Rheumatoid Arthritis: Chabod J

Toussirot E, Robinet E, Saas P, Chabod J, Augé B, Cozma G, Tiberghien P, Roudier J, Wendling D. · Department of Rheumatology, University Hospital Jean Minjoz, Bd Fleming, F-25030 Besançon cédex, France. · Autoimmunity. · Pubmed #16891218 No free full text.

Abstract: The Escherichia Coli bacterial extract (OM-89) is used in the treatment of rheumatoid arthritis (RA). We evaluated the immunological changes induced by oral administration of OM-89 in 12 RA patients (polyclonal T cell reactivity to PHA, T cell precursor frequencies specific for OM-89 and Tetanus toxoid (TT), a control antigen and the release of Th1 (IFN-gamma, TNF-alpha), Th2 (IL-4) and T regulatory 1 cell (Tr1) (IL-10) cytokines in the supernatants of PBMC cultures. Stimulation index in response to PHA decreased at month 3 as well as T cell precursor frequencies specific for TT with similar trends for OM-89-specific T cell precursor frequencies. OM-89 induced a strong production of IL-10, a significant decrease in IL-4 production while TNF-alpha and IFN-gamma production tended to decrease during the study.Our results suggest that OM-89 has immunomodulatory properties by inducing changes in PBMC cytokines release suggestive of an induced Tr1 response to OM-89.

Zhang SL, Chabod J, Penfornis A, Reviron D, Tiberghien P, Wendling D, Toussirot E. · Blood Transfusion Center Bourgogne/Franche-Comté, UPRES-EA 2284, Besançon, France. · Eur J Immunogenet. · Pubmed #12047361 No free full text.

Abstract: The 'transporter associated with antigen processing' (TAP) gene products are involved in the processing of endogenous peptides that bind to class I molecules. Polymorphism within these genes could alter the level of the immune response, a phenomenon relevant to the development of autoimmune diseases. In this study, we examined the polymorphism of TAP1 and TAP2 genes in patients with rheumatoid arthritis (RA). TAP1 and TAP2 typing was performed for 138 Caucasian RA patients and 100 healthy controls, all originating from eastern France. TAP1 polymorphic residues at positions 333 and 637 and amino acid variants 379, 565, 651 and 665 in the TAP2 gene were found using amplification refractory mutation system-polymerase chain reaction (ARMS-PCR). This method enabled us to determine four TAP1 alleles (TAP1A to TAP1D) and eight TAP2 alleles (TAP2A to TAP2H). All patients and controls had been HLA-DRB1* genotyped. The polymorphic residues TAP1333 and TAP1637 did not show any difference in their distribution between patients and controls. Similar findings were obtained for TAP2379 and TAP2665. However, we found an increased frequency of Thr homozygosity and heterozygosity at position 565 in the TAP2 gene in RA patients (RA vs. controls: 25.3 vs. 14%; P = 0.032; OR = 2.09; CI = 1.01-4.38). Similarly, the prevalence of subjects who were homozygote and heterozygote for Cys651 was increased in the RA group (RA vs. controls: 36.8 vs. 11%; P = 0.02). The dimorphic site TAP2565 defines TAP2D and TAP2E alleles, while the site at position 651 characterizes TAP2F. Thus, we found that TAP2D and TAP2E alleles were more prevalent in RA, but not significantly so (RA vs. controls: TAP2D: 10 vs. 3.6%; P = 0.24; TAP2E: 3.6 vs. 0%; P = 0.19). Similarly, the frequency of TAP2F was higher in RA patients (24.5%) than in controls (11.3%), but this was not significant after correction (P = 0.029; Pcorr = 0.17). Finally, we found no linkage disequilibrium between DRB1* RA-associated alleles and amino acid substitution Thr565 or TAP2D and TAP2E alleles, whereas Cys651 (and TAP2F) was not independent of DRB1*04, a strongly RA-associated allele. Finally, Thr at position 565 in the TAP2 gene was associated with manifestations of disease severity in only a few patients. Examination of TAP1 and TAP2 gene polymorphisms in RA patients revealed an association between a particular amino acid residue, namely Thr565 in the TAP2 gene, and RA. This association was found to be weak and did not seem to be a predictor for the severity of the disease.

Toussirot E, Sauvageot C, Chabod J, Ferrand C, Tiberghien P, Wendling D. · Department of Rheumatology, University Hospital Jean Minjoz, Besançon cédex, France. · Hum Immunol. · Pubmed #10689120 No free full text.

Abstract: In this study, the polymorphisms of the HLA DMA and DMB genes in patients with rheumatoid arthritis (RA) were examined.DMA and DMB typing was performed in 120 white RA patients from eastern France and 100 healthy controls, using PCR-SSO (sequence specific oligonucleotide probes) method for DMA determination and PCR-RFLP (restriction fragment length polymorphism) method for DMB typing. All patients and controls had been HLA DRB1* genotyped.DMA*0103 was found significantly increased in RA patients (RA vs. controls: 18.3% vs. 4%) (p(corr) = 0.004; OR: 5.39; CI: 1.67-19.23). A decreased frequency of DMA*0102 was also observed in the RA group (RA vs. controls: 18.3% vs. 31%), but not significantly. There were no differences in the prevalence of DMB alleles between RA and controls. The patients and the controls were then stratified according to the expression of the HLA DRB1* RA-linked alleles (DRB1*01 and *04) and this allowed us to find no linkage disequilibrium between DMA*0103 and DRB1*01 or *04 alleles. Finally, most DMA*0103 patients were positive for rheumatoid factors and had extraarticular involvement such as subcutaneous nodules. Thus, our results suggest that DMA*0103 could be an additional genetic factor for RA susceptibility in French whites.

Toussirot E, Auge B, Tiberghien P, Chabod J, Cedoz JP, Wendling D. · Department of Rheumatology, University Hospital, Besançon, France. · J Rheumatol. · Pubmed #10405928 No free full text.

Abstract: OBJECTIVE: To examine the effects of HLA-DRB1 alleles and amino acid sequences that carry the shared epitope (SE) upon rheumatoid arthritis (RA) susceptibility and disease severity in patients from Eastern France. METHODS: HLA-DRB1 alleles were determined in 120 patients and 104 healthy controls by polymerase chain reaction/sequence specific oligonucleotide probes. Subtyping of DRB1*01 and *04 were performed using sequence specific primers. Patients were retrospectively evaluated for disease duration, age at disease onset, presence of rheumatoid factors, subcutaneous nodules, vasculitis and other extraarticular diseases, for the need for arthroplasty and immunosuppressive/immunoregulatory agents, and for radiographic damage. RESULTS: The prevalence of HLA-DRB1*04 was significantly higher in patients (46.6%) than in controls (17.3%) (Pcorr = 0.000003). HLA-DRB1*0101 and *0401 were the most prominently associated subtypes in patients with RA (33.3%, Pcorr = 0.011, and 28.3%, Pcorr = 0.00008, respectively). A significant fraction of patients (72.5%) expressed one or 2 copies of the SE (p < 0.0000001; OR 4.77, CI 2.61-8.78). The presence of double SE was associated with a higher risk of developing RA (OR 4.83, CI 1.91-12.71; p = 0.0001). No significant differences in the clinical records among patients expressing no RA linked alleles, one and 2 copies of the SE, were observed. However, analyzing the specific effect of each amino acid sequence, we observed a significant association of the QKRAA motif with vasculitis (p = 0.03) and history of joint replacement surgery (p = 0.05), suggesting a role for lysine in position 71 of the shared sequence. CONCLUSION: These findings differ from those of previous HLA-DRB1 allele studies in patients with RA from other regions of France. Thus, the heterogeneity in both the expression of DRB1 alleles and the association of these alleles with disease severity could be relevant within a country such as France.