Class ii major histocompatibility complex gene sequences in rheumatoid arthritis. The third diversity regions of both DRβ1 genes in two DR1, DRw10–positive individuals specify the same inferred amino acid sequence as the DRβ1 and DRβ2 Genes of a DR4 (Dw14) haplotype

The DR1 and DRw10β₁, chain genes were isolated from each of 2 individuals with rheumatoid arthritis who were heterozygous for these class II major histocompatibility complex specificities. The sequences of the DR1β₁ chains from both patients were identical, differing from previously reported DRβ₁ chains of individuals without RA by 2 amino acid substitutions, at positions 85 (Val-Ala) and 86 (Gly-Val), and by a silent mutation at the last nucleotide of codon 78 (C–T), resulting in the loss of a Pst I restriction endonuclease site. Identical DRw10β₁, chain genes were found in both patients. These were shown to encode the epitope recognized by monoclonal antibody 109d6. This antibody also recognizes an epitope on the DRw53β₂ chain of the DR4 haplotype. The third diversity regions of the DR1β (amino acids 67–74) and the DRw10β₁ chains (amino acids 67–73) were identical, respectively, with those of the DR4 (Dw14) β₁, and β₂ chains, raising the possibility that in these patients, the third diversity regions of the two DRβ₁, chain genes present in trans are conformationally equivalent to the cis-encoded third diversity regions of the DR4 (Dw14), DRβ₁, and β₂ chains. The nucleotide sequences of the DQβ complementary DNA clones were identical to that of the DQw1β chain, and no DRβ₂ complementary DNA clones were identified.     

Synergy between T cell receptor β gene polymorphism and HLA–DR4 in susceptibility to rheumatoid arthritis

Objective. To investigate the etiologic significance of germline polymorphisms in the T cell receptor β variable region 6S7 (TCRBV6S7) gene segment and adjacent loci in susceptibility to rheumatoid arthritis (RA). Methods. Ten TCRB allelic polymorphisms were analyzed from 3 groups of white women: 112 with RA, 72 with systemic lupus erythematosus, and 70 healthy controls. All participants were also HLA typed. Results. HLA–DR4+ RA patients showed significantly increased frequencies of TCRBV6S7*1, 13S5P*1 (an allelic variant of BV13S5 promoter), and 12S4*2, compared with healthy controls. The combination of DR4 with either BV6S7*1, 13S5P*1, or 12S4*2 conferred greater risk for RA than HLA–DR4 alone. Pairwise analyses showed a high degree of linkage disequilibrium (P = 10⁻⁵-10⁻⁸) between these 3 TCRBV loci that span 47 kilobases (kb). Conclusion. Our data suggest that a TCR gene segment in or linked to this 47-kb region may be involved in genetic susceptibility to RA through an interaction with HLA–DR4.     

Cytokines in chronic inflammatory arthritis. III. Rheumatoid arthritis monocytes are not unusually sensitive to γ-interferon,but have defective γ-interferon–mediated HLA–DQ and HLA–DR induction

Macrophages present in the synovium and synovial fluid of patients with rheumatoid arthritis (RA) express large amounts of HLA–DR molecules on their surface, despite low levels of γ-interferon (γ-IFN) in the joint. To determine whether this apparent paradox is the result of increased sensitivity to γ-IFN in RA, we compared concentrations of γ-IFN that induced HLA–DR and DQ on peripheral blood monocytes of RA patients and normal donors, using fluorescence-activated cell sorter analysis. Among normal donors, highly variable sensitivity to γ-IFN was observed. Higher amounts of γ-IFN were required to induce class II major histocompatibility complex molecules on RA monocytes versus normal monocytes. The maximum amount of HLA–DR that could be induced on RA and normal monocytes was similar; however, peak levels of HLA–DQ were significantly less in RA. Monocytes from patients with other forms of chronic inflammatory arthritis had intermediate HLA–DQ expression after γ-IFN treatment. These data suggest that an increased sensitivity to γ-IFN in RA does not account for the high level of HLA–DR expression in the joint. Also, a defect in HLA–DQ and HLA–DR induction by γ-IFN was observed.     

Hemoglobinopathies in the dogon country: Presence of βs, βc,and δa'genes

The population of the Dogon, located in Mali, is divided in an endogamic Noble class and two endogamic servant castes (Tanners and Blacksmiths). We find that the polymorphic frequencies of β^c, β^s, and, unexpectedly, a mutation of the δ-chain (δ^A'), are geographically (valley vs. plateau) as well as social status dependent. © 1994 Wiley-Liss, Inc.     

Rheumatoid factor,HLA–DR4, and allelic variants of DRB1 in women with recent-onset rheumatoid arthritis

Objective. To examine the relationship of rheumatoid factor (RF) to HLA–DR4 and alleles of DRB1 in women with recent-onset rheumatoid arthritis (RA). Methods. Incident cases of RA were identified as part of a prospective, population-based case–control study. HLA typing was completed for 246 cases meeting criteria for definite or classic RA. Results. One hundred thirty-six patients (55%) were positive for DR4, and 130 (53%) were RF positive. DR4 was found to be strongly associated with seropositivity (odds ratio 4.1, P < 0.0001). Patients with a shorter interval from RA onset to RF testing had a higher frequency of seropositivity than those with a longer interval (≤18 months 60%, >18 months 33%). Further analysis of patients who had RF testing within 18 months of RA onset showed that the frequency of seropositivity was significantly greater among DR4-positive patients who had the shared sequence stretch of DRβ1 associated with RA susceptibility (76% RF positive) than among DR1-positive patients who had this sequence (45% RF positive) (odds ratio 3.8, P = 0.01). Moreover, the frequency of seropositivity among DR1-positive patients with the sequence did not differ from that among all patients without the shared sequence (47%) (odds ratio 0.9, P = 0.8). Conclusion. HLA–DR4 is strongly associated with seropositivity in women with recent-onset RA. The amino acid sequence of DRβ1 that is associated with susceptibility to RA and is shared between DR4 and DR1 appears not to be the primary determinant of seropositivity in these women.     

KIR2DL3 and the KIR ligand groups HLA‐A‐Bw4 and HLA‐C2 predict the outcome of hepatitis B virus infection

Killer immunoglobulin‐like receptors (KIRs) regulate the activation of natural killer cells through their interaction with human leucocyte antigens (HLA). KIR and HLA loci are highly polymorphic, and certain HLA‐KIR combinations have been found to protect against viral infections. In this study, we analysed whether the KIR/HLA repertoire may influence the course of hepatitis B virus (HBV) infection. Fifty‐seven subjects with chronic hepatitis B (CHB), 44 subjects with resolved HBV infection and 60 healthy uninfected controls (HC) were genotyped for KIR and their HLA ligands. The frequency of the HLA‐A‐Bw4 ligand group was higher in CHB (58%) than subjects with resolved infection (23%) (crude OR, 4.67; P<.001) and HC (10%) (crude OR, 12.38; P<.001). Similar results were obtained for the HLA‐C2 ligand group, more frequent in CHB (84%), than subjects with resolved infection (70%) (crude OR, 2.24; P<.10) and HC (60%) (crude OR, 3.56; P<.01). Conversely, the frequency of KIR2DL3 was lower in CHB (81%) than in subjects with resolved infection (98%) (crude OR, 0.10; P<.05). These results suggest a detrimental role of HLA‐A‐Bw4 and HLA‐C2 groups, which are associated with the development of CHB, and a protective role of KIR2DL3. A stepwise variable selection procedure, based on multiple logistic regression analysis, identified these three predictive variables as the most relevant, featuring high specificity (90.9%) and positive predictive value (87.5%) for the development of CHB. Our results suggest that a combination of KIR/HLA gene/alleles is able to predict the outcome of HBV infection.     

A novel mediterranean “δβ-thalassemia” determinant containing the δ+27 and β°39 point mutations in cis

The term δβ-thalassemia with normal HbF has been recently proposed to define heterogenous δ and β globin gene molecular defects involving the same chromosome in cis. Here, we describe a Sardinian family in which three members showing microcytosis, border-line HbA₂ levels and normal HbF proved to be heterozygotes for δ ⁺27 and β°39 point mutations in cis by allele specific oligonucleotyde hybridization as well as by ECO 0 109 I endonuclease digestion and electrophoresis. As some of these β-thalassemia carriers shows normal HbA₂ levels, knowledge of the molecular basis of this novel δβ-thalassemia silent phenotype would be useful in thalassemia screening and genetic counselling. © 1994 Wiley-Liss, Inc.