HLA-DR and -DQ genotypes of celiac disease patients serologically typed to be non-DR3 or non-DR5/7.

The susceptibility to develop celiac disease (CD) seems to be primarily associated to a particular HLA-DQ alpha/beta heterodimer encoded by the DQA1*0501 and DQB1*0201 alleles, in cis position on the DR3-DQ2 haplotype or in trans position by DR5-DQ7/DR7-DQ2 heterozygotes. However, exceptional patients exist who are neither DR3 nor DR5/DR7, particularly among Southern European populations. We therefore examined the DRB1, DQA1, and DQB1 alleles of 13 Spanish CD patients who were serologically typed to be neither DR3 nor DR5/DR7. Five patients were found to carry the DQA1*0501 and DQB1*0201 alleles either in cis or in trans position, three of them had previously been serologically mistyped. However, two of these patients carried DQA1*0501 and DQB1*0201 on haplotypes other than DR3 or DR5 in combination with DR7. One of the latter patients carried an unusual DR4-DQ2 haplotype, while another had an unusual DR8-DQ2 haplotype. Four of the remaining eight patients carried DR4-DQ8 haplotypes. Taken together, our findings provide further evidence that the DQ alpha/beta heterodimer encoded by the DQA1*0501 and the DQB1*0201 alleles confers the primary HLA-associated susceptibility to develop CD. However, our studies also corroborate that a second (and "weaker") HLA-associated CD susceptibility gene may be present on some DR4-carrying haplotypes.     

Cis-trans complementation of DQA1-DQB1 genes are modulated by DQ alleles: an immunogenetics analysis of DQ association with the down-regulatory function of CD8 cells in trichosanthin-induced immunosuppression

The initiation of a CD8 cell-mediated pathway (M⁺) was adopted as a phenotypic trait to analyse genetic predisposition in trichosanthin (Tk)-induced immunosuppression. Tk is a natural protein antigen with 247 amino acid residues. Based on DNA typing for DR, DQ, DP and TAP genes, data in this paper indicate that only DQ genes were primarily involved and that the alleles DQA1*0501 and DQB1*0201 were strongly associated with the M⁺ phenotype in cis (on DR3 haplotype) or trans (on DR5/DR7 heterozygotes) complementation. This is consistent with our observation that only the DQ-positive cells were capable of expanding after being co-cultured with Tk for 96h. Two points of interest were noted. (1) The susceptible haplotype DRB1*0301-DQA1*0501-DQB1*0201 showed an association with the M⁺ phenotype only if combined with DRB1*04-, DRB1*08-, or DRB1*09-related haplotypes. When co-presented with DRB1*11-, DRB1*15-, DRB1*07-related haplotypes, however, no cis complementation could be detected. A detailed analysis of the association patterns indicated that the DQB1 locus of the non-susceptible haplotypes was the main factor for up- or down-modulation. (2) For M⁺ phenotype-related trans complementation in Tk-induced suppression, it was found that not only DQA1*0501-DQB1*0201 (DR5/7) alleles, but also associated DQA1*0301-DQB1*0201 (DR4/7, 9/7) alleles, were involved. The allele DQB1*0201 was not associated with the DQA1 alleles in DRB1*01-, DRB1*15-, DRB1*13-, DRB1*07-related haplotypes. The results obtained indicate that there are some additional genetic factors involved in the functional expression of cis and trans complementation of DQA1 and DQB1 genes, among which the DQ alleles play a critical role as self-regulators.     

Molecular characterization of HLA class II genes in celiac disease patients of Latin American caucasian origin

Abstract: In the present study, the polymorphic domain of HLA class II genes present in a pediatric population of Argentinian celiac disease patients was analyzed by hybridization to sequence-specific oligonucleotides and DNA sequencing. Sixteen out of 16 DR5/7 heterozygous patients bore the DQA1*0501 and DQB1*0201 alleles implicated in the DQ2 risk specificity. The second exon of DQA1, DQB1 and DRB1 genes from 2 DR5/7 patients was characterized by DNA sequencing. The following alleles were found in both patients: DRB1*1101 and DRB1*0701; DQB1*0301 and DQB1*0201; DQA1*0501 and DQA1*0201. Previous serological analysis in this population had shown the presence of DQ2 in 95% of the patients (40% in controls) and a negative association with DQ1 haplotypes, suggesting the presence of other "permissive" or neutral alleles. The following HLA-DQB1 alleles, besides DQB1*0201, were identified in 31 CD patients: DQB1*0301, 0302, 0401 and 0402. All these alleles share a common pattern of residues between positions 84 and 90, and distinct from that present in DQ1-related alleles.     

HLA-DQA1 AND DQB 1 ALLELE AND GENOTYPE CONTRIBUTION TO IDDM SUSCEPTIBILITY IN AN ETHNICALLY MIXED POPULATION

HLA-DRB1, DQA1 and DQB1 alleles have been determined in 42 families with one IDDM proband and 64 healthy controls, by oligotyping (PCR-SSO) using primers and probes from the XI International Histocompatibility Workshop. A positive DRB1 *03 and DRB1 *04 association with the disease was observed, whereas DRB 1*11 and DRB 1 *07 showed negative association but 19% of patients carried DRB1 alleles different to DRB 1 *03 or *04. When single alleles were considered, DQA1 *03 showed the strongest association with susceptibility to the disease (RR = 8.2, Pc = 0.00001) but this association was outgrown by 2 and 3 allele combinations, with genotype DRB 1 *04-DQA 1 *03-DQB1*0302/DRB1*03- DQA 1*0501- DQB 1*0201 showing the strongest association (RR = 28, Pc = 0.002). Application of the relative predispositional effect (RPE) method to our data, revealed a further susceptibility risk provided by the DRB1*13-DQA1*0102-DQB 1*0604 haplotype once DR3 and DR4 haplotypes were removed. When DQA1-DQB1 genotypes were analysed for presence of Arg 52 (DQ α) and absence of Asp 57 (DQ β), genotypes SS/SS were found significantly increased in diabetics. Interestingly, one of the strongest associations with the disease was observed with the DQA 1*03-DQB 1*0201 combination encoded mainly by genes in trans (RR = 11.7 Pc = 0.00004). These observations and their comparison with DR-DQ haplotypes in more homogeneous ethnic groups support the stronger influence of the DQ molecule rather than the individual DR or DQ alleles in the susceptibility to IDDM. They also emphasize the need for detailed HLA haplotype studies in non-Caucasian and ethnically mixed populations to gain further insight into the nature of genetic and environmental factors contribution to autoimmunity.     

DQCAR microsatellite polymorphisms in three selected HLA class II-associated diseases

Abstract: DQCAR is a very polymorphic CA repeat microsatellite located between the HLA DQA1 and DQB1 gene. Previous studies have shown that specific DQCAR alleles are in tight linkage disequilibrium with known HLA DR-DQ haplotypes. Of special interest was the fact that haplotypes containing long CA repeat alleles (DQCAR > 111) were generally more polymorphic within and across ethnic groups. In these latter cases, several DQCAR alleles were found even in haplotypes containing the same flanking DQA1 and DQB1 alleles. In this work, three HLA class II associated diseases were studied using the DQCAR microsatellite. The aim of this study was to test if DQCAR typing could distinguish haplotypes with the same DRB1, DQA1 and DQB1 alleles in control and affected individuals. To do so, patients with selected HLA DR-DQ susceptibility haplotypes were compared with HLA DR and DQ matched controls. This included: Norwegian subjects with Celiac disease and the HLA DRB1*0301, DQA1*05011, DQB1*02 haplotype; Japanese subjects with Type 1 (insulin-dependent) Diabetes Mellitus and the HLA DRB1*0405, DQA 1*0302, DQB 1*0401 haplotype; and French patients with corticosensitive Idiopathic Nephrotic Syndrome and the HLA DRB 1*0701, DQA 1*0201, DQB1*0202 haplotype. These specific haplotypes were selected from our earlier work to include one haplotype bearing a short DQCAR allele (celiac disease and DR3, DQ2-DQCAR99) and two haplotypes bearing long DQCAR alleles (Diabetes Mellitus and DR4, DQ4-DQCAR 113 or 115 Idiopathic Nephrotic syndrome and DR7, DQ2-DQCAR 111–121). Additional DQCAR diversity was found in both control and patients bearing haplotypes with long CA repeat alleles. The results indicate that DQCAR typing did not improve specificity in combination with high resolution DNA HLA typing as a marker for these three disorders.     

HLA class II alleles associated with celiac disease susceptibility in a Southern European population

Susceptibility to celiac disease in Northern Europe is associated with the human leukocyte antigens (HLA) B8, DR3 and DQ2, which exist together on an extended haplotype. The strong predominance of this haplotype within the Northern European celiac populations, together with the linkage disequilibrium which occurs between these loci, does not allow identification of the gene(s) primarily associated with disease susceptibility. Studies from Southern Europe using both serology and examination of restriction fragment length polymorphisms (RFLP) have demonstrated associations with DR3, DR7 and DQ2, suggesting that the DQ locus is primarily involved. We investigated 43 celiac patients and 41 healthy controls from Rome, Italy, using sequence-specific oligonucleotide (SSO) probes, in conjunction with gene amplification by the polymerase chain reaction (PCR), to determine alleles at the DRB, DQA1, DQB1 and DPB1 loci: 19% of celiac patients possessed the alleles DRB1*0301 DRB3*0101, 33% DRB1*0301 DRB3*0201 and 33% of celiac patients were heterozygous for DRB1*1101-1201/DRB1*0701. The strongest association with celiac disease susceptibility was the combination of alleles DQA1*0501 DQB1*0201 (91% celiac patients vs. 12% controls; p = 0.000002). There was no additional susceptibility associated with alleles at the DPB locus. This study confirms the hypothesis that susceptibility is associated with a particular combination of DQ alleles and the ethnic variation in DR frequencies is secondary to linkage disequilibrium with these DQ alleles.     

系统性红斑狼疮临床表现与HLA Ⅱ类单倍型关联的研究

目的 探讨系统性红斑狼疮（ＳＬＥ）易感基因致病的模式。方法 利用多聚酶链反应／特异寡核控针杂交（ＰＣＲ／ＳＳＯＰＨ）方法检测１１３例确诊ＳＬＥ病人的ＨＬＡⅡ基因型并进行单倍型分析。结果 ＳＬＦ病人的单倍型具有特定的结构特征,即以２个或３个重型ＳＬＥ相关基因共同组成１个单倍型;反之,２个或３个轻型ＳＬＥ相关基因组成另１个单倍型;重型基因和轻型基因之间很少有强连锁不平衡。ＤＱＡ１＊０３０１－ＤＱＢ１＊     

HLA-DQ1 haplotype ruin the effect of cis complementation of DQA10501-DQB10201 in association with trichosanthin-induced immunosuppression

CD8 cell-mediator (M+) or non-mediator (M−) are distinguishable for healthy subjects according to whether their CD8 T cells keep the down-regulatory function in Trichosanthin (Tk)-induced immunosuppression. Tk is a plant protein of 247 amino acid residues purified from a Chinese medicinal herb. The M+ phenotype has been shown in our previous work to be strongly associated with HLA-DQ2. By genotyping with PCR-based techniques, the essential alleles of the DQ2 were identified as DQA1^*0501 and DQB1^*0201, which were either in cis (DR3) or in trans (DR5, DR7) position. A more detailed examination of the HLA association pattern with M+/M− in 42 Chinese candidates, however, revealed another two points of interest. 1) The cis complementation did not work if another DQA1^*01- or DQA1^*02-related haplotype (e.g. DRB1^*0101-DQA1^*0101-DQB1^*0501) were combined. The later seemed to behave like a ‘negative’ factor superimposed on the ‘positive’ role of DQA1^*0501-DQB1^*0201 haplotype in heterozygous condition. 2) In addition to DQA1^*0501, the DQB1^*0201 was actually able to combine all available DQA1 alleles except DQA1^*01 family to form the trans complementation. Again, the DQ1 haplotype acted negatively. It is thus likely that the cis and trans complementary association of DQA1^*0501-DQB1^*0201 could only be detected conditionally or only appeared as a special case in the Tk-induced immunosuppression.     

Association with HLA DQ of early onset myasthenia gravis in Southeast Texas region of the United States

Forty-four Caucasian American myasthenia gravis (MG) patients from Southeast Texas underwent high resolution HLA DQ analysis. For the majority of patients who were late onset or male, no significant associations with DQ were observed. However, associations with DQ increased in female patients and early onset patients. At the allele level, DQB1 *0503, *0604, *0502 and *0402 collectively contributed to a positive association of the DQ locus with early onset MG (EOMG), while individually failing to show significant association. At DQ level, the novel haplotype DQA1*0401:DQB1*0201 was the primary factor in the association of combined DQ loci with early onset. In addition, *0104:*0503, *0102:*0604, *0102:*0502 and *0303:*0402 collectively contributed to the positive association of the haplotype loci. DR3-DQ2.5cis, a well known risk factor for MG in Western Eurasia, was not found associated with disease in any group. For typical EOMG [early onset, no thymoma, anti-acetylcholine receptor (AChR) antibody (Ab) positive] no association with DQA1 locus was found, however DQB1*0604 demonstrated an 'uncorrected' positive association. A few DQ haplotype (DQA1:DQB1) were positively associated with typical EOMG; a positive individual association for *0401:*0201 was complimented by the contributions of *0102:*0604 and *0303:*0402 haplotypes. A small minority of patients that were atypical and EOMG had a strong genetic association with DQA1*0104:DQB1*0503, the group included an anti-MuSK Ab positive and an anti-AChR negative patient. This report finds common ground with European studies regarding MuSK association; however similarities in association for typical early onset disease resembled HLA risk factors in East Asia and Southern Europe.     

A study of Italian pediatric celiac disease patients confirms that the primary HLA association is to the DQ(alpha 1*0501, beta 1*0201) heterodimer.

Celiac disease (CD) has been recently reported to be primarily associated with the DQ(alpha 1*0501, beta 1*0201) heterodimer encoded in cis on DR3 haplotype and in trans in DR5,7 heterozygous individuals. The high incidence of DR5,7 heterozygotes, reflecting the high frequency of the DR5 allele in Italy, makes the analysis of the Italian CD patients critical. Polymerase chain reaction-amplified DNA from 50 CD patients and 50 controls, serologically typed for DR and DQw antigens, was hybridized with five DQA1-specific oligonucleotide probes detecting DQA1*0101 + 0102 + 0103, DQA1*0201, DQA1*0301 + 0302, DQA1*0401 + 0501 + 0601, and DQA1*0501 and a DQB1-sequence-specific oligonucleotide probe recognizing DQB1*0201 allele. As expected by the DR-DQ disequilibria, DQA1*0201 [62% in patients versus 26% in controls, relative risk (RR) = 5] and DQA1*0501 (96% versus 56%, RR = 19) show positive association with the disease. Of CD patients, 92% (50% DR3 and 42% DR5,7) compared to 18% of the controls carry both DQA1*0501 and DQB1*0201 alleles, so that the combination confers an RR of 52, higher than both the risks of the single alleles (DQA1*0501 RR = 19, DQB1*0201 RR = 30), confirming the primary role of the dimer in determining genetic predisposition to CD both in DR3 and in DR5,7 subjects.     

The prevalence of HPA-1a alloimmunization and the potential risk of FNAIT depend on both the DRB3*01:01 allele and associated DR-DQ haplotypes

Alloimmunization against human platelet antigen (HPA)-1a during pregnancy can cause foetal/neonatal alloimmune thrombocytopenia (FNAIT) and severe bleeding in the foetus or newborn and likely depends on several factors. HPA-1a alloimmunization is associated with DRB3*01:01, which is associated with several DR-DQ haplotypes. However, it is not known to what extent these haplotypes contribute to the prevalence of HPA-1a alloimmunization. HPA-1a–alloimmunized women, identified in a prospective study, and random donors were typed for selected DRB3, DRB4, DRB1, DQA1 and DQB1 alleles to determine allele and DR-DQ haplotype frequencies. DRB3*01:01 was carried by 94% HPA-1a–immunized women compared to 27% in the general population. In the first population, the DR3-DQ2 haplotype was overrepresented (P < .003). The prevalence of HPA-1a alloimmunization was estimated to be about twice as frequent with DR3-DQ2 compared to DR13-DQ6, together accounting for about 90% of DRB3*01:01–positive individuals. Further, we examined DQB1*02 and DRB4*01:01 alleles for their reported association with HPA-1a alloimmunization, in the context of DR-DQ haplotypes. Since ~ 80% of DQB1*02 alleles are linked to the DR3-DQ2 haplotype, the association might be coincidental. However, the DQB1*02:02–associated DR7-DQ2 haplotype was also overrepresented in alloimmunized women, suggesting a role for this allele or haplotype in HPA-1a alloimmunization. As DRB4*01:01 is predominantly associated with the DR7-DQ2 haplotype in HPA-1a–alloimmunized individuals, the reported association with FNAIT may be coincidental. Typing for DR-DQ haplotypes revealed important genetic associations with HPA-1a alloimmunization not evident from typing individual alleles, and the presence of different DRB3-associated DR-DQ haplotypes showed different prevalence of HPA-1a alloimmunization.     

The rare HLA-DQA1*03-DQB1*02 haplotype confers susceptibility to type 1 diabetes in whites and is preferentially associated with early clinical disease onset in male subjects

The heterozygous combination of DQA1*03-DQB1*0302 (DQ8) and DQA1*05-DQB1*0201 (DQ2) confers the highest known HLA-DQ-linked risk for type 1 diabetes, suggesting a role for transcomplementation. The trans-heterodimer encoded by DQA1*03 and DQB1*02 is also rarely observed in cis in whites. Islet antibody-positive diabetic patients (P; n = 2,238) and control subjects (C; n = 2,223) of white descent were genotyped by a HLA-DQA1-DQB1 dot-blot method. The presence of the DQA1*03-DQB1*02 haplotype was observed in 22 patients (1%) versus 6 controls (0.3%) (odds ratio [OR] = 3.7, p = 0.005). It was more prevalent in whites of Northern African descent, but both in European (n = 3,813) and in Northern African whites (n = 648), the DQA1*03-DQB1*02 haplotype tended to be associated with diabetes (respectively, P 0.3% vs. C 0.03%, OR = 12.2, p = 0.005; and P 2.1% vs. C 0.6%, OR = 3.8, p = 0.03). DRB1 typing revealed that DQA1*03-DQB1*02 is usually associated with the DRB1*0405 risk allele in European patients and with DRB1*0405, DRB1*07 and DRB1*09 in Northern African whites. Like in DQ2/DQ8-positive patients, the presence of DQA1*03-DQB1*02 is preferentially associated with younger age at clinical onset than in other genotypes, but unlike in subjects carrying DQ2/DQ8, earlier clinical manifestation was mostly restricted to male subjects, often carrying DR3 and/or DQB1*02 on the other chromosome. These results are compatible with an effect of cis-encoded heterodimers or with previously suggested interactions of X-linked genetic factors with (DR3-)DQB1*02 haplotypes.     

Increasing complexity of HLA-DR2 as detected by serology and oligonucleotide typing.

Serological and oligonucleotide typing was performed on a number of HLA-DR2-positive cells from different ethnic origin, including DR2 haplotypes with various DQ associations. Exons 2 of DRB1 and DRB5 of DR2-positive individuals were locus-specific amplified and hybridized with a number of different oligonucleotides capable of discriminating between the various Dw2, Dw12, Dw21, and Dw22 associated sequences. The linkage of DRB with DQA1 and DQB1 in these haplotypes was analyzed. Among the DR2- positive cells we could define 10 different DR DQ haplotypes by serology and 13 by oligonucleotide typing. The DR2.ES specificity is a serological DRw15 variant which could not be discriminated by oligonucleotide typing from a DRw15 DQw5 haplotype. The DR2.JA variant represents a unique DRB1*1602 DRB5*0101 haplotype. The DR1+2s haplotype consists of a DRB1 DQ region from a Dw1 and a DRB5 gene from a Dw2 haplotype. Its short DR2 serum pattern can be explained by the absence of a DR2 DRB1 gene product. DRB5*0101 sequences were found in association with DRB1*1501, *1502, *1602, and *0101 alleles. Since the DRB5 gene is capable of such different associations it is comparable to the DRB3 and DRB4 genes. This may have implications for the definition of the broad DR2 specificity which is predominantly encoded by the DRB5 gene product. New DR2 haplotypes included the following DQ combinations: DQw2-positive DQA1/B1*0301/0201 and DQw6-positive DQA1/B1*0102/0601 and *0102/0603 haplotypes.     

HLA class II haplotype associations with inflammatory bowel disease in Jewish (Ashkenazi) and non-Jewish caucasian populations

Ulcerative colitis (UC) and Crohn's disease (CD) are the clinical entities comprising idiopathic inflammatory bowel disease (IBD). Previous studies on the association of IBD and human leukocyte antigen (HLA) class II genes suggested a role for HLA in this disease. Here we present HLA class II (DRB1, DQB1, DQA1, DPB1) allele and haplotype distributions determined using the polymerase chain reaction and sequence-specific oligonucleotide probe methods. A total of 578 UC and CD Caucasian patients and controls from Jewish (Ashkenazi) and non-Jewish populations was examined. Our previously reported association of DR1-DQ5 with CD was attributable to DRB1*0103. A dramatic association with IBD and the highly unusual DRB1*0103-DQA1*0501-DQB1*0301 haplotype (OR = 6.6, p = 0.036) was found. The more common DR1 haplotype, DRB1*0103-DQA1*0101-DQB1*0501, was also associated with IBD (OR = 3.1, p = 0.014), a result suggesting that interaction between DR and DQ may determine the extent of disease risk. Our previously reported association of DR2 with UC was attributable to DRB1*1502 (OR = 2.6, p = 0.006). At the DPB1 locus, a significant association of DPB1*0401 with CD was observed for the combined populations (OR = 1.85, p = 0.007). These observations indicate that some class II alleles and haplotypes confer susceptibility to both UC and CD, implying common immunogenetic mechanisms of pathogenesis, while others confer risk to only one of these diseases, and illustrate the value of DNA HLA typing in disease susceptibility analyses.     

Novel HLA-DR2 and -DR3 haplotypes among Norwegian Caucasians

In the Northern European population, all DR2 haplotypes encoded by DRB1*1501 have previously been found to carry the DQA1*0102 and DQB1*0602 alleles, and DR3 haplotypes have been found to carry the DQA1*0501 and DQB1*0201 alleles. Here we report a novel recombinant DR2 haplotype carrying the DRB1*1501, DQA1*0102 and DQB1*0603 alleles as well as a novel recombinant DR3 haplotype carrying the DRB1*0301, DRB3*0101, DQA1*0102 and DQB1*0602 alleles.     

Humanized transgenic mice expressing HLA DR4-DQ3 haplotype: reconstitution of phenotype and HLA-restricted T-cell responses

Many autoimmune conditions have close genetic linkages to particular human histocompatibility leukocyte antigen (HLA) class II genes. With the aim of establishing a murine model of autoimmune disease, we have generated an HLA DR4-DQ3 haplotype transgenic (Tg) mouse that expresses a 440-kb yeast artificial chromosome harbouring DRA, DRB1*040101, DRB4*010301, DQA1*030101, DQB1*0302 and all the internal regulatory segments. This Tg mouse line was crossed to human CD4 (hCD4) Tg mice and endogenous class II knockout mice (I-A(o/o) and I-E(o/o)) lines to generate a DR4-DQ3.hCD4.IAE(o/o) Tg line. The Tg DR and DQ molecules are expressed on the physiological cell types in these animals, i.e. on most B cells (>85%), dendritic cells (DCs) and macrophages but not on T cells, with levels of expression comparable with those of human B cells (where DR > DQ expression). The DR4/DQ3 transgenes fully reconstituted the CD4 T-cell compartment, in both the thymus and the periphery, and the analysis of the T-cell receptor repertoire in the Tg mice confirmed that these class II molecules were able to mediate thymic selection of a broad range of Vbeta families. HLA DR4- and DQ3-restricted T-cell responses were elicited following immunization with known T-cell determinants presented by these molecules. Furthermore, the DR4-DQ3-restricted CD4(+) T cells conferred protective antibody-mediated immunity against an otherwise lethal infection with Salmonella enterica var. typhimurium. These new DR4-DQ3 Tg mice should prove to be valuable tools for dissecting the importance of this class II haplotype in autoimmune disorders like rheumatoid arthritis.     

HLA—DR,DQ基因多态性与系统性红斑狼疮相关性的研究

应用聚合酶链反应结合顺序特异的寡核苷酸探针杂交（ＰＣＲ／ＳＳＯＰＨ）方法对江苏籍汉族ＳＬＥ患者和健康对照组ＨＬＡ－ＤＲＢ１、ＤＱＡ１：ＤＱＢ１基因作寡核苷酸分型。结果发现患者组中ＤＲＢ１＊１５０１、ＤＱＡ１＊０１０２等位基因频率及ＨＬＡ－ＤＲＢ１＊１５０１、－ＤＱＡ１＊０１０２、－ＤＱＢ１＊０６０２单倍型频率均明显高于正常对照组；相反，ＤＲＢ１＊０４（ＤＲ４）、ＤＱＡ１＊０６０１频率则明显低于正常对照组。所有ＤＱＢ１等位基因频率在两组间无显著差异，而ＤＱＡ１＊０１０２仅存在于ＤＲ２阳性的个体之中，推测汉族ＳＬＥ的易感基因可能靠近ＤＲ位点，且与单倍型ＨＬＡ－ＤＲＢ１＊１５０１、－ＤＱＡ１＊０１０２、－ＤＱＢ１＊０６０２紧密连锁，该单倍型可作为汉族ＳＬＥ易感的遗传标记。相反ＤＲ４，ＤＱＡ１＊０６０１则对ＳＬＥ发病可能有一定的保护性。     

Novel HLA-DR2-related haplotypes in Hong Kong Chinese implicate the DQB1*0602 allele in susceptibility to multiple sclerosis.

Multiple sclerosis (MS) is strongly associated with the HLA-Dw2 haplotype DRw15.DQw6 in Caucasoids, although the relative contributions of DR and DQ loci to disease susceptibility are unknown. The situation is further complicated by the apparent lack of an association between DR2 and MS in Orientals. This study examined 42 DR2-positive chromosomes in healthy Chinese and 12 DR2-positive chromosomes in MS patients from Hong Kong, using oligonucleotide hybridizations of DQA1, DQB1, DRB1, and DRB5 polymerase chain reaction (PCR) products. There was marked heterogeneity in DR2-related haplotypes in controls (ten types), where the most frequent haplotype, confirmed in one family, involved the novel arrangement DRB1*1501, DQB1*0601. Another common haplotype had the unusual combination of DRB1*1602, DRB5*0101 as confirmed by DNA sequencing of the DRB5 allele. In contrast, the most common DR2-related haplotype in MS patients was the 'classical' Dw2 haplotype DRB1*1501, DQB1*0602, with a frequency of 50% compared with 12% in controls (P = 0.01). Novel DR,DQ linkage disequilibrium relationship in Hong Kong Chinese have permitted recognition of DQB1*0602 as a susceptibility allele in DR2-positive MS patients, although a role for the DRB1*1501 allele in MS pathogenesis has not been excluded by this study.     

DRB1-DQA1-DQB1 loci and multiple sclerosis predisposition in the Sardinian population

Multiple sclerosis (MS) is a common neurological disease caused by genetic and environmental factors. Previous genetic analyses have suggested that theMHC/HLA region on chromosome 6p21 contains an MS- predisposing component. Which of the many genes present in this region is primarily responsible for disease susceptibility is still an open issue. In this study, we evaluated, in a large cohort of MS families from the Mediterranean island of Sardinia, the role of allelic variation at the HLA-DRB1, DQA1 and DQB1 candidate loci in MS predisposition. Using the transmission disequilibrium test (TDT), we found significant evidence of association with MS in both the Sardinian- specific DRB1*0405(DR4)- DQA1*0501-DQB1*0301 haplotype and the DRB1* 0301(DR3)-DQA1*0501-DQB1*0201 haplotype. Detailed comparative analysis of the DRB1-DQA1- DQB1 haplotypes present in this data set did not identify an individual locus that could explain MS susceptibility. The predisposing effect is haplotype specific, in that it is confined to specific combinations of alleles at the DRB1, DQA1 and DQB1 loci. Cross- ethnic comparison between the two HLA haplotypes associated with MS in Sardinians and the DRB1*1501 (DR2)-DQA1*0102-DQB1* 0602 haplotype, associated with MS in other Caucasian populations, failed to identify any shared epitopes in the DR and DQ molecules that segregated with disease susceptibility. These results suggest that another MHC gene(s), in linkage disequilibrium with specific HLA-DRB1, DQA1, DQB1 haploypes, might be primarily responsible for genetic susceptibility to MS. Alternatively, the presence of complex interactions between different HLA haplotypes, other non-HLA predisposing genes and environmental factors may explain different associations in different populations.      

Absence of DRwl5/3 and of DRwl5/7 heterozygotes in Caucasian patients with systemic lupus erythematosus

Polymorphic MHC class II molecules determine immune responsiveness towards pathogens and also contribute to susceptibility or resistance to a number of different autoimmune diseases, including systemic lupus erythematosus (SLE). The HLA-DR and -DQ alleles of 52 patients with SLE were analyzed by serology and, for 42 patients, HLA-DRB1, -B3 and DQB1 allelic polymorphism was determined by oligotyping on PCR-amplified DNA. While we confirm the increase of DR3 (44.2% versus 16% in controls; p less than 0.001) reported by others, we observed a complete absence of DRw15(2)/DR3 and DRw15(2)/DR7 heterozygotes among Caucasian patients. Moreover HLA-DQB1 oligotyping revealed the absence of DQB1*0602/0201 heterozygotes in our panel of Caucasoid SLE patients. Since both DR3 and DR7 haplotypes share the same DQB1*0201-encoded DQ beta chain, and since DRw15 is known to be in linkage disequilibrium with DQA1*0102, it can be predicted that DQA1*0102/DQB1*0201 combinations are absent in Caucasian patients. We therefore propose that a DQA1*0201/DQB1*0201-encoded HLA-DQ trans-dimer formed in these heterozygotes might function as a suppressor-inducer molecule that confers resistance against SLE.