Rheumatoid Arthritis: Amariglio N

Nagar M, Vernitsky H, Cohen Y, Dominissini D, Berkun Y, Rechavi G, Amariglio N, Goldstein I. · Sheba Cancer Research Center, The Chaim Sheba Medical Center, Tel Hashomer and Tel Aviv University-Sackler Faculty of Medicine, Israel. · Int Immunol. · Pubmed #18567616 No free full text.

Abstract: The transcription factor forkhead box P3 (FOXP3 in humans; Foxp3 in mice) controls the development and function of regulatory T cells (Treg). In mice, CD4(+)CD25(-) T cells do not express Foxp3 following TCR activation. Whether FOXP3 is a common activation-induced molecule in human T cells--hence not Treg restricted--is currently a controversial issue. As FOXP3 can significantly modulate the function of T cells, understanding the mode (and regulation) of FOXP3 expression in human T cells is vital. Here we show that in conventional CD4(+)CD25(-) T cells, the induction of FOXP3 expression following TCR activation is both restricted to a fraction of the progeny and transient. Moreover, FOXP3 expression in vivo is particularly infrequent in activated effector CD4(+) T cells that accumulate within inflamed joints. We next demonstrate that the repression of FOXP3 transcription in resting conventional human CD25(-) T cells is linked to complete methylation of an evolutionarily conserved intronic CpG island. The dense methylation pattern is furthermore inherited after activation by progeny. This intronic CpG island, on the other hand, is frequently unmethylated in CD4(+)CD25(+) T cells. Importantly, blocking maintenance DNA methylation, by pharmacological inhibition of DNA methyltransferase-1, induced significant and stable activation-dependent FOXP3 expression in cycling conventional T cells, which was further amplified by co-treatment with transforming growth factor beta. In contrast to natural Treg, such induced CD4(+)FOXP3(+) T cells could produce pro-inflammatory cytokines upon activation. These results indicate that DNA methylation normally restricts FOXP3 transcription in conventional human T cells.

Goldstein I, Simon AJ, Ben Horin S, Matzri S, Koltakov A, Langevitz P, Rechavi G, Amariglio N, Bank I. · Cancer Research Center and Institute of Hematology, The Chaim Sheba Medical Center, Tel Aviv University, Israel. · Clin Immunol. · Pubmed #18456562 No free full text.

Abstract: VLA-1 integrin expressing T cells are more frequent in inflammatory synovial fluids (SF) compared to peripheral blood. Recent studies suggest that VLA-1 expression mainly marks IFNgamma+ T cells while excluding both IL-4+ and regulatory FoxP3+ T cells. To further characterize the TCR repertoire of the potentially pathogenic VLA-1+ IFNgamma+ T cells, isolated from SF of adult patients with rheumatoid and psoriatic arthritis, we determined the complementarity determining region (CDR)3 spectratypes. Here we show in a cohort of 9 patients that VLA-1+ T cells display a perturbed repertoire that, moreover, differs from that of VLA-1- synovial T cells and even VLA-1+ PB T cells. Importantly, random sequencing of the CDR3 region of the TCR variable beta (BV) 6.1 gene of both VLA-1+ and VLA-1- synovial T cells, in one patient, revealed that their sequences were by and large different (29 out of 33 clones). Thus, our results imply that VLA-1+ T cells that infiltrate into inflamed joints represent a partly distinct and highly oligoclonal population of Th1 cells, probably selected by unique antigens.