Molecular analysis of major histocompatibility complex allelic associations with systemic lupus erythematosus in Taiwan

Objective. To investigate the association of HLA class II alleles/haplotypes, type I C2 deficiency gene, and tumor necrosis factor α gene promoter allele (TNF2) with systemic lupus erythematosus (SLE) in the Chinese population in Taiwan. Methods. The HLA-DRB1 and DQB1 alleles were studied in 105 SLE patients and 115 controls by the polymerase chain reaction (PCR)/sequence-specific oligonucleotide probe method, the subtyping of DRB1*15/16 and DRB5 by PCR with sequence-specific primers, type I C2 deficiency gene by PCR, and TNF2 by PCR-Nco I restriction fragment length polymorphism. Results. The frequencies of the HLA class II alleles DRB1*02, DRB1*1502, DRB5*0102, DQB1*0501, and DQB1*0602 and DR2-associated haplotypes DRB1* 1501,DRB5*0101,DQB1*0602 and DRB1*1502,DRB5* 0102,DQB1*0501 were higher among SLE patients than among controls; however, only DQB1*0501 was statistically significantly associated with SLE. No specific allele/haplotype was significantly associated with lupus nephritis. No subject had type I C2 deficiency. SLE patients had a marginally higher percentage of TNF2, which was in linkage disequilibrium with DR3. Since DR3 was not associated with SLE in this Taiwanese Chinese population, TNF2 might play a role in the immunopathogenesis of SLE. Conclusion. Although no HLA-DRB1 allele was found to be significantly associated with SLE, the associations with DQB1*0501 and TNF2 suggest that DQB1 and tumor necrosis factor α may be important genetic factors in SLE susceptibility in the Chinese population in Taiwan.     

HLA-DQB1 DPB1 alleles in Japanese patients with adult-onset Still’s disease

Abstract

Objective: HLA class II alleles are major determinants of genetic predisposition to rheumatic diseases. Predisposing effects of HLA had been suggested in AOSD, however, ethnic differences may account for variations in AOSD association with HLA. We determined the contribution of HLA-DQB1, DPB1 alleles to susceptibility to Adult-onset Still’s disease (AOSD) in the Japanese population.

Methods: HLA-DQB1 and DPB1 alleles were analyzed in 87 Japanese patients with AOSD and 413 Japanese healthy subjects.

Results: We found significant association between HLA-DQB1*06:02 (Pc?=?0.010, odds ratio: 2.54) and AOSD, whereas there was no association between the DQB1*06:02 allele and disease phenotypes of AOSD. Moreover, we did not find a predisposing effect of the HLA-DPB1 allele to AOSD. Haplotype analysis showed that presence of DRB1*15:01–DQB1*06:02 was associated with Japanese patients with AOSD. However, conditional logistic regression tests were unable to demonstrate independent association between DRB1*1501 or DQB1*0602 and AOSD.

Conclusions: Our results show significant association between AOSD and the HLA DQB1*06:02 allele, and between the DRB1*1501–DQB1*06:02 haplotype and AOSD susceptibility. These findings suggest that genetic susceptibility to AOSD depends on the genotype combinations of HLA DRB1 and DQB1 alleles.     

Association of HLA class II genes with systemic sclerosis in Koreans

OBJECTIVE: To investigate HLA class II associations with systemic sclerosis (SSc) in Koreans according to anti-topoisomerase I (anti-topo I), anti-centromere antibody (ACA), and anti-U1 ribonucleoprotein (RNP) status. METHODS: HLA class II alleles (DRB1, DRB5, DQB1) were determined by DNA typing in 200 healthy control subjects and 74 patients with SSc: 35 anti-topo I positive, 3 ACA positive, and 19 anti-U1 RNP positive; among them were 34 diffuse and 40 limited subtypes, and 16 overlap syndrome. RESULTS: Anti-topo I positive SSc was strongly associated with DRB1*1502 compared with both controls (23% vs 5%; Pcorr = 0.003) and anti-topo I negative patients (23% vs 3%; p = 0.009); our study confirms observations in Japanese. HLA-DR 67FLEDR71, especially 38V-67FLEDR71 sequence (carried on DRB5*0102 in linkage disequilibrium with DRB1*1502, DRB1*0802, DRBI*1101), showed the strongest association with anti-topo I response (46% vs 16% in controls; Pcorr = 0.001), and 38L-67FLEDR71 group alleles were not associated with anti-topo I response. Anti-topo I response was not significantly associated with HLA-DQB1 alleles in Koreans. There were only 3 ACA positive patients, and all patients had DRB1*1501 and DQB1*0602 as heterozygotes. Anti-U1 RNP occurred at a high frequency (63%) among patients with overlap syndrome, and was not associated with HLA-DR or DQ genes. Among anti-topo I negative patients, diffuse and limited subtypes of SSc were significantly associated with DRB1*0803 (47% vs 15% in controls; Pcorr < 0.05) and DRB1*1501 (50% vs 17% in controls; Pcorr < 0.01), respectively. These HLA associations have not been reported in other ethnic groups and possible associations with certain autoantibody subsets remain to be confirmed. CONCLUSION: HLA-DR gene has a primary association with anti-topo I response, and HLA-DR 38V-67FLEDR71 group alleles including DRB5*0102 (in linkage disequilibrium with DRB1*1502) show the strongest association with anti-topo I response in Korean patients with SSc.     

HLA class II genotypes associated with chronic hepatitis C virus infection and response to α‐interferon treatment in Poland

Abstract: Aims/Background: Recent evidence suggests that spontaneous clearance of hepatitis C virus (HCV) may be associated with the HLA DQB1*0301 allele but there is still some debate over the role of other alleles and HLA haplotypes in HCV infection. As this may best be resolved by studying genetically different populations, we have investigated HLA class II‐encoded susceptibility and resistance to HCV infection in a relatively sedentary population of patients from northwestern Poland. Methods: The distributions of HLA class II DRB1, DQA1, DQB1 and DPB1 alleles were determined by standard PCR‐protocol in 129 unrelated patients with chronic hepatitis C (anti‐HCV and HCV‐RNA positive) and 103 healthy unrelated racially‐matched control subjects. Fifty‐five patients were treated with α‐interferon (5 MIU thrice weekly for 6 months) out of whom 29 showed a complete response and 26 were non‐responders. Results: A significantly reduced frequency of the DQB1*0301 allele in the patients was observed (24.0% vs. 38.8%; p=0.015). Additionally, two different DR‐DQ haplotypes were found to be associated with chronic HCV infection: DRB1*1501‐DQA1*01‐DQB1*0602 (24.0% vs. 12.6%; p=0.027) and DRB1*0701‐DQA1*0201‐DQB1*02 (31.8 vs. 12.6%; p=0.0006), the latter difference being most pronounced in those patients who responded to α‐interferon treatment (41.4% vs. 12.6%; p=0.00048). Conclusions: The results confirm the negative association between chronic HCV and DQB1*0301 and identify two novel genetic associations. In particular, the DRB1*0701‐DQA1*0201‐DQB1*02 haplotype is associated with both chronic infection and response to α‐interferon. Interestingly, the same haplotype is reportedly associated with non‐response to hepatitis B vaccination.     

D6S265*15 marks a DRB1*15, DQB1*0602 haplotype associated with attenuated protection from type 1 diabetes mellitus

Aims/hypothesis The HLA class II DQB1*0602 allele confers strong dominant protection against type 1 diabetes but protection is not absolute. The aim of this study was to identify markers within the HLA region that differentiate DQB1*0602 haplotypes and show different associations with disease risk. Methods We defined alleles at eight microsatellite markers spanning the HLA region in a case-control cohort from Sweden. Results We found that allele 15 at marker D6S265 (109 kb centromeric of HLA-A) was over-represented among patients carrying DRB1*15, DQB1*0602. A detailed haplotype analysis showed that DRB1*15, DQB1*0602 haplotypes carrying D6S265*15 have a ten-fold higher odds ratio (OR) than those carrying other alleles and thus confer reduced protection [OR D6S265*15=0.186 (95% CI 0.074, 0.472) vs OR D6S265*15−=0.017 (95% CI 0.005, 0.062), p<0.001]. Conclusions/interpretation Our data support the existence of a locus that modifies the protective effect associated with DQB1*0602. Typing for allele D6S265*15 can identify a less protective DQB1*0602 haplotype, thereby allowing a more accurate prediction of type 1 diabetes risk. Electronic Supplementary Material Supplementary material is available for this article at * For full lists of members of these study groups, see Electronic Supplementary Material.     

HLA-patterns in patients with multiple sclerosis and type I diabetes mellitus: evidence for possible mutual exclusion of both diseases

BACKGROUND: Type I diabetes mellitus (T1DM) and multiple sclerosis (MS), both immune-mediated diseases, rarely co-exist in the same individual or co-segregate in families. HLA susceptibility genes for T1DM (DRB1*0401, DRB1*0404, DQB1*0302, DRB1*0301, DQB1*0201) rarely occur in MS patients. HLA genes known to confer "resistance" to T1DM (DRB1*1501, DQB1*0602-DQA1*0102) predispose to MS. To test the hypothesis of mutually exclusive HLA patterns, patients affected by T1DM plus MS were compared to those of patients affected by either of the diseases alone in a case-control study. METHODS: Blood was sampled for analysis of HLA class I and class II alleles from 66 patients of German ancestry, of whom 33 had T1DM plus MS, and 33 had MS-only. For comparison to patients with T1 DM-only we referred to published data. HLA typing was performed using conventional serology (immuno-magnetic beads) and genotyping (SSP-PCR Dynal(R) SSP low/high resolution kits). RESULTS: Individuals with co-existing MS plus T1DM displayed the expected T1DM associated HLA-pattern (75.8% carried DRB1*04, 69.7% carried DQB1*0302, 42% were DR4, DR3 heterozygous), but failed to display the expected MS associated HLA-pattern (0% carried DQB1*0602, 3.1% carried DQA1*0102).The expected MS associated HLA-pattern of Caucasoid patients, however, was found in the MS-only patients (42% carried DRB1*1501-DQB1*0602, 58% carried DQA1*0102), while the prevalence of T1DM susceptibility and 'resistance' alleles was not different from the general population. The allele frequency of DRB1*1501 was 16/66, 24.2% in the 33 MS-only patients, and 0% in the 33 MS plus T1DM patients. The allele frequency of DQB1*0602 was 16/66, 24.2% in the 33 MS-only patients, and 0% in the 33 MS plus T1DM patients. The allele frequency of DQA1*0102 was 18/66, 27.3%, in the 33 MS-only patients, and 1/66 1.5% in the 33 MS plus T1DM patients. CONCLUSION: These data confirm the hypothesis of mutually exclusive HLA-patterns of T1DM and MS, and are consistent with a low rate of co-morbidity of both diseases.     

Clinical,serologic, and immunogenetic studies in childhood-onset systemic lupus erythematosus

Objective. To determine the frequency of systemic lupus erythematosus (SLE)—associated clinical manifestations, autoantibodies, and HLA class II alleles in a large cohort of patients with childhood-onset SLE. Methods. Eighty children with SLE onset before age 18 (27 before age 11) were studied for the frequency of renal, neuropsychiatric, and hematologic complications as well as for anti—native DNA, Ro, La, Sm, and U1 RNP autoantibodies. HLA—DR, DQ, and DP alleles were determined by oligotyping. The results were compared with findings in 213 adults with SLE onset at or after age 18 years. Results. Renal involvement was more frequent in those with childhood-onset SLE, especially those with onset before age 11 (82%, compared with 53% in adults). Anti—U1 RNP was more common in American blacks with SLE onset before age 18. HLA—DRB1*0301, DQA1*0501, DQB1*0201 was more common in Caucasians and DRB1*1503, DRB5*0101, DQA1*0102, DQB1*0602 in American blacks, regardless of age at SLE onset. Anti-Sm autoantibodies were most highly associated with HLA—DQA1*0102 and DQB1*0602. Conclusion. While childhood-onset SLE shares many immunogenetic and serologic similarities to adultonset disease, important clinical differences nevertheless exist in children with this disease.     

Evidence for HLA-related susceptibility for stroke in children with sickle cell disease

Cerebral infarction occurs in one quarter of all children with sickle cell anemia (SCA). There is an increased risk of stroke in siblings with SCA, suggesting genetic factors may influence risk of stroke. The authors investigated whether HLA type was associated with risk of stroke in children with SCA. Fifty-three patients with SCA underwent complete HLA typing at both HLA class I (HLA-A, B) and HLA class II (HLA-DR, DQ, DP) loci. Of the 53 patients, 22 had magnetic resonance imagining (MRI)-documented evidence of cerebral infarction, and the remaining 31 patients had negative MRI scans. Comparison of the results of HLA typing between the SCA patients with a positive and those with a negative MRI documented that the 2 groups differed with respect to the class I HLA-B (P =.012), and the class II HLA-DRB1 (P =.0008) and DQB1 (P =.029). Susceptibility associations at the HLA-DRB1 locus included both DR3 alleles, where DRB1*0301 and *0302 were both associated with an increased risk of stroke. Protective associations were found in the DR2 group, where DRB1*1501 was protective for stroke. DQB1*0201, which is in linkage disequilibrium with DRB1*0301, was also associated with stroke. Similarly, DQB1*0602, in linkage disequilibrium with DRB1*1501, was protective. Specific HLA alleles may influence the risk of stroke in children with SCA. HLA typing may prove useful in identifying SCA patients at higher risk for stroke.     

DR- and DQ-associated protection from type 1A diabetes: comparison of DRB1*1401 and DQA1*0102-DQB1*0602*

The transmission disequilibrium test was used to analyze haplotypes for association and linkage to diabetes within families from the Human Biological Data Interchange type 1 diabetes repository (n = 1371 subjects) and from the Norwegian Type 1 Diabetes Simplex Families study (n = 2441 subjects). DQA1*0102-DQB1*0602 was transmitted to 2 of 313 (0.6%) affected offspring (P < 0.001, vs. the expected 50% transmission). Protection was associated with the DQ alleles rather than DRB1*1501 in linkage disequilibrium with DQA1*0102-DQB1*0602: rare DRB1*1501 haplotypes without DQA1*0102-DQB1*0602 were transmitted to 5 of 11 affected offspring, whereas DQA1*0102-DQB1*0602 was transmitted to 2 of 313 affected offspring (P < 0.0001). Rare DQA1*0102-DQB1*0602 haplotypes without DRB1*1501 were never transmitted to affected offspring (n = 6). The DQA1*0101-DQB1*0503 haplotype was transmitted to 2 of 42 (4.8%) affected offspring (P < 0.001, vs. 50% expected transmission). Although DRB1*1401 is in linkage disequilibrium with DQB1*0503, neither of the two affected children who carried DQA1*0101-DQB1*0503 had DRB1*1401. However, all 13 nonaffected children who inherited DQA1*0101-DQB1*0503 had DRB1*1401. In a case-control comparison of patients from the Barbara Davis Center, DQA1*0101-DQB1*0503 was found in 5 of 110 (4.5%) controls compared with 3 of 728 (0.4%) patients (P < 0.005). Of the three patients with DQB1*0503, only one had DRB1*1401. Our data suggest that both DR and DQ molecules (the DRB1*1401 and DQA1*0102-DQB1*0602 alleles) can provide protection from type 1A diabetes.     

Sequence analysis of the diabetes-protective human leukocyte antigen-DQB1*0602 allele in unaffected, islet cell antibody-positive first degree relatives and in rare patients with type 1 diabetes.

The human leukocyte antigen (HLA)-DQA1*0102/DQB1*0602/DRB1*1501 (DR2) haplotype confers strong protection from type 1 diabetes. Growing evidence suggests that such protection may be mostly encoded by the DQB1*0602 allele, and we reported that even first degree relatives with islet cell antibodies (ICA) have an extremely low diabetes risk if they carry DQB1*0602. Recently, novel variants of the DQB1*0602 and *0603 alleles were reported in four patients with type 1 diabetes originally typed as DQB1*0602 with conventional techniques. One inference from this observation is that DQB1*0602 may confer absolute protection and may never occur in type 1 diabetes. By this hypothesis, all patients typed as DQB1*0602 positive with conventional techniques should carry one of the above diabetes-permissive variants instead of the protective DQB1*0602. Such variants could also occur in ICA/DQB1*0602-positive relatives, with the implication that their diabetes risk could be significantly higher than previously estimated. We therefore sequenced the DQB1*0602 and DQA1*0102 alleles in all ICA/DQB1*0602-positive relatives (n = 8) previously described and in six rare patients with type 1 diabetes and DQB1*0602. We found that all relatives and patients carry the known DQB1*0602 and DQA1*0102 sequences, and none of them has the mtDNA A3243G mutation associated with late-onset diabetes in ICA-positive individuals. These findings suggest that diabetes-permissive DQB1*0602/3 variants may be very rare. Thus, although the protective effect associated with DQB1*0602 is extremely powerful, it is not absolute. Nonetheless, the development of diabetes in individuals with DQB1*0602 remains extremely unlikely, even in the presence of ICA, as confirmed by our further evaluation of ICA/DQB1*0602-positive relatives, none of whom has yet developed diabetes.     

HLA Class II Polymorphism in Egyptian Children with Lymphomas

The major histocompatibility complex (MHC) is a set of closely-linked genes encoded on the short arm of chromosome 6. It is important for understanding human immunological diseases, transplantation and in host defense against infection. The membrane proteins are two types; class I MHC proteins and class II MHC proteins. Strong arguments supporting genetic linkage between susceptibility to lymphomas and human leukocyte antigens (HLA)-class II are reported and give a clue about susceptibility or protection from the disease.

Aim: To evaluate the possible changes of HLA class II (DR, DQ) alleles in children with lymphoma.

Methods: Thirty cases were included in this limited study. Nineteen cases of non Hodgkin's lymphoma (NHL) and eleven patients with Hodgkin's lymphoma (HD). Their ages ranged from 1.5 to 15 years. The control group consisted of 121 unrelated healthy subjects for DRB1 alleles and 59 unrelated healthy subjects for DQB1 alleles (only 59 subjects were typed for both DRB1 and DQB1). All cases in the study were assessed by thorough history taking, physical examination and laboratory investigations that included complete blood count, renal function tests, liver function tests, serum uric acid and HLA typing. Patients and controls were typed for HLA class II DRB1 and DQB1 alleles using INNO-LIPA reverse hybridization line probe assay (Innogenetic, Belgium).

Results: HLA-DRB1 *0403 and *1301 and HLA-DQB1 *0501,* 0201 and *0301 were significantly increased in patients with NHL when compared with control; whereas HLA-DRB1 *1302 and HLA-DQB1 *0502 and *0602 were significantly decreased when compared with control. In patients with HD, HLA-DRB1 *0403 and *1202 and HLA-DQB1 *0604, *0201 and *0203 were significantly increased when compared with control.

Conclusions: (1) The susceptibility to NHL is related to HLA-DRB1 *0403 and *1301 and HLA-DQB1 *0501,* 0201 and *0301. (2) The susceptibility to HD is related to HLA-DRB1 *0403 and *1202 and HLA-DQB1 *0604, *0201 and *0203. (3) HLA-DRB1 *1302 and HLA-DQB1 *0502 and *0602 may confer protection to NHL. (4) Different HLA alleles may have a role in patients with both groups of lymphoma and further study is needed to better define the possible prognostic value of different HLA associations in patients with lymphomas regarding increased risk in the presence of certain HLA alleles and the possibility for treatment modifications in the future based on the presence or absence of certain HLA alleles.     

Analysis of B- and T-cell clonality and HLA class II alleles in patients with idiopathic thrombocytopenic purpura: Correlation with Helicobacter pylori infection and response to eradication treatment

Many authors have recently found a positive correlation between Helicobacter pylori infection and idiopathic thrombocytopenic purpura (ITP), the most common autoimmune hematological disorder. In order to clarify the pathogenic mechanism of H. pylori-associated ITP, we have investigated 52 consecutive ITP adult patients for Helicobacter pylori infection, B- and T-cell clonality and HLA class II alleles. Thirty-four ITP patients (65.4%) were infected by H. pylori and bacterium eradication was accompanied by a long-term platelet response in 17 (53.1%) of them. A B-cell clonality was found in three patients (5.8%, two patients H. pylori-negative and one patient H. pylori-positive). The ITP patients with H. pylori infection showed a HLA–DRB1*11, *14 and –DQB1*03 frequencies significantly higher and a –DRB1*03 frequency significantly lower than in H. pylori-negative patients. Moreover, an HLA–DQB1*03 pattern was associated with a higher probability of platelet response to eradication treatment. If our study documents the efficacy of eradication treatment in H. pylori-infected ITP patients, it may also help to identify different subgroups of ITP patients with probably different pathogeneses of thrombocytopenia and, finally, different responses to eradication treatment.     

HLA class II genotypes associated with chronic hepatitis C virus infection and response to alpha-interferon treatment in Poland

AIMS/BACKGROUND: Recent evidence suggests that spontaneous clearance of hepatitis C virus (HCV) may be associated with the HLA DQB1*0301 allele but there is still some debate over the role of other alleles and HLA haplotypes in HCV infection. As this may best be resolved by studying genetically different populations, we have investigated HLA class II-encoded susceptibility and resistance to HCV infection in a relatively sedentary population of patients from northwestern Poland. METHODS: The distributions of HLA class II DRB1, DQA1, DQB1 and DPB1 alleles were determined by standard PCR-protocol in 129 unrelated patients with chronic hepatitis C (anti-HCV and HCV-RNA positive) and 103 healthy unrelated racially-matched control subjects. Fifty-five patients were treated with alpha-interferon (5 MIU thrice weekly for 6 months) out of whom 29 showed a complete response and 26 were non-responders. RESULTS: A significantly reduced frequency of the DQB1*0301 allele in the patients was observed (24.0% vs. 38.8%; p=0.015). Additionally, two different DR-DQ haplotypes were found to be associated with chronic HCV infection: DRB1*1501-DQA1*01-DQB1*0602 (24.0% vs. 12.6%; p= 0.027) and DRB1*0701-DQA1*0201-DQB1*02 (31.8 vs. 12.6%; p=0.0006), the latter difference being most pronounced in those patients who responded to alpha-interferon treatment (41.4% vs. 12.6%; p=0.00048). CONCLUSIONS: The results confirm the negative association between chronic HCV and DQB1*0301 and identify two novel genetic associations. In particular, the DRB1*0701-DQA1*0201-DQB1*02 haplotype is associated with both chronic infection and response to alpha-interferon. Interestingly, the same haplotype is reportedly associated with non-response to hepatitis B vaccination.     

Contribution of major histocompatibility complex genes to susceptibility and resistance in Helicobacter pylori related diseases.

BACKGROUND/AIM: Although there have been numerous reports concerning the virulence factors of isolates for investigating the pathogenesis of Helicobacter pylori infection, few studies have been carried out regarding the association of HLA class II genes of the host with H. pylori related diseases. Two published studies have only analysed the HLA DQ locus alone. The aim of this study was thus to determine the association of HLA class II genes (DR, DQ and DP) with H. pylori related diseases using the DNA typing method. METHODS: Fifty-eight patients with H. pylori positive gastric ulcers, 44 patients with H. pylori positive duodenal ulcers, 45 patients with H. pylori positive gastritis and 34 healthy subjects without H. pylori infection were typed for HLA class II genes by means of DNA typing with the polymerase chain reaction-sequence specific oligonucleotide probes method. RESULTS: A negative association with DRB1*1501, DQA1*01021 and DQB1*0602 alleles was noted in all three of the patient groups studied. Compared with the healthy controls, a positive association with DPA1*0201 (P= 0.032) and DPB1*0901 (P=0.005) in gastric ulcers, a positive association with DRB1*0405 (P=0.022) and DQB1*0401 (P=0.044) in duodenal ulcers, and a positive association with DPB1*0901 (P=0.016) in gastritis were observed. A haplotype analysis showed that the association of alleles with H. pylori related disease was with the haplotype rather than with either of the alleles individually. After correction for multiple comparisons, all the significant associations obtained between H. pylori related diseases and HLA class II genes disappeared. CONCLUSIONS: The interplay between host immunogenetic factors, bacterial virulence factors and environmental conditions may thus play a more important role in the outcome of H. pylori infection than immunogenetic factors alone.     

Autoantibodies to fibrillarin in systemic sclerosis (scleroderma). An immunogenetic,serologic, and clinical analysis

Objective. To determine the frequency, clinical associations, and any major histocompatibility complex correlations of antifibrillarin antibodies in patients with systemic sclerosis (SSc). Methods. Antifibrillarin antibodies were determined by indirect immunofluorescence, immunoblotting, and immunoprecipitation, and HLA class II alleles by DNA oligotyping, in a large cohort of SSc patients. Results. Antifibrillarin was found in 8% of 335 SSc sera and was significantly more common in blacks (16%) than whites (5%), in males (33%) than females (14%), and in patients with cardiac, renal, or gut involvement. The HLA class II haplotype DRB1*1302, DQB1*0604 was found significantly more frequently in SSc patients with antifibrillarin compared with racematched normal controls and 260 SSc patients without antifibrillarin. In addition, 1 or more of the HLA–DQB1 alleles *0604, *0301, *0602, and/or *0302 was found in all antifibrillarin-positive patients, and 62% of the antifibrillarin-positive patients had 2 of these HLA–DQB1 alleles, a highly significant difference from both race-matched normal controls and antifibrillarin-negative SSc patients. Conclusion. Antifibrillarin, although an infrequent nucleolar autoantibody, is a marker for severe SSc, especially in blacks and males, and is strongly associated with a unique HLA haplotype, as well as with combinations of certain HLA–DQB1 alleles.     

HLA polymorphisms and cervical human Papillomavirus infection in a cohort of Montreal University students

BACKGROUND: Only a minority of women with human papillomavirus (HPV) infection eventually develop cervical cancer, which suggests that host immune mechanisms play a role in the disease. HLA polymorphisms have been linked to the risk of cervical cancer, but very little is known about the role that they play in the acquisition and persistence of HPV infection. METHODS: A cohort study of cervical HPV infections was used to examine the role that 5 HLA alleles (B*07, DQB1*03, DQB1*0602, DRB1*13, and DRB1*1501) play in determining the risk of HPV positivity and persistence in 524 female university students in Montreal. HPV positivity was determined by use of the MY09/11 polymerase-chain-reaction protocol. HLA alleles from purified DNA from cervical specimens were typed by use of a polymerase-chain-reaction technique using sequence-specific primers. RESULTS: HLA DRB1*13 was associated with cumulative risk of HPV infections (odds ratio [OR], 1.7 [95% confidence interval {CI}, 1.0-2.8]), for oncogenic HPV (OR, 1.6 [95% CI, 0.9-2.8]), and for HPV-16 (OR, 2.0 [95% CI, 0.9-4.4]). DQB1*03 was consistently associated with a lower cumulative risk of HPV infections, but this association was not statistically significant. None of the alleles affected the risk of HPV persistence. CONCLUSIONS: The results of this study support the hypothesis that certain HLA class II polymorphisms mediate genetic susceptibility to the acquisition of HPV infection.     

Major histocompatibility complex class ii gene associations with anti–u1 small nuclear ribonucleoprotein antibody relationship to immunoreactivity with individual constituent proteins

Objective. To better define immunogenetic associations with the anti–U1 ribonucleoprotein (U1 RNP) autoantibody response. Methods. HLA class II alleles were determined by genotyping in 49 Japanese rheumatic disease patients with anti–U1 RNP antibody and 43 race-matched healthy controls. Immunoreactivities to U1 RNP constituent proteins (70K, A, B/B′, and C) were detected by immunoblots using purified HeLa cell Sm antigen, and antibody titer was determined by passive hemagglutination assay. Results. DQB1*0302 was significantly more frequent in anti–U1 RNP–positive patients than in controls (43% versus 14%; odds ratio [OR] = 4.6, corrected P = 0.03). All anti–U1 RNP–positive patients had either a DQB1*0601, *0602, *0301, *0302, or *0303 allele, which share tyrosine at position 30, and the amino acid sequence Thr, Arg, Ala, Glu, Leu, Asp, and Thr at positions 71–77 in the DQB1 ß1 domain. In contrast, one of these alleles was found in 81% of the controls (OR = 24, P = 0.002). In addition, anti–U1 RNP antibody was associated with unique DQB*0302; DRB1*0401 haplotype. Anti-70K reactivity and antibody titer were positively associated with a basic amino acid residue, arginine or histidine, at position 13 (DR2 or DR4) and were negatively associated with the amino acid sequence Ile, Leu, Glu, and Asp at positions 67–70, which was present in some of the DR5-, DR6-, and DR8-associated alleles, in the DRB1 ß1 domain. Anti-C reactivity was strongly associated with DR2, particularly with DRB1*1502. Conclusion. The several shared epitopes located on HLA–DRB1 and DQB1 genes control the anti–U1 RNP autoantibody response.     

Ribosomal P autoantibodies in systemic lupus erythematosus. Frequencies in different ethnic groups and clinical and immunogenetic associations

Objective. To determine the frequencies and clinical associations of antiribosomal P antibodies (anti-P) in a large multiethnic cohort of patients with systemic lupus erythematosus (SLE), and to assess whether anti-P was associated with any major histocompatibility complex (MHC) class II alleles or shared amino acid sequences. Methods. Sera from 394 SLE patients were studied for anti-P using an enzyme-linked immunosorbent assay, and MHC class II alleles (HLA-DRB1, DQA1, and DQB1) were determined by DNA oligotyping. Results. Anti-P antibodies were found in 13-20% of patients in the majority of ethnic groups, but were perhaps more frequent in Chinese patients (36%) and less common in Bulgarian patients (6%). Neuropsychiatric lupus (psychosis and/or depression) was significantly associated with anti-P. The HLA-DR2, DQ6 haplotypes DRB1*1501 or *1503, DQA1*0102, and DQB1*0602 were increased in anti-P-positive whites, blacks, and Mexican Americans. The HLA-DQB1*0602 allele showed the strongest association with anti-P when these 3 ethnic groups were combined and compared with both race-matched anti-P—negative SLE patients and normal controls. The HLA-DQ8 specificity (DQB1*0302) was increased both in whites and in Mexican-Americans with anti-P who were negative for HLA-DQB1*0602, and perhaps also increased in Greeks, but not in blacks, in whom HLA-DQB1*0301 was increased. A shared amino acid sequence in HLA-DQB1 (at position 26 of leucine and position 30 of tyrosine) was strongly associated with anti-P positivity (70%) versus anti-P negativity (42%) across ethnic lines. Conclusion. The anti-P response in SLE patients, occurring in ∼ 15% of patients, was strongly influenced by certain MHC class II alleles and was correlated with diffuse neuropsychiatric dysfunction.     

Influence of human leukocyte antigen class II alleles on susceptibility to Entamoeba histolytica infection in Bangladeshi children

BACKGROUND: The association of antibody responses with both innate and acquired immunity to amebiasis indicate that CD4+ T cells play a role in protection against Entamoeba histolytica infection. To test this hypothesis, we compared the genotype frequencies of human leukocyte antigen (HLA) class II alleles in a cohort of Bangladeshi children intensively monitored for E. histolytica infection for a 3-year period. METHODS: Using logistic regression, we calculated the odds of disease by genotype and by haplotype. RESULTS: The DQB1*0601 heterozygous and homozygous genotypes were found in 55% of E. histolytica-negative children but in only 34% of E. histolytica-positive children (overall odds ratio, 2.39; 95% confidence interval [CI], 1.26-4.54). Children who were heterozygous for the DQB1*0601/DRB1*1501 haplotype were 10.1 times (95% CI, 2.02-50.6) more likely to be both E. histolytica negative and serum anti-lectin immunoglobulin G negative at baseline. Other DQB1 and DRB1 alleles (DQB1*0202, DQB1*0301, and DRB1*0701) were not associated with any of the clinical outcomes related to amebiasis. CONCLUSION: A potential protective association was observed with the HLA class II allele DQB1*0601 and the heterozygous haplotype DQB1*0601/DRB1*1501. This association may explain why amebiasis does not occur in some children who are exposed to the parasite and implicates HLA class II-restricted immune responses in protection against E. histolytica infection.