Anti-LGI1 encephalitis is strongly associated with HLA-DR7 and HLA-DRB4.

Leucine-rich glioma-inactivated1 (LGI1) encephalitis is an antibody-associated inflammation of the limbic area. An autoimmune etiology is suspected but not yet proven. We performed human leukocyte antigen (HLA) analysis in 25 nontumor anti-LGI1 patients and discovered a remarkably strong HLA association. HLA-DR7 was present in 88% compared to 19.6% in healthy controls (p = 4.1 × 10-11 ). HLA-DRB4 was present in all patients and in 46.5% controls (p = 1.19 × 10-7 ). These findings support the autoimmune hypothesis. An exploratory analysis was performed in a small group of 4 tumor-LGI1 patients. The strong HLA association seems not applicable in these patients. Therefore, the absence of HLA-DR7 or HLA-DRB4 could raise tumor suspicion in anti-LGI1 patients. Ann Neurol 2017;81:193-198.

Isolation of human CD4/CD8 double-positive, graft-versus-host disease-protective, minor histocompatibility antigen-specific regulatory T cells and of a novel HLA-DR7-restricted HY-specific CD4 clone.

Minor histocompatibility (H) Ags are classically described as self-peptides derived from intracellular proteins that are expressed at the cell surface by MHC class I and class II molecules and that induce T cell alloresponses. We have isolated three different T cell populations from a skin biopsy of a patient suffering from acute graft-versus-host disease following sex-mismatched HLA-identical bone marrow transplantation. The first population was: 1) CD4(+)/CD8(+) double-positive; 2) specific for an HLA class I-restricted autosomal Ag; 3) expressed a Tr1 profile with high levels of IL-10, but low IL-2 and IFN-γ; and 4) exerted regulatory function in the presence of recipient APCs. The second was CD8 positive, specific for an HLA class I-restricted autosomally encoded minor H Ag, but was only weakly cytotoxic. The third was CD4 single positive, specific for an HLA-DR7-restricted HY epitope and exerted both proliferative and cytotoxic functions. Identification of the peptide recognized by these latter cells revealed a new human HY epitope, TGKIINFIKFDTGNL, encoded by RPS4Y and restricted by HLA-DR7. In this paper, we show human CD4/CD8 double-positive, acute graft-versus-host disease-protective, minor H Ag-specific regulatory T cells and identify a novel HLA-DR7/ HY T cell epitope, encoded by RPS4Y, a potential new therapeutic target.

Paediatric celiac patients carrying the HLA-DR7-DQ2 and HLA-DR3-DQ2 haplotypes display small clinical differences.

AIM: The aim of this study was to determine the relevance of HLA-DR7-DQ2 typing in a prospective cohort of paediatric coeliac disease patients from Southern Europe. METHODS: This cross-sectional study tested 249 paediatric patients with coeliac disease. HLA-DR3-DQ2 was typed in combination with HLA-DR7-DQ2 to screen for the HLA-DQ2 haplotype. The histological, analytical and clinical characteristics of the subjects were recorded. RESULTS: A total of 91 coeliac patients were diagnosed: 96.7% carried HLA-DQ2 and 4.4% carried HLA-DQ8. In percentage terms, 80.2% of patients carried HLA-DR3-DQ2 and 34.1% carried HLA-DR7-DQ2. We did not find significant differences between HLA-DR7-DQ2 and HLA-DR3-DQ2 paediatric patients with respect to histological damage and clinical characteristics, except for irritability and weight loss. These characteristics were more frequent in HLA-DQ2trans than in HLA-DQ2cis (22.2% vs. 0.0% [p = 0.035] and 55.6% vs. 21.4% [p = 0.017], respectively). Coeliac-specific autoantibody levels were higher in HLA-DQ2cis than one half of HLA-DQ2trans patients (105.5 vs. 19.2 U/mL, p = 0.014). CONCLUSION: Small clinical differences were found between paediatric coeliac patients carrying HLA-DR7-DQ2 and HLA-DR3-DQ2. For a correct screening of HLA-DQ2, at least in our geographical population, the HLA-DR7-DQ2 haplotype should be typed due to its frequency and clinical presentation.

Individual genetic variations directly effect polarization of cytokine responses to superantigens associated with streptococcal sepsis: implications for customized patient care.

Host immunogenetic variations strongly influence the severity of group A streptococcus sepsis by modulating responses to streptococcal superantigens (Strep-SAgs). Although HLA-II-DR15/DQ6 alleles strongly protect against severe sepsis, HLA-II-DR14/DR7/DQ5 alleles significantly increase the risk for toxic shock syndrome. We found that, regardless of individual variations in TCR-Vß repertoires, the presentation of Strep-SAgs by the protective HLA-II-DR15/DQ6 alleles significantly attenuated proliferative responses to Strep-SAgs, whereas their presentation by the high-risk alleles augmented it. Importantly, HLA-II variations differentially polarized cytokine responses to Strep-SAgs: the presentation of Strep-SAgs by HLA-II-DR15/DQ6 alleles elicited significantly higher ratios of anti-inflammatory cytokines (e.g., IL-10) to proinflammatory cytokines (e.g., IFN-γ) than did their presentation by the high-risk HLA-II alleles. Adding exogenous rIL-10 significantly attenuated responses to Strep-SAgs presented by the high-risk HLA-II alleles but did not completely block the response; instead, it reduced it to a level comparable to that seen when these superantigens were presented by the protective HLA-II alleles. Furthermore, adding neutralizing anti-IL-10 Abs augmented Strep-SAg responses in the presence of protective HLA-II alleles to the same level as (but no higher than) that seen when the superantigens were presented by the high-risk alleles. Our findings provide a molecular basis for the role of HLA-II allelic variations in modulating streptococcal sepsis outcomes and suggest the presence of an internal control mechanism that maintains superantigen responses within a defined range, which helps to eradicate the infection while attenuating pathological inflammatory responses that can inflict more harm than the infection itself.

HLA-DR and HLA-DP restricted epitopes from human cytomegalovirus glycoprotein B recognized by CD4+ T-cell clones from chronically infected individuals.

PURPOSE: Helper CD4(+) T cells presumably play a major role in controlling cytomegalovirus (CMV) by providing help to specific B and CD8(+) cytotoxic T cells, as well as through cytotoxicity-mediated mechanisms. Since CMV glycoprotein B (gB) is a major candidate for a subunit vaccine against CMV, we searched for gB-epitopes presented by human leukocyte antigen (HLA)-class II molecules. METHODS: Dendritic cells obtained from CMV-seropositive donors were loaded with a recombinant gB and co-cultured with autologous CD4(+) T cells. Microcultures that specifically recognized gB were cloned by limiting dilution using autologous Epstein-Barr virus (EBV)-immortalized B cells pulsed with gB as antigen-presenting cells. To pinpoint precisely the region encoding the natural epitope recognized by a given CD4(+) clone, we assessed the recognition of recombinant Escherichia coli expressing gB-overlapping polypeptides after their processing by autologous EBV-B cells. RESULTS: We isolated several gB-specific CD4(+) T-cell clones directed against peptides gB(190-204), gB(396-410), gB(22-36) and gB(598-617) presented by HLA-DR7, HLA-DP10 and HLA-DP2. While their precise role in controlling CMV infection remains to be established, gB-specific CD4(+) T cells are likely to act by directly targeting infected HLA-class II cells in vivo, as suggested by their recognition of EBV-B cells infected by the Towne CMV strain. CONCLUSIONS: The characterization of such gB-epitopes presented by HLA-class II should help to understand the contribution of CD4(+) T-cell responses to CMV and may be of importance both in designing a vaccine against CMV infection and in immunomonitoring of subjects immunized with recombinant gB or with vectors encoding gB.

Race-specific type 1 diabetes risk of HLA-DR7 haplotypes.

The aim of this study was to test the hypothesis that closely related human leukocyte antigen (HLA) haplotypes containing the DRB1*07:01 gene ['DR7' (DRB1*07:01-DQA1*02:01-DQB1*02:01g or DRB1*07:01-DQA1*03:01-DQB1*02:01g) haplotypes] derived from European and African populations differ in their genetic susceptibility for type 1 diabetes (T1D) depending on the DQ-α molecule present. A combined total of 98 African American T1D patients from the Type 1 Diabetes Genetics Consortium and from Children's Hospital and Research Center Oakland were genotyped for the HLA class II loci DRB1, DQA1, and DQB1. DNA samples extracted from newborn blood spot cards from African Americans born in California (n = 947) were used as a population-based control group. Among African American cases, the European-derived DRB1*07:01-DQA1*02:01-DQB1*02:01g haplotype was protective for T1D risk (odds ratio (OR) = 0.34; 95% confidence interval (CI) 0.14-0.78; P < 0.011), but the African-derived DRB1*07:01-DQA1*03:01-DQB1*02:01g haplotype increased T1D risk (OR = 3.96; 95% CI 1.94-8.08; P < 5.5E-05). The effect of DRB1*07:01-DQB1*02:01g on T1D susceptibility depends on the DQA1 allele. DRB1*07:01-DQA1*02:01-DQB1*02:01g is protective for T1D; however, the presence of DQA1*03:01 on the DRB1*07:01-DQB1*02:01g haplotype not only renders the DR7 haplotype not protective but also creates a haplotype with significant T1D risk. These data underscore the importance of assessing genetic effects within ethnic context.

Does HLA-DR7 differentiate the overlap syndrome of auto-immune hepatitis-primary biliary cirrhosis (AIH-PBC) from those with auto-immune hepatitis type 1?

INTRODUCTION: Autoimmune hepatitis (AIH) and overlap-syndrome (OS) are autoimmune liver diseases of unknown etiology. Although HLA-DR3/DR4 plays a susceptibility role in AIH but there is limited information in regard to OS. OBJECTIVE: Determine the genetic expression of HLA-DR among patients with AIH versus OS in order to establish susceptibility alleles in comparison to healthy controls (HC). METHODS: 26 patients with AIH and 15 patients with OS were studied. Ninety-nine healthy historical controls without autoimmunity were evaluated. Patients with AIH and OS were selected based on the international group for the study of AIH criteria and the Chazouilleres criteria for OS. Patients had at least one liver biopsy. Characterization of HLA-DR was extracted from peripheral blood leukocytes. Alleles were obtained for AIH, OS and HC and comparisons were made between groups. RESULTS: There was a significant increase in HLADR3 and DR1 in AIH compared with the HC group (p = 0.04, OR 2.6, 0.87-7.9, 95% CI). In the AIH group there was a decreased frequency in allele HLA-DR8 when compared with HC (p = 0.04, OR 3.2). There were no statistical differences between the genetic frequencies in the OS group compared with HC. However, HLA-DR7 was able to distinguish between OS patients from those with AIH (p = 0.02, OR 9.8, 1.02-233.6, 95% CI). CONCLUSIONS: HLA-DR1/DR3 is increased in AIH, but contrary to data reported in AIH, HLA-DR7 frequency is increased in OS, suggesting increased susceptibility which distinguishes patients with AIH from those with OS.

The role of polymorphic HLA-DR beta chain residues in presentation of viral antigens to T cells.

The relative importance of 11 polymorphic positions in the HLA-DR7 beta 1 chain in T cell recognition of foreign antigens was investigated using transfectants expressing mutant DR7 beta 1 chains as APC for five rabies virus-specific T cell clones. The results indicate that multiple amino acids, located in both the beta-strands and alpha-helix of DR7 beta 1 in the model of a class II molecule, are involved in DR7-restricted T cell recognition of these antigens. Many of the substitutions appeared to reduce the affinity of an antigenic peptide for the mutant DR7 molecules but did not prevent binding. The heterogeneity of responses of the three G-specific T cell clones to presentation of the G11.3 peptide by several of the mutant DR7 molecules indicates that the T cell receptor (TCR) of each these clones requires a different view of the G11.3/DR7 complex and raises the possibility that the G11.3 peptide may bind to the DR7 molecule in more than one conformation.

MHC Class II alleles in ulcerative colitis-associated colorectal cancer.

OBJECTIVES: Patients with ulcerative colitis are at risk for colorectal cancer (CRC). Although prior studies have shown a link between HLA genotypes and ulcerative colitis (UC) susceptibility, none have investigated HLA genotypes and UC-CRC. We therefore investigated HLA-DR/DQ alleles in UC-CRC cases and UC-controls. Furthermore, since methylation of the Class II transactivator (CIITA) gene may silence HLA expression in tumours, we correlated HLA allele frequencies with CIITA gene methylation and HLA-DR expression. METHODS: Cases and controls were matched for duration/extent of ulcerative colitis, age, ethnicity and gender, but not for primary sclerosing cholangitis (PSC). DNA was extracted from archived tissue blocks from 114 UC-CRC cases and 114 UC-controls. HLA-DR/DQ genotyping was performed using sequence-specific-oligonucleotide polymerase chain reaction (SSO-PCR). CIITA methylation was determined using methylation-specific PCR. HLA-DR immunohistochemistry was done following standard protocols. RESULTS: UC-CRC cases were more likely than UC-controls to carry the DR17 or DR13 alleles (p<0.0001 or p = 0.02, respectively). Although CIITA methylation did not vary significantly between cases and controls, DR17 and DQ2 were associated with CIITA methylation (p = 0.04 and 0.02, respectively). UC-controls more frequently carried the DR7, DR1 or DQ5 alleles (p = 0.002, 0.05 or 0.01, respectively). After adjusting for PSC, DR17 remained significantly associated with an increased risk for UC-CRC while DR7 and DQ5 remained protective. CONCLUSIONS: We report a significant association between specific HLA alleles and either the risk for (DR17) or protection from (DR7, DQ5) UC-CRC. This suggests a possible genetic predisposition for increased UC-CRC risk. In addition, DQ2 and DR17 were associated with CIITA methylation.

Immune predispositions for cytomegalovirus retinitis in AIDS. The HNRC Group.

CMV retinitis develops in approximately 28-35% of all AIDS patients at later stages of disease, often leading to blindness. To determine whether the subset of AIDS patients who developed CMV retinitis (CMV-R) were immunologically predisposed, T cell proliferation responses to CMV were examined prospectively in an HIV infected, HLA typed, longitudinal study population. Individuals who developed CMV-R had significantly lower T cell proliferation responses to CMV, both early and late in disease, compared to CD4 matched controls who have not developed CMV-R. Since HLA proteins influence T-cell recognition, phenotypes of 21 CMV-R patients were examined to determine whether certain HLA alleles were associated with low immune response and predisposed AIDS patients to CMV-R. HLA DR7 and B44 were at increased (nearly twice the expected) frequency in those with CMV-R. The combined association of either B44, 51 or DR7 with CMV-R was highly significant (P = .008, relative risk of CMV-R = 15) with correction for multiple comparisons. Low immune responses were twice as frequent in those with (61%) compared to those without (30%) predisposing alleles. Thus, AIDS patients with immunogenetically related hyporesponsiveness to CMV antigens may be at increased risk of retinitis.

Association of fatal aneurysmal subarachnoid hemorrhage with human leukocyte antigens in the Finnish population.

Human leukocyte antigens (HLA) have been reported to associate with the risk of aneurysmal subarachnoid hemorrhage (SAH) and poor outcome after SAH. Our aim was to identify HLA antigens that associate with the risk of fatal SAH in the Finnish population. Medical records of 600 cadaveric organ donors were reviewed to find organ donors that succumbed to SAH (n = 232) or brain trauma (n = 151). HLA antigen frequencies in these groups were compared with HLA frequencies in a reference population of 10,000 bone marrow donors. Chi-Square test with Bonferroni correction and multiplicative logistic regression models were used and false positive result probabilities (FPRP) were calculated. Alpha-level was 0.01. HLA-A3 associated with fatal SAH (p = 0.0014, OR 1.3 and 95%CI 1.1-1.6) and HLA-DR7 inversely associated with fatal SAH (p = 0.0040, OR 0.3 and 95%CI 0.2-0.6). HLA-A3 but not HLA-DR7 showed also a positive trend in donors with brain trauma. FPRP was below 0.5 for HLA-A3, but clearly above 0.5 for HLA-DR7. HLA-A3 seems to associate with fatal SAH in the Finnish population. Further studies are needed to reveal the pathobiologic mechanisms for how HLA-A3 associates with the risk of fatal SAH in Finns.

HLA-DR7 and HLA-DQ2: Transgenic mouse strains tested as a model system for ximelagatran hepatotoxicity.

The oral thrombin inhibitor ximelagatran was withdrawn in the late clinical trial phase because it adversely affected the liver. In approximately 8% of treated patients, drug-induced liver injury (DILI) was expressed as transient alanine transaminase (ALT) elevations. No evidence of DILI had been revealed in the pre-clinical in vivo studies. A whole genome scan study performed on the clinical study material identified a strong genetic association between the major histocompatibility complex alleles for human leucocyte antigens (HLA) (HLA-DR7 and HLA-DQ2) and elevated ALT levels in treated patients. An immune-mediated pathogenesis was suggested. Here, we evaluated whether HLA transgenic mice models could be used to investigate whether the expression of relevant HLA molecules was enough to reproduce the DILI effects in humans. In silico modelling performed in this study revealed association of both ximelagatran (pro-drug) and melagatran (active drug) to the antigen-presenting groove of the homology modelled HLA-DR7 molecule suggesting "altered repertoire" as a key initiating event driving development of DILI in humans. Transgenic mouse strains (tgms) expressing HLA of serotype HLA-DR7 (HLA-DRB1*0701, -DRA*0102), and HLA-DQ2 (HLA-DQB1*0202,-DQA1*0201) were created. These two lines were crossed with a human (h)CD4 transgenic line, generating the two tgms DR7xhCD4 and DQ2xhCD4. To investigate whether the DILI effects observed in humans could be reproduced in tgms, the mice were treated for 28 days with ximelagatran. Results revealed no signs of DILI when biomarkers for liver toxicity were measured and histopathology was evaluated. In the ximelagatran case, presence of relevant HLA-expression in a pre-clinical model did not fulfil the prerequisite for reproducing DILI observed in patients. Nonetheless, for the first time an HLA-transgenic mouse model has been investigated for use in HLA-associated DILI induced by a low molecular weight compound. This study shows that mimicking of genetic susceptibility, expressed as DILI-associated HLA-types in mice, is not sufficient for reproducing the complex pathogenesis leading to DILI in man.

Identification of helper T-cell epitopes that encompass or lie proximal to cytotoxic T-cell epitopes in the gp100 melanoma tumor antigen.

The melanocyte-associated antigen gp100 constitutes one of the most attractive targets for T-cell-based immunotherapy against malignant melanoma. Although several MHC class I-restricted epitopes have been identified for CTLs, thus far, only one MHC class II T helper epitope (restricted by HLA-DR4) has been described in the literature. Using an algorithm to identify promiscuous helper T-cell epitopes, here we describe three additional MHC class II-restricted epitopes from gp100. Whereas one T helper epitope, gp100(175-189), was restricted by the HLA-DR53 and DQw6 alleles, the T-cell responses to two other epitopes, gp100(74-89) and gp100(576-590), were restricted by HLA-DR7. Most interestingly, the newly identified helper T lymphocyte epitopes encompass or lie proximal to previously described CTL epitopes for this tumor-associated antigen. Together with the previously described HLA-DR4-restricted epitope, these T helper epitopes offer coverage for the majority of the human population. Moreover, the use of peptide vaccines containing both CTLs and T helper epitopes could offer therapeutic advantages over current approaches that focus solely on eliciting antitumor CTL responses.

Human leukocyte antigens as psoriasis inheritance and susceptibility markers.

Psoriasis is a multifactoral and heterogenetically inherited disease. The role of hereditary transmission is supported by familial association, twin studies, and correlation with human leukocyte antigens (HLA). Numerous studies have proved that B13, B17, Cw6, and DR7 antigens are positively associated with psoriasis. Cw6 antigen has been repeatedly indicated to be the most significant marker for the risk prediction of the disease. On the basis of epidemiological studies and HLA analysis, a concept of two distinct disease patterns of psoriasis vulgaris was proposed. In type I psoriasis the disease has an early onset, strong correlation with Cw6, B13, B17, and DR7 antigens, and familiar inheritance. Type II psoriasis has a late onset, weak correlation with HLA antigens, and sporadic familiar occurrence. Both types seem to differ clinically. Moreover, some extended haplotypes were shown to be correlated with the disease, especially with the type I psoriasis. Although a psoriasis susceptibility gene(s) has not been yet identified, a number of candidate genes were studied, with evidence for a major locus located within the major histocompatibility complex (PSORS 1). Cw6 allele is the most extensively investigated candidate gene, but present evidence suggests that it is rather in strong linkage disequilibrium with the PSORS 1 gene than the susceptibility allele itself. This article reviews past and current data on the genetic background of psoriasis with special attention to its correlation with HLA antigens.

Polymorphism of three HLA-DR7 bearing major histocompatibility complex extended haplotypes.

We have studied the complexity of HLA class II region in DR7 bearing extended haplotypes by restriction fragment length polymorphism (RFLP). Genomic DNA from homozygous cell lines and from unrelated individuals was digested with a number of restriction endonucleases and probed with DR alpha, DR beta, DQ alpha and DQ beta cDNA probes. We detected RFLPs that distinguished subspecificities of DRA, DRB1, DQA1 and DQB1 chain genes. On the basis of polymorphism in these genes, three distinct types of DR7 bearing extended haplotypes could be identified: (1) B44 or Bw47 or B14, DR7a (DRA1, B1.1), DRw53a (DRA1,B4), DQw2 (DQA1.1, B1.1); (2) B13 or B40, DR7b (DRA1, B1.2), DRw53a (DRA1, B4), DQw2 (DQA1.1, B1.1); and (3) Bw57, DR7c (DRA2, B1.2), DRw53b (DRA2, B4), DQw9 (DQA1.2, B1.2). Available evidence indicates that independent examples belonging to a haplotype were similar in RFLP patterns, suggesting that most examples of an extended haplotype belonging to a subtype are similar. The results in the present study have important implications for immune function and disease susceptibility.

HLA-DRB4 gene encoded HLA-DR53 specificity segregating with the HLA-DR7, -DQ9 haplotype: unusual association.

HLA phenotyping of a leukemia patient of Caucasoid origin revealed the presence of the serological HLA-DR53 specificity. Comprehensive pedigree analysis demonstrated that the HLA-DR53 specificity segregated with the HLA-DR7, -DQ3 haplotype. High resolution PCR- SSP genotyping of the HLA class II genes revealed the presence of the HLA-DRB4*0101101 allele segregating together with the HLA-DRB1*0701, -DQA1*0201 and DQB1*03032 alleles. This finding is in contrast to known linkages in that thus far, the HLA-DR7, -DQ9 haplotype has only been described in association with the non-expressed HLA-DRB4*0103102N allele. The existence of this "novel" haplotype may be explained by a homologous recombinational event that occurred between the HLA-DR7, -DR53, -DQ2 and the HLA-DR7, -DQ9 haplotypes.

Substitutions in the HLA-DR alpha chain differentially affect DR7-restricted T-cell recognition of rabies virus antigen.

To investigate the functional roles of DR alpha residues in T-cell recognition, 20 mutants of the DR alpha chain were constructed by site-directed mutagenesis. These DR alpha mutants were expressed with WT DR(beta 1*0701) on mouse L cells and used as APC for four DR7-restricted T-cell clones specific for rabies virus antigens. The results indicate that the DR alpha residues are differentially involved in recognition of rabies virus antigen by different T-cell clones. Mutations in the floor of the antigen-binding groove (positions 9, 11, 22, and 24), on the alpha-helix (47, 55, 65, 66, and 72), and surprisingly on the outer loop (15, 18, and 19), abrogated recognition by at least one T-cell clone. Most of these residues appear to be involved in either peptide or TCR contact, based on the DR1 crystal structure. The involvement in T-cell recognition of DR alpha residues located in the outer loop outside the binding groove suggests that these residues may directly contact TCR, or indirectly contribute to the conformation of peptide sitting in the groove.

Restriction fragment length polymorphism of HLA-DRw53 detected in South African blacks and individuals of mixed ancestry.

The HLA-DRw53 specificity has not until now been shown to demonstrate polymorphism. We have studied 33 DRw53 haplotypes, comprising 19 DR4, 10 DR7, and 4 DR9 haplotypes, from 6 homozygous typing cells, 11 families, and 8 random individuals. All the subjects studied were South African blacks or of mixed ancestry (Cape Coloureds), with the exception of four homozygous typing cells from whites. The DNA was digested with TaqI and, after Southern blotting, was hybridized with a full-length DRB cDNA probe. Fragments correlating with DR4 (5.5 kb), DR7 (4.0 kb), and DR9 (4.1 kb) were observed. Two fragments of 14.5 and 2.8 kb correlated with DRw53. In addition, two pairs of fragments demonstrated a diallelic pattern, which is likely to correlate with a polymorphism of the DRB4 (DRw53) gene, since one or other of the two patterns was observed in all cells carrying the DRw53 specificity. The first allelic pattern, called DRw53a, was characterized by the presence of 7.5- and 2.6-kb fragments, while the second pattern, called DRw53b, had 5.8- and 2.7-kb fragments. DRw53a occurred in 10 of the 19 DR4 haplotypes and 7 of the 10 DR7 haplotypes. All three DR9,DQw2 haplotypes were also associated with DRw53a. These findings may have important implications for disease associations and the use of unrelated donors for organ transplantation.