DR2 antigens are associated with severity of disease in toxic oil syndrome (TOS)

Toxic oil syndrome (TOS) was an epidemic which broke out in Spain in 1981, caused by the ingestion of rapeseed oil denatured with 2% aniline and sold illegally as edible oil. More than 20,000 people were affected and mortality rate was 8.4%. Genetic susceptibility appears to be involved in the pathology of this disease. Several reports have described association between the chronic stage of the disease and DR-DQ antigens (DR3, DR4, DR2 and DQ8). In the present work, we have reassessed the HLA class II antigens in a well-designed case-control study. Triplets of subjects (n=265) composed by chronic patients (n=117), non-affected family members (n=71) and non-related controls (n=77) were studied. Also, HLA class II antigens were analyzed in patients who had died from TOS (n= 34) and in TOS control patients who died from other non-TOS related causes (n=13). Regarding surviving patients no significant association was found between HLA and disease. In contrast, an increase in phenotypic frequency of DR2 antigen, was found in patients who had died from TOS (73.5%) compared with the whole study group: TOS-affected alive patients (25.6%, corrected P<0.001), non-affected family members (28.5%, corrected P<0.001), non-related controls (23.9%, corrected P<0.001) and dead controls (38.4%, P=0.03).     

Immunogenetic markers in patients with Graves' disease

Summary 110 carefully characterized Caucasoid patients with Graves' disease were tested for HLA class I and class II antigens. Compared with Caucasian controls (n=193), the frequencies of HLA B8, Cw7 and DR3 were significantly increased (p_c<0.05). In the subgroups with and without exophthalmos, HLA A3 exhibited a negative but insignificant association with the eye involvement, while A19 and Cw2 showed positive, however even weaker correlations with eye disease. HLA DR5 was associated with relapsing thyrotoxicosis, whereas HLA DR7 and B12 were negatively correlated with relapse. These results confirm the positive correlation of HLA B8 and DR3 with Graves' disease and reveal a not yet observed association with Cw7. Reported correlations of antigen frequencies with eye disease and relapsing thyrotoxicosis could not be confirmed. Other previously unknown, however subtle differences in disease subgroups were observed.Abbreviations EF etiologic fraction - HLA Human leukocyte antigens - RR relative risk - TRAb TSH receptor antibodies - TSH Thyroid stimulating hormone     

Human lymphocyte antigens (HLA) and Graves' disease in Turkey

To evaluate the association of HLA types with Turkish patients with Graves' disease, HLA typing, clinical findings, and thyroid antibodies were correlated. The HLA types, clinical findings (ophthalmopathy and age at onset), and thyroid stimulating hormone (TSH) receptor (TRAb) and antithyroid microsomal antibodies (MAb) were analyzed. Seventy Turkish patients with Graves' disease and 306 control subjects were assessed. Serological HLA typing was performed in HLA A, B, C, DR, and DQ loci. There was a significantly increased prevalence of HLA B8, B49, DR3, DR4, and DR10 in Graves' disease. The association of Graves' disease with HLA DR3 was found to be less strong than previously described. The HLA DR4 antigen may contribute to the predisposition of Graves' disease in Turkey. The results suggest that HLA B7, B13, DR7, DQw2, and DQw3 may confer a protective effect for Graves' disease in Turkey. Patients carrying HLA B12, B18, and B44 haplotypes had a tendency to develop the disease at a later age. The difference from the other studies may be the result of the selection of the controls; in part, of the variability in serological typing reagents; and, also, of the rather weak HLA associations with the disease.This study was presented in part at the Annual Meeting of the National Endocrinology and Diabetes Association, Bursa, Turkey, May 25–28, 1992.     

HLA antigens in IGA deficient paediatric patients

HLA antigens (A, B, C and DR loci) were studied in 62 IgA-deficient (IgAd) paediatric patients: 17 with coeliac disease (CD), 13 with juvenile arthritis (JA), 27 with frequent respiratory tract infections (RTI) and five with other diseases. The frequencies of HLA antigens in IgAd patients were compared with those in healthy blood donors, and in CD and JA patients with normal serum IgA levels. The IgA deficiency in the patients showed significant associations with HLA A1, B8, B13, Cw6, DR3 and DR7 (P less than 0.0005, P corr less than 0.02 vs controls) and decreased frequencies of DR2 (P less than 0.0005, P corr less than 0.02 vs controls). The HLA associations typical of coeliac disease, increased frequencies of HLA-B8 and DR3, were evident among the IgAd coeliacs; in contrast to the coeliacs with normal IgA levels, the IgAd coeliacs showed a significant increase of the HLA-Cw6 allele (P less than 0.0005, P corr less than 0.02 vs control coeliacs). Increased frequencies of HLA-A1, B8, B13, Cw6, DR3 and DR7 were noted in the patients with RTI, which can be explained by the frequent occurrence of the haplotypes A1, B8, DR3 and B13, DR7, the latter haplotype often also having the Cw6 allele. Among the IgAd JA patients, the antigen frequencies were similar to those in the JA patients with normal serum immunoglobulins.     

HLA typing in classical and African Kaposi's disease

HLA A, B, C, typing have been done in 39 patients with clinically and histologically documented classical Kaposi's sarcoma. Thirty three were also typed for HLA DR antigens. Twenty seven were males, 12 were females and three ethnic groups were represented: european caucasoids 41%, north african caucasoids 38.5% and negroids 20.5%. The only statistically significant abnormality is an increase of HLA DR5 frequency (60.6 vs 26. p less than 0.001 et RR = 4.2). Such an increase has been evidenced also in AIDS patients, with or without Kaposi's sarcoma and then is not discriminant between all this different types of the disease.     

Lyme-Borreliosis and possible association with HLA-antigens*

The frequencies of HLA A, B, C and DR antigens were evaluated in 220 persons from West Germany with inapparent and manifest Borrelia burgdorferi infections. Thirty-seven forest workers showing elevated antibody titres against Borrelia burgdorferi had asymptomatic infection, and are described as stage 0. One hundred and eighty-three patients presented with the clinical stages 1-3 of the infection. Control persons (n = 655) were typed in the same time period and by identical staff. HLA CW3 was present in 36.3% of patients as compared to 23.2% of the controls (RR = 1.88, pcorr = 0.03) and was significantly associated with manifest infection. In addition, the antigen A2 was found slightly but not significantly more frequent in the patients (55.2% vs 44%; pcorr = 0.41). The phenotype combination HLA A2 and Cw3, however, was significantly elevated in patients (24.6% vs 10.8%; pcorr = 0.0005). In contrast to these class 1 antigens, HLA DR3 showed a tendency of negative association with manifest infection. But this finding was not yet found to be significant (15.3% vs 25.3%; RR = 0.53, pcorr = 0.26). The frequency of HLA DR2 showed a constant decrease from stage 0 to stage 3 (inapparent infection to late complications). Using the rank correlation coefficient of Spearman, this association was found to be significant (-1.00, p less than or equal to 0.05). All other tested HLA antigens and antigen combinations showed no significant differences. The data suggest that HLA CW3 may be associated with Borrelia burgdorferi infection, whereas HLA DR2 and DR3 may be associated with less incidence of severe courses and less complications in this disorder.     

Analysis of HLA class II genes in Hashimoto's thyroiditis reveals differences compared to Graves' disease

Graves' disease (GD) and Hashimoto's thyroiditis (HT) represent the commonest forms of autoimmune thyroid disease (AITD) each presenting with distinct clinical features. Progress has been made in determining association of HLA class II DRB1, DQB1 and DQA1 loci with GD demonstrating a predisposing effect for DR3 (DRB1(*)03-DQB1(*)02-DQA1(*)05) and a protective effect for DR7 (DRB1(*)07-DQB1(*)02-DQA1(*)02). Small data sets have hindered progress in determining HLA class II associations with HT. The aim of this study was to investigate DRB1-DQB1-DQA1 in the largest UK Caucasian HT case control cohort to date comprising 640 HT patients and 621 controls. A strong association between HT and DR4 (DRB1(*)04-DQB1(*)03-DQA1(*)03) was detected (P=6.79 x 10(-7), OR=1.98 (95% CI=1.51-2.59)); however, only borderline association of DR3 was found (P=0.050). Protective effects were also detected for DR13 (DRB1(*)13-DQB1(*)06-DQA1(*)01) (P=0.001, OR=0.61 (95% CI=0.45-0.83)) and DR7 (P=0.013, OR=0.70 (95% CI=0.53-0.93)). Analysis of our unique cohort of subjects with well characterized AITD has demonstrated clear differences in association within the HLA class II region between HT and GD. Although HT and GD share a number of common genetic markers this study supports the suggestion that differences in HLA class II genotype may, in part, contribute to the different immunopathological processes and clinical presentation of these related diseases.     

HLA class II (DR, DQ, DP) in patients with sarcoidosis: evidence of an increased frequency of DRw6.

The distribution of HLA class II (DR, DQ, and DP) antigens was studied in 41 patients with symptomatic sarcoidosis (SA) and ethnically matched healthy controls. HLA-DR, -DQw1 and -DQw3 typings were performed with alloantisera in the conventional microcytotoxic test, whereas -DP typings were done using primed lymphocyte typing. The frequencies of DRw6 were 41.5% in SA patients and 17.9% in controls (relative risk, RR = 3.2, p = 0.00087, p less than 0.05 when corrected). DR3 was decreased to 14.6% in SA patients compared to 25.9% in controls (RR = 0.49, p = 0.07, i.e., not statistically significant). The decreased frequency of DR3 was only seen in patients with severe, long-standing disease. In contrast, the DRw6 increase was most pronounced in patients with severe disease (RR = 6.4; p = 0.003). There were no statistically significant deviations in the frequencies of DQ and DP alleles between patients and controls. In conclusion, our data suggest that DRW6 confers susceptibility and DR3 resistance to severe, long-standing disease.     

HLA and Kaposi''s sarcoma in Sardinia

Twelve Sardinian patients affected by histologically defined classic Kaposi's sarcoma (KS) were HLA-A, B, C and DR typed. Compared to 220 age and ethnically matched healthy controls, KS patients showed a significant increase in HLA-DR5 (66.6 vs 23.1%, P less than 0.001) and a considerable decrease in HLA-DR3 (8.3 vs 53.6%, P = 0.0055). No definite association was observed for other HLA antigens. These results confirm the existence of an HLA associated genetic control of KS susceptibility and support the hypothesis that HLA-DR5 plays the role of a predisposition marker while HLA-DR3 bears a genetic resistance to the disease.     

HLA Bw46 and DR9 associations in Graves' disease of Chinese patients are age- and sex-related

The HLA-A, -B antigens in 159 Chinese patients with Graves' disease were compared with those of 330 controls. The HLA-DR antigens of the patients were also studied in 100 normals. Analysis of the increased prevalence of Bw46, according to the sex and age of onset of disease of the patients, showed that the strong association of Bw46 resided with male patients (n = 58), Pc = 0.0000052, RR = 4.2. Although the frequency of Bw46 was also increased in female patients (n = 101), it was statistically not significant. For the DR9 antigens, the strong association with male patients was also observed, viz. Pc = 0.019, RR = 3.2. Males also had higher risks of Graves' disease if they had homozygous Bw46 at presentation. Further analysis by age of onset of disease revealed the segregation of significant association with Bw46 for the males at 1-19 yr, Pc = 0.0011, RR = 17.5 HLA associations (Bw46 and DR9) with Graves' disease in Chinese are observed primarily in males, especially those whose known ages of onset of the disease are between 1-19 yr (Bw46).     

HLA antigens and Graves' disease in Black South Africans

This study concerns the frequencies with which 36 HLA-A, -B and -C antigens occurred in 84 Black Africans with Graves' disease and in 311 Black controls. In the hyperthyroid patients significant reductions were found in the frequencies of HLA-B7 ( P <0.001, relative risk (RR) 0.33), HLA-Bw42 ( P <0.001, RR 0.32) and the HLA-B7-Bw42 crossreactive group (CREG) ( P <0.0001, RR 0.27), and in the frequencies of the phenotypic combinations HLA-A1, B7 ( P <0.001) and Aw30, B7-Bw42 ( P <0.001). HLA-B8 was increased in frequency ( P <0.01, RR 2.84). In patients without circulating antithyroglobulin or antimitichondrial antibodies the frequencies of HLA-A2 and B17 were increased when compared to those with antibodies or to the controls. In patients with and without clinically evident infiltrative ophthalmopathy the frequencies of HLA antigens were similar. In 62 Caucasian patients with Graves' disease, no antigens or phenotypic combinations occurred with increased or decreased frequency when compared to 278 controls.
Analysis of the frequencies of 9 HLA antigens and phenotypic combinations common in Caucasians but rare in Blacks revealed that only two antigens (A2 and B8) occurred with increased frequency in Black patients, suggesting that a contribution of Caucasian genes to the Black thyrotoxic subjects was unlikely.
Similarly, only one common Black antigen (A28) of 8 common antigens and phenotypic combinations, occurred in Caucasian patients with a frequency similar to that of Black controls. Thus it is unlikely that Black genes contributed to the lack of a significant increase of HLA antigens in the Caucasian thyrotoxic patients. The possession of HLA-B7-Bw42 CREG or related genes may be a protection against Graves' disease in Black Africans.     

HLA-DQ3 is Associated with Graves' Disease in African-Americans

HLA heterogeneity occurs in various ethnic groups and has been significantly associated with Graves' disease. In this study we have determined that DQ3 is associated with Graves' disease in African-Americans. Human leukocyte antigen (HLA) typing of D-region antigens in 139 controls and 45 Graves' disease patients reveals significant differences for HLA-DR2, DR9, DQ1, and DQ3. The latter remained significant after correction. Increases in HLA-DR9 and DR3 are associated with increases in DQ3 and DQ2, respectively. The decrease in DR2 is associated with a decrease in DQ1. The associated increases and decreases in DR with DQ antigens probably reflect linkage disequilibrium. Patients were evaluated for autoantibodies against microsomal antigens and/or against thyroglobulin. All of the normal control volunteers were negative for thyroid antibodies and thirteen percent of patients produced autoantibodies. No significant associations were detected for antibody production, type of treatment required, age of onset, family history of Graves', status of T₃, T₄ levels, goiter and/or ophthalmopathy.     

Study of host- and virus-related factors associated with spontaneous hepatitis C virus clearance

Epidemiologic parameters, virologic characteristics and frequency of HLA class II DR and DQ antigens were compared between 63 subjects with spontaneous hepatitis C virus clearance (group 1) and 282 patients with chronic active hepatitis C virus infection (group 2). DRB1*1101 and moreover DQB1*0301 alleles were more frequent in group 1 than in group 2 (33.8% vs. 14.7% and 64.4% vs. 28.6%; P=0.012 and P=0.003, respectively). The frequency of DQB1*02 was lower in group 1 than in group 2 (25.4% vs. 49%; P=0.04). No difference was observed in viral genotype distribution between group 1 and group 2. Univariate analysis showed that female sex and contamination by intravenous drug use were associated with self limited infection. However, by multivariate analysis, the only independent factor associated with hepatitis C virus RNA clearance was female sex (P=0.004). In conclusion, spontaneous hepatitis C virus RNA clearance is determined by class II antigens (mainly DQB1*0301) and female sex, while viral genotype plays no role.     

Immunogenetic and racial determinants of gold toxicity in rheumatoid arthritis

Typing for antigens HLA-A,B,C and DR was performed on 165 rheumatoid arthritis patients (14 black, 151 white) who had received gold therapy to determine the relationship between HLA antigens and gold dermatitis, stomatitis, thrombocytopenia, and proteinuria. Dermatitis and stomatitis occurred in both black and white patients. Thrombocytopenia and proteinuria occurred only among the white patients studied. The absence of thrombocytopenia and proteinuria among the black patients was not statistically significant. Antigen HLA-DR7 was uncommon among black and white subjects with dermatitis (0 of 6 blacks, 4 of 48 whites), but this decrease in frequency was not statistically significant. Antigen HLA-DR3 was an important risk factor for thrombocytopenia (relative risk = 11.8, P = .0043) and proteinuria (RR = 5.8, P = .032). These results are consistent with previous studies of HLA-DR3 and gold toxicity. The only black patient with stomatitis possessed the A1B8DR3 phenotype. Future studies should examine whether the same HLA antigen confers risk of different gold toxicities in different racial groups, and whether there are HLA antigens that provide a protective effect.     

HLA and Graves'' disease in Koreans

The HLA-A, B, C and DR antigen distribution in 128 Korean patients with Graves' disease was compared with that in 220 controls. The frequency of HLA-B13, DR5 and DRw8 (relative risk 3.8, 4.4, and 2.3, respectively) was significantly increased in patients with Graves' disease. There was no significant correlation between the presence of these HLA antigens and the clinical features.     

Support for an association between HLA‐DR1 and schizophrenia in the Japanese population

An increase of HLA‐DR1 has been observed in schizophrenia patients from the Japanese population. A decrease of DR4, which was reported in Caucasian patients, has also been found in some of the Japanese studies. This small study further investigated frequencies of HLA‐DR1 and DR4 in unrelated Japanese patients with schizophrenia (n = 45) and healthy comparison subjects (n = 117). The number of patients possessing DR1 was higher (10 of 45, 22%) compared with the comparison group (11 of 117, 9.4%, P = 0.03). This may support the previous observation of an increased DR1 frequency in the Japanese patients. When the present data is combined with three previous studies, proportions of the Japanese subjects with DR1 were 98 of 588 schizophrenia patients (16.7%) vs. 93 of 942 comparison subjects (9.9%). However, no difference was observed in DR4 frequencies between the patients (51%) and comparison subjects (44%). Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:725–727, 2000. © 2000 Wiley‐Liss, Inc.     

Comparative study on IgG and IgA antibodies against human thyroid and eye-muscle antigens in Graves' ophthalmopathy.

Circulating IgG and IgA anti-thyroid and anti-eye muscle antibodies were investigated in 87 patients with Graves' disease (60 cases with ophthalmopathy). The ELISA method was used. Both IgG and IgA antibodies were demonstrated against human thyroid and eye-muscle membrane or cytosol antigens. Anti-eye-muscle antibodies of the IgA type were observed more frequently than those of the IgG type (25 cases vs. 18 were demonstrated with membrane antigens and 37 cases vs. 23 with cytosol antigens). The respective distributions for thyroid antigens the cytosol fraction were 55 cases vs. 13 and 18 cases vs. 36. A significant difference was observed in the anti-thyroid IgG levels and the anti-eye-muscle membrane or cytosol levels between the patients with Graves' disease and those in control group (P less than 0.001). The difference in the IgA antibody to thyroid and eye-muscle antigens was significant between the patients with and without ophthalmopathy (P less than 0.002). The strong correlation between the levels of IgA antibodies to thyroid and those to the eye-muscle cytosol fractions might be connected with the theory of the common aetiology of the thyroid and eye diseases in Graves' ophthalmopathy (P less than 0.001). Circulating IgA anti-human thyroid and eye-muscle antibodies seemed to have a diagnostic relevance in the development of ophthalmopathy in Graves' ophthalmopathy.     

HLA-DRB and -DQB1 alleles in Polish patients with hepatitis B associated membranous nephropathy

Abstract: We have studied the HLA-DRB and -DQB1 alleles of 42 paediatric patients who have suffered from membranous nephropathy associated with a hepatitis B infection (HBVMN). These patients were all from the Gdansk area of Northern Poland and the disease was diagnosed by light and electron microscopy. The control population consisted of 55 healthy children, approximately age matched, from schools in Gdansk. In addition we have also analysed 40 patients chronically infected with hepatitis B, without any renal involvement, as hepatitis B disease controls. The HLA alleles were defined using PCR/SSP. As idiopathic membranous nephropathy and low responsiveness to hepatitis B vaccine have been found to be associated with DR3 in Caucasoids, our hypothesis was that the HBVMN patients would show an increase in DR3. Our results indicate that, although there is a small increase in the frequency of DRBl*0301 in the HBVMN patients (16/42 38%) when compared to the healthy controls (15/55 31%), this does not approach significance. There is a significant increase in the frequency of DQBl*0303 in the HBVMN patients vs the healthy controls, after correction for the number of antigens detected ( P ) (13/42 vs 2/55, RR=11.6, P =0.0007, P _c=0.02). A similar increase in DQBl*0303 is seen in the HBVMN patients when compared to the hepatitis controls (13/42 vs 4/40) but this is only significant before correction (RR=4.3, P =0.04).     

Possible HLA influence in governing susceptibility to non-cirrhotic portal fibrosis

Forty-eight unrelated North Indian patients with non-cirrhotic portal fibrosis were studied for the distribution of HLA-A, B and DR antigens. No significant differences were observed in the distribution of HLA-A and B locus antigens. In the DR locus, the frequency of DR3 was significantly increased in the patients as compared to the controls (71.7% vs 26.1%, X2 = 25.3), while HLA-DR2 was significantly reduced (X2 = 11.3). Another striking observation was the presence of DR7 in all males negative for HLA-DR3. The results suggest an autoimmune pathogenesis of the disease and that susceptibility to non-cirrhotic portal fibrosis may be HLA class II mediated, with HLA-DR3 influencing susceptibility and DR2 conferring protection. Other genetic factors are also involved.