DR2 positivity and response to methotrexate in rheumatoid arthritis.
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Biomedical subjects
Publications and source records attributed to B O Barger.
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An increase in the frequency of DR3 in rheumatoid arthritis (RA) patients exhibiting toxic reactions to gold salt (GS) therapy has been observed in several studies of Caucasoid patients. Likewise, the association of B35 with gold-induced mucocutaneous reactions has also been reported in Caucasoid RA patients. Similar studies in other ethnic groups have not been previously documented. The present study was performed in American black RA patients receiving GS to determine if there were similar HLA associations with toxic reactions as those reported in Caucasoids. Eight-two seropositive and 18 seronegative American black RA patients were studied. Forty-one of the seropositive (50.0%) and six of the seronegative (33.3%) developed a toxic manifestation. No significant differences in the frequency distribution of HLA-B8, HLA-B35, DR, or DQw antigens were observed between the patients who had a toxic reaction and those who did not in either the seropositive or the seronegative RA patients. In particular, DR3 was not increased in patients with renal toxicity and B35 was not increased in patients with mucocutaneous reaction. Our study demonstrates that American black RA patients exhibiting GS toxicity do not have the same HLA associations as Caucasoids. The possibility that other genetic factor(s) may account for the occurrence of gold salt toxicity in American blacks requires further investigation.
This study was undertaken to determine whether defects in leukocyte function or in genes at the MHC play a role in the etiology of either localized (LJP) or generalized (GJP) juvenile periodontitis. Thirteen LJP and five GJP patients (ranging in age from 13 to 22 years) and their matched controls were compared with respect to selected leukocyte functions and HLA phenotypic frequencies. The results of these studies indicated that there were significant decreases in the phagocytic and chemotactic abilities of polymorphonuclear leukocytes (PMN) in both LJP and GJP. All JP patients displayed intrinsic cell defects in chemotaxis compared with controls; in addition, some patients displayed multiple defects, including those which were serum-associated. Also, there appeared to be a significant association between JP and HLA-DR2 and HLA-A33 phenotypes. Fifty percent of the JP patients were HLA-DR2-positive, whereas only six percent of the matched controls were positive. Thirty-six percent of JP patients were HLA-A33-positive, whereas none of the controls was positive. The association seen with DR2 may be due to sampling, since there were no significant differences between the JP cases and a larger unmatched control sample which was not evaluated for periodontal disease. We conclude from these data that increased susceptibility of some patients to a very aggressive and destructive form of periodontal disease (JP) is based on defects in PMN responsiveness. Further investigations are necessary to determine whether these defects are under genetic control.
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The information available in the literature is controversial as to the association between HLA-DR and systemic sclerosis (SS). We studied 44 Caucasians with SS and found DR1 (P = 0.025; RR = 2.4) and DR5 (P = 0.05; RR = 3.8) to be increased whereas DR3 was not found to be increased when compared to local controls. The possible influence of a DR specificity in the clinical manifestations of SS was also investigated but not found.
An increase in the frequency of DR3 in rheumatoid arthritis (RA) patients exhibiting toxic reactions to chrysotherapy has been reported in several studies of white patients. This study was designed to compare DR antigen frequencies in local white RA patients undergoing chrysotherapy with their response to treatment. The results from our sample of RA patients (n = 148) confirm the fact that there is increased frequency of DR3 in patients who develop toxic reactions to gold therapy, as reported in other studies of white patients. The DR3 increase was attributable to those gold-treated patients who developed proteinuria, and was not observed in patients who developed skin toxicity. Interestingly, the associations were not as strong as those found in other reports. Only 21.1% of the patients with DR3 manifested toxic reactions overall, with only one-third of the patients with proteinuria being DR3 positive. There was also an association of toxicity, albeit not significant, with a decreased frequency of DR2, which is consistent with the suggestion that this phenotype may protect against adverse reactions to gold treatment. These results suggest that while DR3 is significantly associated with adverse response to gold treatment, the relationship is not as strong as that previously reported. Explanation of these differences remains to be elucidated.
The complement component C4 variants C4A 4, C4B 4 and C4B Q0 were found to be significantly increased in 64 black patients with Type 1 (insulin-dependent) diabetes compared with 169 black control subjects, yielding relative risks of 3.3, 2.9 and 3.4, respectively. The increased frequencies of C4B 4 and C4B Q0 in black Type 1 diabetic patients are similar to those found in Caucasoid Type 1 diabetic patients. The data suggest that Type 1 diabetes in black Americans may be partially due to admixture of genes from whites.
The effect of pretransplant stored donor-specific blood transfusions (DSBTs) on renal allograft survival in 108 consecutive one-haplotype living-related donor (LRD) transplant recipients (group A) was compared with a similar consecutive series of 40 one-haplotype LRD recipients (group B) who did not receive DSBTs. All transplant recipients in both groups received identical immunosuppressive protocols using azathioprine and prednisone. One hundred twenty-eight patients received pretransplant stored DSBTs. Twelve of these patients (9%) developed cytotoxic antibodies to their respective donors and those transplants were not performed. Eight patients who had negative final crossmatches with their prospective donor experienced delay or cancellation of their transplants due to late donor withdrawal, or illness of the donor or recipient. Actuarial graft survival for group A and group B patients was compared at 6, 12, 18, and 24 months. Group A graft survival was 94, 90, 90, and 85% and Group B 73, 68, 63, and 63% at the comparison periods. This experience suggests that stored DSBTs are convenient, associated with a low frequency of recipient sensitization, and improved the prospects of success in one-haplotype LRD renal transplantation.
The chicken thymus-specific antigen (T1) was localized within certain cell types of the thymus using an indirect immunofluorescent (FA) test. One of the cell types was similar to small mononuclear cells, whereas the other was much larger and irregular in shape and probably of the recticuloepithelial type. The small cells occurred in clumps mostly at the cortico-medullary junction, although single cells were found scattered in both the medulla and cortex. The large cell was restricted to the medulla and often was surrounded by the smaller cells. The antigen was not detected in frozen tissue sections from bursa, spleen or liver which suggests that the cells expressing the antigen are restricted to the thymus. Using the same antiserum, T1 was localized in thymus sections of other avian species. Soluble extracts prepared from the thymus of various avian and mammalian species were tested for T1 by immunoelectrophoresis (IE) and passive hemagglutination inhibition (HI) using anti-T1 serum. T1 was found in all avian species tested, but was not found in mammalian thymuses. The amount of T1 was quantitated in chickens of various ages by radial immunodiffusion (RID). The concentration of T1 increased linearly with age, and ranged from 32 micrograms/mg protein at 1 day of age to 45.6 micrograms/mg protein at 20 weeks of age. The total amount of T1 present reached maximal levels at 12 weeks of age and then declined during the period of thymus involution.
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B27 and the CREG antigens (-7, -27, -40, -42, and -22) have been shown to be related to the spondyloarthropathies. We have studied the frequency distribution of these antigens in patients with RA. Two hundred ninety-six patients with either classical or definitive RA by ARA criteria were studied: 199 were whites and 97 were blacks. Appropriate local control subjects were also studied (242 whites and 283 blacks). In the white RA patients 48.7% possessed a CREG antigen (97 of 199) while in the black patients 28.9% were CREG positive (28 of 97). In the white control subjects, 45.9% had a CREG antigen and 31.4% for the black control subjects. The relationship between CREG antigens and disease expression was compared using clinical, demographic, radiologic, and therapeutic parameters. For the white group there was no difference in the age and sex, disease duration, functional capacity, anatomic grading, C/M ratio, seropositivity, frequency of extraarticular manifestations (subcutaneous nodules, vasculitis, sicca symptoms, pleuropulmonary, or pericardial disease), frequency of remittive therapy, and toxicity to chrysotherapy. For the blacks all parameters were comparable except for a decrease in the frequency of extraarticular manifestations among the CREG-positive patients (21.4 vs. 46.4%) which is significant (p less than 0.05). Our data show no significant differences in the frequency of the CREG antigens in either blacks or whites with RA as compared to normal subjects. However, a possible sparing of some of the extraarticular manifestations of the disease appears to associate with the CREG antigens.
In order to try to detect heterogeneity within insulin dependent diabetes mellitus (IDDM) and to distinguish a mode of inheritance of IDDM, population genetic analyses were performed using HLA allele frequencies. HLA-A and -B typing performed on 231 IDDM individuals and 268 controls from the southeastern U.S. showed significant increases with IDDM in A2, B8, B15 and B18, and significant decreases in Aw23, B7, B14 and B17. The combination of HLA-B8/B15 showed a greatly increased risk (RR = 25.5). Between the 120 IDDM individuals and 123 controls HLA-DR typed, HLA-DR3 and -DR4 were significantly increased among the IDDM group and DR2 and DR7 were decreased. The risk for DR3/4 was 29.2. It appeared that the B15 association was secondary to the DR4, but the B8/DR3 association showed no difference. Using the method of Curie-Cohen, no significant increases in risk were found for the B8/B15 or DR3/DR4 heterozygotes when compared to the respective homozygotes. Using the method of Thomson and Bodmer, the dominant mode of inheritance was excluded for DR4 only. There was a significant increase in B15 and DR4 in those with onset before age 20. No significant differences were found among the DR phenotypes with respect to season.
C4 is composed of two tightly linked genes (C4A and C4B) lying within the major histocompatibility complex of chromosome 6 that can be demonstrated by agarose gel electrophoresis. Seven alleles and five alleles at the C4A and C4B loci, respectively, were detected in 169 black individuals from the southeastern United States. Furthermore, the phenotypic frequencies of C4A6, C4A5, C4A4, C4B4, C4B3 and C4BQ0 were significantly different between black and white Americans.
The present study combines segregation and linkage information on 30 families ascertained through a proband and a first degree relative affected with insulin-dependent diabetes mellitus (IDDM). An autosomal dominant model with incomplete penetrance was much more likely to fit the family data than a recessive model, whether or not linkage to HLA was assumed. The lod scores for linkage to HLA were 2.46 at theta M = theta F = 0.00 for dominant and 1.45 at theta M = theta F = 0.22 for a recessive model. The results are discussed in light of heterogeneity in likelihood and lod scores when the families are grouped by familial types, which indicate that the increase in likelihood of a dominant hypothesis can be attributed to the parent-child families and not the sib-sib families.
DR antigen distribution was studied in 85 Blacks with either classical or definite rheumatoid arthritis (RA). Sixty-three were seropositive and 22 were seronegative by latex fixation titer. The frequency of DR4 was 7.41% in our control Black population (n = 162), 22.22% in the seropositive (0.01 greater than p greater than 0.001; RR 3.57) and 22.72% in the seronegative RA (0.01 greater than p greater than 0.001; RR 3.67). Our data confirm the association of DR4 with seropositive RA in Blacks, and suggest a similar association of DR4 with seronegative RA. It also suggests that DR4 may be a risk factor for more aggressive disease in Blacks with seropositive RA.