HLA antigens in north american patients with takayasu arteritis

Objective. To determine the frequency of HLA class I and II antigens in Caucasian North American patients with Takayasu arteritis (TA). Methods. Seventy-three class I antigens and 13 class II antigens were examined in 21 Caucasian North American patients with TA, and their frequencies were compared with findings in 243 healthy, untreated controls. HLA typing was performed by microlymphocytotoxicity assay. Results. We found no statistically significant positive association of TA with DR2, DR4, DQw3, or any of the other class I or class II antigens studied. A negative association between TA and DR1 was noted. There was no significant association between any of the HLA antigens and the severity of the disease or the presence of complications. Conclusion. The negative association between TA and the DR1 antigen suggests that this antigen may be protective against the development of the disease.     

HLA and rheumatoid arthritis: a combined analysis of 440 British patients.

Four hundred and forty unrelated British Caucasoid patients with rheumatoid arthritis (RA) have been HLA typed for class I and class II antigens. Analyses of HLA antigen associations were performed on the overall group and in patient subsets selected according to particular disease parameters or sex, or both. The results confirm previously reported positive associations of HLA-DR4, Dw4, and DRw53 and negative associations of HLA-DR2 and DR7 with RA. Patients subsets with severe erosions, seropositivity, and features of extra-articular disease showed a stronger association, also confirming earlier reports. The link between HLA and disease severity was emphasised by a significant trend of increased Dw4 frequency with increasing severity of radiological erosions. In addition, a positive association of RA with HLA-A2 was observed and a strong negative association with DR3. The frequency of HLA-B27 was significantly increased in patients with subluxation of the spine. Differences were observed between male and female patients in relation to the HLA association. In men an increase in the frequency of the haplotype HLA/Dw4/DR4/Bw62/Cw3/A2 was observed. This showed no relationship with parameters of disease severity other than extra-articular disease. In women only class II antigens (DRw53/Dw4/DR4) showed an increased frequency. This increase was strongly associated with disease severity. A significant decrease of this class II association was observed with increasing age of disease onset; this was not seen in men.     

Disease expression and class II HLA antigens in systemic lupus erythematosus.

The aim of this investigation was to examine the relationship between Class II HLA antigens and disease expression in systemic lupus erythematosus (SLE). HLA-DR and DQ antigen frequency was studied serologically in 217 SLE patients followed prospectively and compared to 320 healthy controls. The relationship between HLA antigens and the presence of disease manifestations, as well as death was investigated in 117 SLE patients enrolled within the first year of their disease. A univariate analysis confirmed the association between HLA-DR3 and SLE. HLA antigen DR1, DR6, DR7, DQw1 and DQw3 were decreased in patient group compared to the controls. A logistic regression model showed a significantly negative association with HLA-DR1, DR6 and DR7, and a positive association with HLA-DR3. The reduced frequency of HLA-DQw1 and DQw3 was maintained using a logistic procedure. Cox Proportional Hazards models revealed no association between HLA-Class II antigens and death. Logistic regression models revealed no associations between central nervous system (CNS) disease nor musculoskeletal manifestations with any of the DR antigens. There was a trend towards a lower frequency of HLA-DR6 in patients with renal involvement and lower prevalence of HLA-DR1 and HLA-DR7 in patients with vasculitis.     

Susceptibility to relapsing polychondritis is associated with hla–-dr4

Objective. To determine the frequency of HLA class II antigens in Caucasian central European patients with relapsing polychondritis (RP). Methods. HLA class I, DR, and DQ specificities were identified in 41 patients with RP, and the frequencies were compared with those in 204 healthy, unrelated control subjects. HLA typing was performed using the standard complement-dependent microcytotoxicity assay. HLA–DR genotyping of 12 DR4-positive RP patients and 57 controls was performed by allele-specific oligonucleotide probing after amplification of genomic DNA by polymerase chain reaction. Results. A significant increase in DR4 antigen frequency was found in the patients (56.1%) as compared with that in healthy controls (25.5%) (P_corr < 0.001). Genotyping of DR4-positive patients and controls revealed no predominance of any DR4 subtype. Conclusion. There are important clinical similarities and overlaps between RP and rheumatoid arthritis (RA). In RA, the association with DR4 has been well established. Our findings show that although there is a DR4 association with RP, the situation is sufficiently distinct from that of RA to imply considerable differences in pathogenesis of the two conditions.     

Class I and Class II HLA Antigens in a Homogeneous Argentinian Population with Whipple''s Disease: Lack of Association with HLA-B 27

The prevalence of class I and class II HLA antigen was analyzed in 14 patients (12 males, two females) with Whipple's disease, diagnosed an average of 9.7 yr (range 6 months to 25 yr) before the typing. They were compared with 174 healthy control subjects of the same geographic area in Argentina. Class I antigens (locus A, B, C) were studied by lymphocytotoxic test, and class II antigens (locus DR, DQ) were detected by the double immunofluorescence technique. HLA-B27 was positive in one patient (7.7%) and in 4% of the control population. No significant association was found with the antigens tested. We observed no difference in the clinical picture or in the frequency of arthralgias, compared with those reported in the literature. Our data suggest that there is no conclusive proof of an association between HLA-B27 and Whipple's disease.     

Associations between HLA and antibodies to collagen in rheumatoid arthritis.

Associations between HLA types and serum antibodies to native and denatured type II collagen were sought in 105 patients with rheumatoid arthritis (RA). Antibodies were measured using a solid phase radioimmunoassay. There were no significant associations between any HLA antigen (A, B, or DR) and a high antibody titre to native collagen. There were significant associations, however, between HLA antigens and high antibody titres to denatured collagen. Although DR4 did not show an association, the phenotype A2+DR4+ did; this was not related to A2 as A2+DR- was not associated with a high antibody titre. No single B locus antigen showed an association, but several B locus antigens, B12, B15, and B40, were included in phenotypes with A2 and DR4 which were associated with a high antibody titre to denatured collagen. These HLA associations with anticollagen type II are best explained by a gene other than DR4 (but in linkage with it) which may regulate the antibody response to denatured collagen. If so, this would represent an HLA gene in addition to DR4 that is active in RA.     

HLA-DR antigens and anticardiolipin antibodies in northern Italian systemic lupus erythematosus patients

Eighty systemic lupus erythematosus (SLE) patients attending 3 clinical centers were evaluated immunologically and immunogenetically. No HLA class II antigens were found to be significantly associated with SLE in these patients. A highly significant (P = 6.17 x 10(-7) association was observed between anticardiolipin antibodies and DR7. A lesser association (P less than 0.025) was also observed between DR2 and/or DR3 and anti-Ro (SS-A) antibodies. No relationship was found between any DR antigen and anti-Sm/RNP, anti-double-stranded DNA, or anti-La (SS-B) antibodies.     

HLA gene and phenotype data of 60 insulin-dependent diabetic patients from north-eastern Italy. A negative association with DR5 rather than DR2?

Summary The purpose of our study was to evaluate what kind of relationships exist between HLA antigens and insulin-dependent diabetes mellitus (IDDM), in 20 families and in 40 single patients coming from and living in North Eastern Italy. The subjects studied show a strong association with HLA-DR3 and/or -DR4; at least one of these antigens is present in 88% of the diabetic subjects; this confirms that these antigens play a role in the pathogenesis of IDDM. We also noticed a negative association between IDDM and DR5 rather than DR2 and DR7. This result supports the hypothesis of a specific protective effect of DR5, at least as regards the population studied. Possibly, the gene(s) hypothetically involved in the protection against IDDM is (are) in linkage disequilibrium with DR2 and/or DR7 in some Caucasian populations and with DR5 in others. Another important result is the frequent HLA identity (75% of cases) among diabetic siblings of the same families. This result indicates that HLA identity is the main condition respondible for the susceptibility to the disease in the healthy siblings with HLA antigens identical to the diabetic siblings.     

HLA class I and class II antigens associated with multiple myeloma in southern Africa

While the exact aetiology of myeloma is unknown, genetic factors feature among the potential risk factors. The HLA phenotypes in African blacks with myeloma (the commonest haematopoietic malignancy in this group) have not been characterized. The purpose of this study was to determine the HLA class I and class II phenotypes of patients with multiple myeloma and to compare the findings to an ethnically matched control group of 100 individuals. Analysis of the HLA class I and class II phenotypes in 62 myeloma patients revealed: (i) a corresponding statistically significant association with HLA B18 [odds ratio (OR) 6.3; 95% confidence interval (CI) 1.013-39.727; P < 0.005]; (ii) no statistically significant association with HLA B13, Cw2, Cw6 or the DR and DQ antigens; and (iii) a statistically significant negative (protective) association with HLA Cw7 (OR 0.4; 95% CI 0.21-0.87; P < 0.005). This study suggests that although genetic factors may play a role in the multifactorial aetiology of multiple myeloma, with the exception of HLA B18, there is no specific association between HLA types and multiple myeloma in South African blacks.     

Immunohistologic studies of differential HLA expression in patients with various intestinal diseases

Histocompatibility antigens (HLA) play an important part in immunoregulation and in cell differentiation. This study analyses the expression of HLA class I and class II antigens (DR, DP, DQ) in intestinal biopsy specimen from patients with Crohn's disease, ulcerative colitis, GvHD, radiation colitis and intestinal adenomas using the indirect immunoperoxidase technique. 92 of 94 inflamed specimen from patients with inflammatory bowel disease showed a neoexpression of HLA II (DR greater than DP greater than DQ) on their epithelial cells. The intensity of HLA-DR neoexpression was significantly dependent on an endoscopic as well as a histological index of inflammation. All 75 non-inflamed specimen except 4 from patients with Crohn's disease did not show any evidence of HLA II display on the epithelium. 4 of 18 intestinal adenomas expressed HLA II on their epithelial cells without any correlation to the type of adenoma or the degree of cell dysplasia. Furthermore all specimen from a patient with intestinal GvHD showed an aberrant epithelial HLA II expression, but not that from radiation colitis. The expression of HLA class I antigens was similar in all biopsies studied. Our results suggest, that the epithelial neoexpression of HLA class II antigens may be an important event in the pathogenesis of various bowel diseases.     

HLA-DR and -DQ phenotypes in inflammatory bowel disease: a meta-analysis.

BACKGROUND: Susceptibility to inflammatory bowel disease (IBD) is partially genetically determined and the HLA class II genes are candidates for a role in genetic susceptibility to IBD, because their products play a central role in the immune response. Multiple studies have reported associations between HLA-DR or -DQ phenotypes and either ulcerative colitis or Crohn's disease, but much of the data are still controversial. AIMS: To estimate overall associations between HLA class II phenotypes and IBD, and to establish the relative risk conferred by HLA-DR and -DQ phenotypes by meta-analysis. METHODS: Medline was searched for publications reporting on the relation between IBD and HLA class II phenotypes. Raw data were extracted by recalculating the number of phenotypes or the number of alleles of the main antigens. Odds ratios and confidence intervals were calculated according to the Mantel-Haenszel method. RESULTS: DR2, DR9, and DRB1*0103 were positively associated with ulcerative colitis, and a negative association was found for DR4 and ulcerative colitis. For Crohn's disease a positive association was found with DR7, DRB3*0301, and DQ4 and a negative association with DR2 and DR3. CONCLUSIONS: Both ulcerative colitis and Crohn's disease are associated with specific HLA class II phenotypes. Further analysis of these phenotypes and subgroup analysis may elucidate how these alleles contribute to susceptibility to IBD.     

Hla—dr antigens and anticardiolipin antibodies in northern italian systemic lupus erythematosus patients

Eighty systemic lupus erythematosus (SLE) patients attending 3 clinical centers were evaluated immunologically and immunogenetically. No HLA class I1 antigens were found to be significantly associated with SLE in these patients. A highly significant (P = 6.17 × 1o⁻⁷) association was observed between anticardiolipin antibodies and DR7. A lesser association (P < 0.025) was also observed between DR2 and/or DR3 and anti—Ro (SS-A) antibodies. No relationship was found between any DR antigen and anti-Sm/RNP, antidouble-stranded DNA, or anti—La (SS-B) antibodies.     

Association between DR antigens, rheumatoid arthritis with and without extraarticular features and systemic lupus erythematosus in northern Italy

Seventy-two patients with rheumatoid arthritis (RA) and 18 with systemic lupus erythematosus (SLE) were typed for HLA class I and II antigens. No association was found with any of the antigens tested. However, B8 and DR3 were increased in patients with extraarticular features (EAF), while DR1 was increased in those with RA without EAF. In SLE a trend towards an increased frequency of DR7 was observed. DR5 was the negative marker in both diseases. Our results confirm the peculiar genetic characteristics in our population.     

HLA class II alleles associated with susceptibility and resistance to Crohn's disease in the Jewish population

Previous studies have suggested that susceptibility to Crohn's disease (CD) is associated with the histocompatibility complex (HLA) class II alleles DR1, DQ5, and DR13 in the Caucasian population, DR7 in the French and German populations, and DR4 and DQ4 in the Japanese population. However, little is known about the relationship between HLA class II alleles and CD in the Jewish population since these previous studies included few Jewish individuals. In order to determine whether the HLA associations observed with predominantly non-Jewish populations were also present in the Jewish CD population and whether there were any HLA class II alleles uniquely associated with CD in the Jewish population, 132 CD patients, of which 82 were Ashkenazi Jewish, were HLA-typed using serologic and DNA methods. Ethnically matched controls were similarly typed. No association with DR1 or DR13 was observed in the Jewish CD population although an association with DR13 (OR [odds ratio] = 5.3, p = 0.02) was observed in the non-Jewish CD population. However, an association with DR15 (OR = 2.7, p = 0.03), which is normally associated with ulcerative colitis, was observed in the Jewish, but not non-Jewish, CD group. In addition, a strong negative association was observed with DR3, which was especially striking in the Jewish population (OR = 0.35, p = 0.025); similar negative associations with DR3 have been observed by others using non-Jewish populations. Furthermore, a significant negative association with DR7 (OR = 0.45, p = 0.04) was observed in the Jewish, but not non-Jewish, population. Consistent with this was the negative association with DQ2 (OR = 0.38, p = 0.005), which is in strong linkage disequilibrium with both DR3 and DR7, in the Jewish, but not non-Jewish, population. These studies support previous suggestions that susceptibility to CD in Jewish and non-Jewish populations is determined by distinct genes and provide further support to the hypothesis that a gene on the DR3 haplotype may protect against CD. Furthermore, protection is conferred by the same or another gene found on Jewish, but not non-Jewish, DR7 haplotypes.     

Histocompatibility Antigens in Primary Biliary Cirrhosis

HLA-A, -B, and -DR antigens were examined in 71 patients with primary biliary cirrhosis (PBC) enrolled in a randomized, double-blind trial of colchicine versus placebo. All patients had typical laboratory and histological features of PBC, except that six had a negative test for antimitochondrial antibody. Frequencies of these antigens were compared with the international Caucasian panel of the Eighth International Workshop and with a local Caucasian panel. Antigen frequencies were compared using the chi 2 test, with a correction for the number of antigens tested. The PBC patients had a significant excess of DR4 (29 of 70 typed, or 41.1%) compared to the international (804 of 3811, or 21.1%, corrected p value less than 0.05) but not the local panel (47 or 129, or 36.4%). Of PBC patients, 52.9% had only one DR antigen identified, compared to 67.5% for the international panel and 49.6% for the local panel. In past studies, the HLA antigen most strongly correlated with PBC was DR8, but this was not included in our panel of antisera. However, no significant relationship between HLA and PBC was found among the antigens screened.     

Association of human leukocyte class II antigens with rheumatic fever or rheumatic heart disease in a Brazilian population

BACKGROUND. The incidence of rheumatic heart disease is great in Brazil. We analyzed the distribution of human leukocyte (HLA) antigens in a Brazilian population sample with rheumatic fever or rheumatic heart disease, with the aim of better understanding the mechanisms involved. METHODS AND RESULTS. HLA class I (A, B, and C) and class II (DR and DQ) antigen distribution was studied in 40 patients with diagnosis of rheumatic fever or rheumatic heart disease and compared with a control group of 617 healthy individuals for class I typing, from which 118 were drawn for class II typing. A strong correlation between rheumatic fever and rheumatic heart disease and HLA-DRw53 (72.9% in the disease group versus 39% in the control group: p = 0.00061, relative risk, 4.2; etiologic fraction, 0.43) was found. We also found an increase in the frequency of HLA-DR7 (57.5% in the disease group versus 26.3% in control group: p = 0.00715; relative risk, 3.8; etiologic fraction, 0.56). HLA class I and HLA-DQ typing did not point to any association with these diseases. CONCLUSIONS. HLA-DR7 and HLA-DRw53 are markers for susceptibility to rheumatic fever and rheumatic heart disease in Brazil. These results could be explained by genetic differences resulting from racial or geographical diversity.     

HLA antigens in primary fibromyalgia syndrome.

HLA antigens, both class I (A,B,C) and II (DR), were determined in 60 patients with primary fibromyalgia syndrome and compared to 159 healthy controls. No significant association between primary fibromyalgia syndrome and alleles of the HLA system was detected.     

Molecular typing of HLA class I and class II antigens in Indian kala-azar patients

HLA has been shown to be associated with many diseases. To find out whether host genetic factors like the HLA are involved in susceptibility to kala‐azar (visceral leishmaniasis) in India, we formulated an association study with genetically related controls. All samples were typed by PCR SSOP (sequence specific oligonucleotide probes) for HLA class I (A and B) and class II (DR) antigens. The test of association we used was the transmission disequilibrium test (TDT). No significant evidence for association with any of the three HLA loci was obtained.     

HLA typing in families with multiple cases of rheumatoid arthritis.

Thirty one white patients from 14 families with multiple cases of rheumatoid arthritis (RA) and 42 of their healthy relatives were completely HLA typed. In contrast with class I antigens, the class II antigens DR1 and DR4 were significantly more common in the patients than in a group of 200 healthy local white controls (DR1: 32% v 12%; DR4: 48% v 28%, in patients and controls respectively). Owing to the small number of cases the data from this study were combined with those of published reports. Examination of patients for DR1 and DR4 homozygosity and DR1/4 heterozygosity showed an increase of DR1 homozygous patients, which was not statistically significant. There was no striking deviation from random expectation in haplotype sharing of affected sib pairs. These results are compatible with a dominant influence of DR1 and DR4 in the mode of inheritance. The nearly random haplotype sharing and the molecular relation between DR1 and DR4 support the hypothesis of a direct influence of these antigens in the pathogenesis of RA. Only 68% of the patients in this study possessed either DR1 or DR4, possibly indicating a subtype of RA which is independent of HLA. Clinical and serological variables were measured and indicated no significant difference between DR1 (or DR4) positive and DR1 (or DR4) negative disease. In this small group of patients the clinical course of RA seemed to be determined mainly by other genetic or environmental factors.     

HLA Antigens in Addisonian Pernicious Anaemia: Absence of an HLA and Disease Association

S ummary . An examination of HLA antigens in 72 unrelated Caucasian subjects with pernicious anaemia (PA) has revealed no significant association of any HLA-A or B genes with the disease. These data do not confirm the previous reports in the literature which had suggested an increased frequency of the B7 and/or A3 antigen among patients. In addition, the study of four families, each with two or more PA patients, does not support close linkage between disease susceptibility or autoantibody formation and the HLA locus. These data suggest that genes in or near the HLA region may not significantly affect susceptibility to PA.