of nonsteroidal anti-inflammatory agents in 18% of cases. 1 Similar triggering agents have been identified for both isolated AIN and TINU syndrome, but it is not known whether TINU syndrome and AIN without uveitis are different presentations of the same disease. Both cell-mediated immune responses and autoantibody production 1,3 have been implicated in the pathogenesis of TINU syndrome, and putative autoantigens, although not well defined, have been identified. 3 Thus, TINU syndrome may be the result of an autoimmune process. Several investigators have reported human leukocyte antigen (HLA) phenotypes in patients with TINU syndrome. 1,4 14 Each report was limited to five or fewer patients, and these studies were performed during a period of 20 years, using different techniques to determine HLA phenotypes, making it impossible to determine the relative risks for any HLA antigen. We examined the HLA-A, -B, -DRB1, -DQA1, and -DQB1 gene frequencies in 18 patients who had TINU syndrome treated at three institutions to determine whether associations with TINU syndrome could be demonstrated. METHODS The study was performed at three institutions: the Jules Stein Eye Institute, University of California, Los Angeles (UCLA) School of Medicine (Los Angeles, CA); the Casey Eye Institute, Oregon Health Sciences University (Portland, OR); and the Massachusetts Eye and Ear Infirmary, Harvard Medical School (Boston, MA). The diagnosis of TINU syndrome was made by uveitis specialists based on criteria to be listed herein. Institutional review board approval was obtained at each of the study institutions. The study adhered to the Declaration of Helsinki for research involving human subjects. Informed consent was obtained from all participants. All patients met the diagnostic criteria for TINU syndrome described by Mandeville et al. 1 The diagnosis of TINU syndrome requires the documentation of AIN and uveitis, without evidence of other systemic disease or infection that could cause both renal and ocular inflammation. Study participants were further classified as having definite, probable, or possible TINU syndrome. The classification was based on the strength of the diagnosis of AIN and the nature of the uveitis, as described in detail elsewhere. 1 Briefly, the diagnosis was considered definite if there was either histologic evidence of AIN on Investigative Ophthalmology & Visual Science, February 2003, Vol. 44, No. 2 Copyright Association for Research in Vision and Ophthalmology 653

2 654 Levinson et al. IOVS, February 2003, Vol. 44, No. 2 TABLE 1. Patient Characteristics and Features of the Uveitis Component of Disease in 18 Patients with TINU Syndrome, Compared with Data from Published Case Reports Study Sample (n 18) Published Cases* (n 133) P Patient characteristics Median age (range, y) 42 (10 56) 15 (9 74) Gender Female 15 (83%) 98 (74%) 0.38 Race White 17 (94%) African-American 1 (6%) Uveitis characteristics Anatomic Classification Anterior uveitis 8 (44%) 80% (n 122) Intermediate, posterior panuveitis 10 (56%) 20% (n 122) Laterality Unilateral /alternating 0 (0%) 23% (n 109) 0.08 Bilateral 18 (100%) 77% (n 109) 0.02 Course Single episode 1 (6%) 59% (n 126) Recurrent/chronic 17 (94%) 41% (n 126) * Previously published data from Mandeville et al. 1 P 2 analysis. All 10 patients in this group had bilateral anterior uveitis in addition to either vitreous inflammatory reaction (n 7), vitreous inflammatory reaction with papillitis (n 2), or panuveitis (n 1). Data given as percent, with the number of patients for whom the data were available in parentheses. 1 renal biopsy or strong clinical evidence for the diagnosis of AIN (complete clinical criteria comprised three components: abnormal renal function, abnormal urinalysis results, and typical systemic findings, all of which are consistent with AIN), as well as typical uveitis (defined as bilateral anterior uveitis, with or without other signs of ocular inflammation). The diagnosis was considered probable if complete clinical criteria or histologic evidence for AIN was established, but the uveitis was atypical, or if there was typical uveitis without histologic confirmation of AIN and there were fewer than three components of the complete clinical criteria for diagnosis of AIN. For patients who had received a diagnosis of AIN from their medical consultants, the presence of any documented laboratory abnormality that is consistent with AIN, in the absence of other diseases that account for the abnormality, was considered to be sufficient for the classification of probable TINU syndrome. The diagnosis was considered possible if the uveitis was atypical without histologic confirmation of AIN and there were fewer than three components of the complete clinical criteria for the diagnosis of AIN. Individuals in whom the uveitis developed more than 1 month before, or 12 months after, the renal disease were classified as having possible TINU syndrome. To confirm that patients met the criteria for diagnosis, they were reexamined and their medical records reviewed. No additional diagnostic testing was performed. Demographic and historical information was obtained to allow comparison of study patients to patients with TINU syndrome described in the medical literature. 1 The following information was obtained regarding demographics: age at onset of TINU syndrome, gender, and race; regarding renal disease: date of onset of systemic signs and symptoms of AIN, results of tests and procedures used to diagnose AIN, and treatment and course of the renal disease; and regarding uveitis: date of onset of uveitis, classification (anterior, intermediate, posterior or panuveitis), other inflammatory signs (vitreous inflammatory reaction, papillitis), laterality (unilateral, bilateral), and course of uveitis (single episode, recurrent, or chronic uveitis). All HLA typing in patients was performed at the UCLA Immunogenetics Center. DNA was isolated from peripheral blood leukocytes using a commercial extraction method (Qiagen, Inc., Valencia, CA) and typed for HLA class I and II gene polymorphisms, by using polymerase chain reaction (PCR) followed by hybridization with sequence-specific oligonucleotide probes, as published elsewhere. 15 Oligonucleotide probes for typing the HLA-A, -B, -DQB, and -DRB loci were obtained from Dynal Biotech, Ltd., Wirral, UK). HLA-DRB*01 alleles were further characterized at the allele level, by using sequence-specific primers (SSPs; One Lambda, Canoga Park, CA) and in some cases were confirmed by sequence-based typing (Amersham Pharmacia Biotech, Inc., Piscataway, NJ). Allele level typing of HLA-DQA1 was performed by SSP using reagents from GenoVision, Inc. (West Chester, PA). Statistical evaluation of the results was performed by contingency table analysis. Relative risk (RR) was estimated from the odds ratio. Probabilities were determined by the Fisher exact test. Because of nine multiple comparisons, P was chosen as the threshold for statistical significance. Because 17 of 18 patients were white (one patient was African American, patient 4), published rates of specific HLA alleles for North American whites were used as the control. 16 A 2 analysis was used to compare the characteristics of the study group with the data from previously published individuals with TINU syndrome. 1 RESULTS The demographic and clinical features of TINU syndrome for the 18 patients are given in Table 1. The study group was older and had higher rates of chronic and recurrent uveitis and intermediate, posterior, or panuveitis compared with previously reported patients. 1 No patient required treatment for chronic renal disease. Patient 18 had elevated serum creatinine of 2.2 mg/dl when last examined; however, information about the interval from the onset of disease to the date of this test was not available. Only one individual required dialysis for a limited period (patient 13). All 18 patients met the diagnostic criteria for TINU syndrome. The diagnostic classification for individual patients is given in Table 2. Patients 14, 15, and 16 had typical bilateral anterior uveitis, but there were insufficient data for confirmation of suspected AIN, and these patients were therefore classified as having probable TINU syndrome. Patient 14 had bilateral anterior uveitis that developed within 6 months of a

3 IOVS, February 2003, Vol. 44, No. 2 HLA Alleles and TINU Syndrome 655 TABLE 2. MHC Class I and II Genotypes of 18 Patients with TINU Syndrome Patient TINU Syndrome Classification HLA Specificity A B DRB1 DQB1 DQA1 1 Definite 2,68 13, , , , Definite 1, , , , Definite 2, , Definite 2,32 8, , , , Definite 26,69 38, , , , Definite 1,3 8, , , , Definite 32,33 55, , , , Definite 2,3 50, , , , Definite 2,33 51, , , , Definite 1,33 8, , , , Definite 11,33 8, , , , Definite 2, , , , Definite 1,2 44,60 15, , , Probable 2,33 62, , Probable 11,2 55, , Probable 1, , , , Possible 2,23 49, , , , Possible 1,68 8,35 04, , ,0505 systemic illness characterized by mild renal insufficiency and non-nephrotic proteinuria, presumed to be caused by AIN. A subsequent renal biopsy revealed tubular atrophy consistent with, but not diagnostic of, previous interstitial nephritis. Patient 15 had bilateral anterior uveitis concurrent with nonnephrotic proteinuria and sterile pyuria, thought to be caused by AIN. Because there was no additional information about clinical and laboratory findings in the available records, she was also classified as having probable TINU syndrome. Patient 16 had bilateral anterior uveitis and a history of clinical signs and symptoms consistent with AIN, but no renal function studies or urinalysis had been obtained when she had systemic disease. She was therefore classified as having probable TINU syndrome. Her urinary 2-microglobulin was elevated 4 months after the systemic disease had resolved. The urinalysis and renal function test results were otherwise normal at that time. Persistent elevation of the urinary 2-microglobulin after resolution of other abnormalities in laboratory test results has been documented in patients with TINU syndrome. 13 The timing of the onset of uveitis relative to the renal disease was not well documented in patients 17 and 18, but the onset of uveitis may have been more than 12 months after AIN occurred. They were therefore classified as having possible TINU syndrome. All other patients met the criteria for definite TINU syndrome. The HLA genotypes for the study group are given in Table 2, and the relative risk (RR) with 95% confidence interval (CI) and probability for HLA antigens with a statistically significant association to TINU syndrome are given in Table 3. HLA antigens that were found to be associated with TINU syndrome were HLA-B14 (6/18 patients, 33.3%; control subjects, 5.5%; P ; RR 8.5), HLA-DQA1*01 (17/18 patients, 94.4%; control subjects, 46.6%, P ; RR 19.5), HLA- DQB1*05 (14/18 patients, 77.8%; control subjects 17.7%; P ; RR 16.3), and HLA-DRB1*01 (14/18 patients, 77.8%; control subjects, 12.1%; P ; RR 25.5). High-resolution molecular typing revealed a significant association between TINU syndrome and HLA-DQA1*0101 (14/18 patients, 77.8%; control subjects 22.2%; P ; RR 12.2), HLA- DQB1*0501 (13/18 patients, 72.2%; control subjects 12.9%; P ; RR 17.6), and HLA-DRB1*0102 (13/18 patients, 72.2%; control subjects, 1.6%; P , RR 167.1). HLA- DQB1*06 was decreased in patients compared with control subjects (3/18 patients, 16.7%; control subject, 22%), but this did not reach statistical significance. Because the HLA alleles of family members were not examined, our patients haplotypes could not be determined directly. The probable haplotypes are therefore presumptive, based on the strongest linkage between DR/DQ observed in family segregation studies and population studies using maximum-likelihood estimation for linkage disequilibrium and are given in Table 4. 16,17 The most frequent haplotype in the study patients was HLA-DQA1*01/DQB1*05/DRB1*01 (13/18 patients, 72.2%). This haplotype was found in 11 (84.6%) of 13 TABLE 3. Selected HLA Genotypes and Associated Relative Risk for TINU Syndrome HLA Phenotype* Patients (n 18) Controls Subjects RR 95% CI P HLA-B14 6 (33.3%) 5.5% HLA-DQA1*01 17 (94.4%) 46.6% HLA-DQA1* (77.8%) 22.2% HLA-DQB1*05 14 (77.8%) 17.7% HLA-DQB1* (72.2%) 12.9% HLA-DRB1*01 14 (77.8%) 12.1% HLA-DRB1* (72.2%) 1.6% * Included only are HLA antigens and alleles that were significantly associated with TINU syndrome. Control data were published for North American Whites (Gjertson and Terasaki 16 ). Relative risk as measured by the odds ratio, used to represent the relative risk, assuming that the disease is rare. A statistically significant result was defined as P

4 656 Levinson et al. IOVS, February 2003, Vol. 44, No. 2 TABLE 4. Class II Haplotypes of 18 Patients with TINU Syndrome Patient Haplotype 1 Haplotype 2 1 DQA1*0101-DQB1*0501-DRB1*0102 DQA1*0201-DQB1*0202-DRB1* DQA1*0101-DQB1*0501-DRB1*0102 DQA1*0501-DQB1*0201-DRB1* DQA1*0101-DQB1*0501-DRB1*0102 DQA1*0101-DQB1*0501-DRB1* DQA1*0101-DQB1*0501-DRB1*0102 DQA1*0501-DQB1*0201-DRB1* DQA1*0101-DQB1*0501-DRB1*0102 DQA1*0503-DQB1*0301-DRB1* DQA1*0101-DQB1*0501-DRB1*0103 DQA1*0201-DQB1*0202-DRB1*07 7 DQA1*0101-DQB1*0501-DRB1*0102 DQA1*0102-DQB1*0604-DRB1*13 8 DQA1*0101-DQB1*0501-DRB1*0102 DQA1*0201-DQB1*0202-DRB1* DQA1*0101-DQB1*0501-DRB1*0102 DQA1*0301-DQB1*0301-DRB1*04 10 DQA1*0101-DQB1*0501-DRB1*0102 DQA1*0505-DQB1*0201-DRB1* DQA1*0101-DQB1*0501-DRB1*0101 DQA1*0501-DQB1*0202-DRB1* DQA1*0101-DQB1*0605-DRB1*0102 DQA1*0303-DQB1*0303-DRB1* DQA1*0102-DQB1*06-DRB1*15 DQA1*0301-DQB1*0302-DRB1* DQA1*0101-DQB1*0501-DRB1*0102 DQA1*0101-DQB1*0501-DRB1* DQA1*0104-DQB1*0503-DRB1*1401 DQA1*0104-DQB1*0503-DRB1* DQA1*0103-DQB1*0603-DRB1*1301 DQA1*0501-DQB1*0201-DRB1* DQA1*0101-DQB1*0501-DRB1*0102 DQA1*0601-DQB1*0301-DRB1* DQA1*0301-DQB1*0302-DRB1*04 DQA1*0505-DQB1*0201-DRB1*03 patients classified as having definite TINU and was also found in the single African-American patient. The frequency of this haplotype in the control population is not available, and therefore the relative risk could not be calculated. DISCUSSION We found the prevalence of HLA-DQA1*01, -DQB1*05, -DRB1*01, and -B14 in our patients with TINU syndrome to be significantly elevated when compared with published HLA phenotype frequencies for North American whites. The HLA- DQA1*01/DQB1*05/DRB1*01 haplotype was found in 13 of 18 individuals with TINU syndrome. These genes are in linkage disequilibrium, however, making an assessment of the contribution of the individual alleles, or any combination of alleles, difficult. It is intriguing that all 13 of our patients classified as having definite TINU syndrome had HLA-DQA*01, and 11 had HLA- DQA1*01/DQB1*05/DRB1*01. All our patients met diagnostic criteria for TINU syndrome, however, and because this was a retrospective study, the classification of an individual as having probable, possible, or definite TINU syndrome may reflect the data available rather than true differences in the disease between patients. The DQ molecules encoded by HLA-DQA1*01 and HLA- DQB1*05 alleles appear to be particularly important in TINU syndrome. The presence of HLA-DQA1*01 in all but one patient in our series is remarkable. The one patient (patient 18) who did not have DQA1*01 was atypical in that he was an older man classified as having possible TINU, and who may have had mild chronic renal insufficiency, which is uncommon in TINU syndrome. 1 Previous reports of HLA phenotypes in patients with TINU syndrome also suggest that it is associated primarily with the HLA-DQ alleles we found in our patients HLA-DQ5 is a subtype of HLA-DQ1, as determined by serologic techniques, and HLA-DQ1 or HLA-DQ5 was found in seven of nine individuals with TINU syndrome for whom HLA-DQ testing was reported. 5,6,10,11 Furthermore, HLA-DQ5 is strongly linked to HLA-DR1 and DR10 and weakly to DR12, DR14(6), and DR2. 18 HLA-DR types that are linked to HLA-DQ5 were found in 8 of 12 patients for whom HLA-DR, but not HLA-DQ, phenotypes were examined in previous reports. 4,7 9,12 14 In a recent report from Spain of three patients with TINU syndrome, two were found to have the HLA-DR14(6) phenotype, but all three had the HLA-DQ5 phenotype. 6 Only patient 15 in the present study had HLA-DRB1*14. This individual also had HLA-DQA1*01 and -DQB1*05. HLA-DRB1*01 alleles may also play a role in the pathogenesis of TINU syndrome. Patient 10 had HLA-DRB1*0102 and -DQB1*06 rather than -DQB1*05. Perhaps more important, linkage disequilibrium between HLA-DRB1*01 and -DQB1*05 would not explain the high frequency of HLA-DRB1*0102 in our patients, with a relative risk of On the other hand, the relative risk for HLA-DRB1*0102 in our patients was based on calculations using the low incidence of this allele in the published control population. Determination of the frequencies of specific class II alleles using PCR techniques is an evolving field, and the HLA-DRB1*0102 allele may be more common than previously appreciated. 19 When evaluating class II major histocompatibility complex (MHC) haplotypes in disease pathogenesis, it is important to consider that the MHC on chromosome 6 contains an abundance of genes that encode products critical to the immune response. For example, HLA-B51 may be linked to other susceptibility genes on chromosome 6 in patients with Behçet disease. 20 Few of these genes are highly polymorphic, and the strong association of the specific HLA alleles with TINU syndrome that we have found argues against the likelihood of other, non-hla linked genes being more important in the pathogenesis of TINU syndrome. It is possible, however, that the HLA-DQA1/DQB5/DR1 haplotype is in linkage disequilibrium with genes on chromosome 6 that may be related to disease pathogenesis. HLA-B14 was also found to be associated with TINU syndrome in our patients, but this gene is in linkage disequilibrium with HLA-DR1, and most likely is not independently associated with TINU syndrome. The HLA-DQB1*06 phenotype was found less often in patients with TINU than in control subjects, but the difference did not reach statistical significance. The data do not allow us to reach any conclusions about possible failure of protection by HLA alleles. There were significant differences between our patients and patients in the literature in demographics and disease characteristics (Table 1). 1 Whether our patients represent a unique subset of patients or whether the differences reflect a reporting bias is not clear. Many reports of individuals with TINU syndrome have been limited by short follow-up times. The true frequency of chronic uveitis in TINU syndrome may be higher than previously reported. 1,21 Nonetheless, the recruitment of study participants from the referral practices of

5 IOVS, February 2003, Vol. 44, No. 2 HLA Alleles and TINU Syndrome 657 uveitis specialists may have caused a selection bias that resulted in a subset of patients with chronic uveitis. Although unlikely, it is possible that the association of TINU syndrome with specific HLA alleles found in this report reflects an association with a subpopulation of patients. It would be helpful to know whether the HLA alleles that were associated with TINU syndrome in our study group increase the risk of development of either chronic uveitis or AIN independently, to evaluate more precisely the role of HLA alleles in the pathogenesis of disease presentations. We found no reports examining HLA associations with either idiopathic chronic uveitis without AIN, or AIN without uveitis (PubMed search of the National Library of Medicine database). Other ocular inflammatory diseases characterized by chronic anterior uveitis that have shown class II MHC associations include Vogt-Koyanagi-Harada (VKH) disease and uveitis associated with juvenile rheumatoid arthritis. 25 VKH disease may be of particular relevance, as there is a report of TINU syndrome developing in an individual whose father had VKH disease, 26 and there is an association of HLA-DR1 with VKH disease in some populations. 23 It is possible that genes not shared by the father and son played a role in determining the different clinical manifestations of their putative autoimmune processes. Nevertheless, the immunopathogenesis of disease is likely to be complex. There is a report of monozygotic twins in which one sibling had AIN without uveitis and the other sibling had TINU syndrome, 4 implying that the same genotype in two individuals may result in different disease presentations, perhaps depending on the nature of the environmental triggers. Further studies to examine the relationship of specific HLA alleles and disease phenotypes in individuals with idiopathic chronic anterior uveitis, AIN, and other populations with TINU syndrome may help clarify the role of HLA molecules. In conclusion, HLA-DQA1*01, -DQB1*05, and -DRB1*01 are strongly associated with TINU syndrome. It is likely that the HLA-DQA1*01/DQB1*05 heterodimer is particularly important, but the HLA-DRB1*01 allele or other genes in linkage disequilibrium with the DQA1*01/DQB1*05/DRB1*01 haplotype may contribute to the risk of development of the disease as well. A better understanding of the role of HLA molecules in TINU syndrome may give insight into the immunopathogenesis of uveitis and AIN, as well as other forms of autoimmunity, leading to the design of preventative strategies and safer novel therapies. Acknowledgments The authors thank David W. Gjertson, PhD (Immunogenetics Center, UCLA School of Medicine) for performing the statistical analyses; Joyce Yuge, BS, MT (Immunogenetics Center, UCLA School of Medicine) for coordinating laboratory specimen testing; Trudy Doyle, BS (Casey Eye Institute, Oregon Health and Science University), Yen Tran, BA (Ocular Inflammatory Disease Center, Jules Stein Eye Institute, UCLA School of Medicine), and Cindy Vredeveld, BA (Massachusetts Eye and Ear Infirmary, Harvard Medical School), for coordinating data management at the study sites. References 1. Mandeville JTH, Levinson RD, Holland GN. The tubulointerstitial nephritis and uveitis syndrome. Surv Ophthalmol. 2001;46: Rosenbaum JT. Bilateral anterior uveitis and interstitial nephritis. Am J Ophthalmol. 1988;105: Wakaki H, Sakamoto H, Awazu M. Tubulointerstitial nephritis and uveitis syndrome with autoantibody directed to renal tubular cells. Pediatrics. 2001;107: Gianviti A, Greco M, Barsotti P, Rizzoni G. Acute tubulointerstitial nephritis occurring with 1-year lapse in identical twins. Pediatr Nephrol. 1994;8: Gafter U, Kalechman Y, Zevin D, et al. Tubulointerstitial nephritis and uveitis: association with suppressed cellular immunity. Nephrol Dial Transplant. 1993;8: Gorrono-Echebarria MB, Calvo-Arrabal MA, Albarran F, Alvarez- Mon M. The tuberculointerstitial nephritis and uveitis (TINU) syndrome is associated with HLA-DR14 in Spanish patients. Br J Ophthalmol. 2001;85: Hirano K, Tomino Y, Mikami H, et al. A case of acute tubulointerstitial nephritis and uveitis syndrome with a dramatic response to corticosteroid therapy. Am J Nephrol. 1989;9: Iitsuka T, Yamaguchi N, Kobayashi M, et al. HLA tissue types in patients with acute tubulointerstitial nephritis accompanying uveitis [in Japanese]. Nippon Jinzo Gakkai Shi. 1993;35: Ljutiac D, Glavina M. Tubulointerstitial nephritis with uveitis syndrome following varicella zoster reactivation. Nephron. 1995;71: Morino M, Inami K, Kobayashi T, et al. Acute tubulointerstitial nephritis in two siblings and concomitant uveitis in one. Acta Paediatr Jpn. 1991;33: Paul E, Van Why S, Carpenter TO. Hyperthyroidism: a novel feature of the tubulointerstitial nephritis and uveitis syndrome. Pediatrics. 1999;104: Sanchez Roman J, Gonzalez Reina I, Castillo Palma MJ, Rocha Castilla JL. Posterior uveitis associated with acute tubulointerstitial nephritis with favorable response to cyclosporine: pathogenic implications. Med Clin (Barc). 1995;104: Takemura T, Okada M, Hino S, et al. Course and outcome of tubulointerstitial nephritis and uveitis syndrome. Am J Kidney Dis. 1999;34: Tanaka H, Waga S, Nakahata T, et al. Tubulointerstitial nephritis and uveitis syndrome in two siblings. Tohoku J Exp Med. 2001; 194: Erlich H, Bugawan T, Begovich AB, et al. HLA-DR, DQ and DP typing using PCR amplification and immobilized probes. Eur J Immunogenet. 1991;18: Gjertson DW, Terasaki PI. HLA. Lenexa, KS: American Society for Histocompatibility and Immunogenetics; Department of Pathology, Immunogenetics Center: International Cell Exchange Monthly Report Since Los Angeles: UCLA; Antigen society report #27 (DQ1). Immunobiology of HLA. In: Dupong BO, ed. Histocompatibility Testing. Vol. 1. Springer- Verlag; 1987: Collins MM, Tang T, Slack R, et al. The relative frequencies of HLA-DRB1*01 alleles in the major US populations. Tissue Antigens. 2000;55: Gul A, Hajeer AH, Worthington J, et al. Linkage mapping of a novel susceptibility locus for Behcet s disease to chromosome 6p Arthritis Rheum. 2001;44: Levinson RD, Mandeville JTH, Holland GN, Rosenbaum JT. Tubulointerstitial nephritis and uveitis syndrome: recognizing the importance of an uncommon disease. Am J Ophthalmol. 2000;129: Islam SM, Numaga J, Fujino Y, et al. HLA class II genes in Vogt- Koyanagi-Harada disease. Invest Ophthalmol Vis Sci. 1994;35: Weisz JM, Holland GN, Roer LN, et al. Association between Vogt- Koyanagi-Harada syndrome and HLA-DR1 and -DR4 in Hispanic patients living in southern CA. Ophthalmology. 1995;102: Kim MH, Seong MC, Kwak NH, et al. Association of HLA with Vogt-Koyanagi-Harada syndrome in Koreans. Am J Ophthalmol. 2000;129: Giannini EH, Malagon CN, Van Kerckhove C, et al. Longitudinal analysis of HLA associated risks for iridocyclitis in juvenile rheumatoid arthritis. J Rheumatol. 1991;18: Zaoutis LB, Rose CD, McKay CP. Intrafamilial occurrence of tubulointerstitial nephritis with uveitis and Vogt-Koyanagi-Harada syndrome. J Rheumatol 1999;26: