CMV Causes Rheumatoid Arthritis

Expansion of unusual CD4+ T cells in severe rheumatoid arthritis. PB Martens, JJ Goronzy, D Schaid, CM Weyand. Arthritis Rheum 1997 Jun;40(6):1106-1114. "Carriers of CD4+ CD28- T cells accumulated in the RA population (64% versus 45%; P = 0.02). The expansion of CD4+ CD28- T cells correlated with extraarticular involvement, but not with disease duration, antirheumatic treatment, or severity of joint destruction. The patient subsets with nodular disease (P = 0.02) and rheumatoid organ disease (P = 0.04) had the highest proportion of CD4+ CD28- T cell carriers. The size of the CD4+ CD28- compartment correlated with extraarticular progression of RA (P = 0.001 in nodular RA, P = 0.003 in rheumatoid organ disease)."

Cytomegalovirus seropositivity is associated with the expansion of CD4+CD28- and CD8+CD28- T cells in rheumatoid arthritis. M Hooper, EG Kallas, D Coffin, D Campbell, TG Evans, RJ Looney. J Rheumatol 1999 Jul;26(7):1452-1457. 45 RA patients (36 women). "Previous researchers have found expansion of CD4+CD28- T cells in patients with rheumatoid arthritis (RA) compared to age matched controls, and have identified expanded clones of autoreactive cells within this population.... (CD28 and CD57 are reciprocally related.) CD4+CD28-CD57+ T cells were expanded only in CMV seropositive patients. CONCLUSION: The "carrier" phenotype that has been hypothesized based on a 2 population model for the distribution of CD4+CD28- T cells in RA can be explained by prior infection with CMV."

Clonality and longevity of CD4+CD28null T cells are associated with defects in apoptotic pathways. AN Vallejo, M Schirmer, CM Weyand, JJ Goronzy. J Immunol 2000 Dec 1;165(11):6301-6307. "CD4(+)CD28(null) T cells are oligoclonal lymphocytes rarely found in healthy individuals younger than 40 yr, but are found in high frequencies in elderly individuals and in patients with chronic inflammatory diseases... In this study, we show that CD4(+)CD28(null) T cells are protected from undergoing activation-induced cell death. Whereas CD28(+) T cells underwent Fas-mediated apoptosis upon cross-linking of CD3, CD28(null) T cells were highly resistant. CD28(null) T cells were found to progress through the cell cycle, and cells at all stages of the cell cycle were resistant to apoptosis, unlike their CD28(+) counterparts."

The expansion of CD4+CD28- T cells in patients with rheumatoid arthritis. A Pawlik, L Ostanek, I Brzosko, M Brzosko, M Masiuk, B Machalinski, B Gawronska-Szklarz. Arthritis Res Ther 2003;5(4):R210-R213. 42 patients with RA and 24 healthy subjects. "Cells of this CD4+CD28- subset have several features differentiating them from classic T helper cells. They do not depend on the B7/CD28 pathway for activation, do not express the CD80 receptor, are incapable of activating B cells, have significant cytolytic activity, and express high levels of IFN-γ and IL-2 [4]. Thus, the presence of significant numbers of CD4+CD28- T cells could shift immune response from B-cell activation and production of immunoglobulins toward activation of type-1 T helper cells and production of IFN-γ and involvement of macrophages releasing matrix-degrading proteases. CD4+CD28- T cells are infrequent in healthy individuals (comprising 0.1–2.5% of T cells), whereas higher levels have been seen in patients with unstable angina, multiple sclerosis, Wegener's granulomatosis, and rheumatoid arthritis with extra-articular manifestations.... The frequency of CD4+CD28- T cells was 4.82% in patients with limited joint manifestations, 7.05% in those with advanced joint involvement, and 10.35% in those with extra-articular manifestations."

Expression of activation-induced, T cell-derived, and chemokine-related cytokine/lymphotactin and its functional role in rheumatoid arthritis. S Blaschke, P Middel, BG Dorner, V Blaschke, KM Hummel, RA Kroczek, K Reich, P Benoehr, M Koziolek, GA Muller. Arthritis Rheum 2003 Jul;48(7):1858-1872. 20 RA patients and 15 osteoarthritis controls. "OBJECTIVE: To evaluate the possible role of activation-induced, T cell-derived, and chemokine-related cytokine (ATAC)/lymphotactin (Lptn) in the pathogenesis of rheumatoid arthritis (RA)... Levels of ATAC/Lptn were similar in sera and synovial fluids from RA patients (n = 20) and osteoarthritis controls (n = 15). In phorbol myristate acetate/ionomycin-stimulated PBMCs, ATAC/Lptn expression was detected in CD8+ T cells and in a significantly increased proportion of CD4+,CD28- T cells from RA patients as compared with healthy controls. In synovial tissues, ATAC/Lptn was predominantly localized in CD3+ T cells in the sublining layer. Lymphocytes, synovial macrophages, and, unexpectedly, fibroblast-like synoviocytes (FLS) were identified as major target cells for ATAC/Lptn in RA synovium, as determined by analysis of the ATAC/Lptn receptor XCR1. In vitro, ATAC/Lptn stimulation of FLS resulted in a marked down-regulation of matrix metalloproteinase 2 production."

Stimulation of T cell autoreactivity by anomalous expression of NKG2D and its MIC ligands in rheumatoid arthritis. V Groh, A Bruhl, H El-Gabalawy, JL Nelson, T Spies. Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9452-9457. "In rheumatoid arthritis (RA), the severity of autoimmune and inflammatory joint disease correlates with large numbers of CD4+CD28- T cells, which are scarce in healthy individuals.... CD4+CD28- T cells in peripheral blood and synovial tissue of RA patients were found to express NKG2D, a costimulatory receptor that is absent on normal CD4 T cells. NKG2D was induced by tumor necrosis factor alpha and IL-15, which are abundant in inflamed synovia and RA patient sera. RA synoviocytes aberrantly expressed the stress-inducible MIC ligands of NKG2D, which stimulated autologous CD4+CD28- T cell cytokine and proliferative responses. Peripheral blood serum samples of RA patients contained substantial amounts of synoviocyte-derived soluble MICA, which failed to induce down-modulation of NKG2D because of the opposing activity of tumor necrosis factor alpha and IL-15."

Emergence of a CD4+CD28- granzyme B+, cytomegalovirus-specific T cell subset after recovery of primary cytomegalovirus infection. EM van Leeuwen, EB Remmerswaal, MT Vossen, AT Rowshani, PM Wertheim-van Dillen, RA van Lier, IJ ten Berge. J Immunol 2004 Aug 1;173(3):1834-1841. "In this study, we show that in primary CMV infections, CD4(+)CD28(-) T cells emerge just after cessation of the viral load, indicating that infection with CMV triggers the formation of CD4(+)CD28(-) T cells. In line with this, we found these cells only in CMV-infected persons [emphasis added]. CD4(+)CD28(-) cells had an Ag-primed phenotype and expressed the cytolytic molecules granzyme B and perforin. Importantly, CD4(+)CD28(-) cells were to a large extent CMV-specific because proliferation was only induced by CMV-Ag, but not by recall Ags such as purified protein derivative or tetanus toxoid. CD4(+)CD28(-) cells only produced IFN-gamma after stimulation with CMV-Ag, whereas CD4(+)CD28(+) cells also produced IFN-gamma in response to varicella-zoster virus and purified protein derivative. Thus, CD4(+)CD28(-) T cells emerge as a consequence of CMV infection."

Tissue trafficking patterns of effector memory CD4+ T cells in rheumatoid arthritis. X Zhang, T Nakajima, JJ Goronzy, CM Weyand. Arthritis Rheum 2005 Dec;52(12):3839-3849. "CD4+,CD28- T cells resemble both short-lived effector memory cells and long-lived central memory cells, and they find a niche both in inflamed synovium and in lymph nodes. Nonspecific cytokine stimulation, not antigen recognition, triggers the transition from the lymph node to the synovium. By maintaining CCR7 expression, these end-differentiated T cells can home to lymphoid organs, enhance their survival, support clonal expansion, and perpetuate autoreactivity."

Strong selection of virus-specific cytotoxic CD4+ T-cell clones during primary human cytomegalovirus infection. EM van Leeuwen, EB Remmerswaal, MH Heemskerk, IJ ten Berge, RA van Lier. Blood 2006 Nov 1;108(9):3121-3127. "In the acute response, CMV-specific CD4+ T cells are highly activated and proliferating, have a CD45RA+CD45R0+CD28+CD27+ phenotype, and produce IFN after stimulation with CMV antigen in vitro. Late after primary infection, CMV-specific CD4+ T cells have returned to a resting stage, and the percentage of IFN-producing CMV-specific CD4+ T cells is considerably lower than during the acute infection. Moreover, a considerable number of CMV-specific CD4+ T cells have progressed toward a further differentiated phenotype, characterized by the loss of both CD27 and CD28 and the acquisition of cytolytic molecules such as perforin and granzyme B (grB). CD4+CD28– grB+ T cells appear to be characteristic for CMV infection because they emerge after primary CMV infection and can be found only in CMV-seropositive individuals. Consequently, proliferation and cytokine production by CD4+CD28– T cells can be induced by CMV but not by other viral antigens."

Analyses of immunosenescent markers in patients with autoimmune disease. M Thewissen, V Somers, K Venken, L Linsen, P Van Paassen, P Geusens, J Damoiseaux, P Stinissen. Clin Immunol 2007 Feb 20; [Epub ahead of print]. "T cell receptor excision circles (TREC) and the percentage of CD4(+)CD28(null) T cells were studied as markers of immunosenescence in 175 patients with chronic autoimmune arthritis, other connective tissue autoimmune diseases, multiple sclerosis and 60 healthy controls. In both the rheumatoid arthritis (RA) and multiple sclerosis patient group, TREC numbers were age-inappropriately declined which points to an accelerated thymic output. Furthermore, enhanced percentages of CD4(+)CD28(null) T cells could be detected in a significant proportion of patients included in this study. These immunosenescent phenomena seemed to be present already early in the disease process. High percentages of CD4(+)CD28(null) T cells were associated with the presence of RA linked HLA DR4 alleles and with plasma reactivity to cytomegalovirus."

Surface expression of fractalkine receptor (CX3CR1) on CD4+/CD28 T cells in RA patients and correlation with atherosclerotic damage. E Pingiotti, P Cipriani, A Marrelli, V Liakouli, S Fratini, M Penco, R Giacomelli. Ann N Y Acad Sci 2007 Jun;1107:32-41. 50 early RA patients and 26 healthy controls (HC). "We observed: a higher expansion of CD4+/CD28- subset in RA patients when compared to HC (7.7%, 5.15-9.7 vs. 0.7%, 0.2-1.5, P < 0.01; respectively); this expansion directly correlated with increased IMT (0.91 mm, 0.5-1.3 vs. 0.7 mm, 0.2-1, P < 0.01; RA vs. C, respectively) and inversely correlated with FMV [flow-mediated vasodilation] (3.5%, 1.7-7 vs. 9%, 3.5-11, P < 0.01; RA vs. C, respectively); the large majority of CD4+/CD28-, in RA, coexpressed CX3CR1 (93%, 67-99 vs. 30%, 10-48, P < 0.01; RA vs. C, respectively); this expansion significantly correlated with both the parameters of premature vascular damage and DAS 28."

Unchecked CD70 expression on T cells lowers threshold for T cell activation in rheumatoid arthritis. WW Lee, ZZ Yang, G Li, CM Weyand, JJ Goronzy. J Immunol 2007 Aug 15;179(4):2609-2615. "Rheumatoid arthritis (RA) is characterized by premature immune aging with accumulation of degenerate T cells deficient for CD28. Gene expression profiling of CD4(+)CD28(-) and CD4(+)CD28(+) T cells to discover disease-promoting activities of CD28(-) T cells identified expression of CD70 as a most striking difference. Hence, CD70 was significantly more expressed in CD4 T cells from RA patients compared with age-matched controls (p < 0.006). The underlying mechanism was a failure to repress CD70 expression after activation-dependent induction. This defect in RA was not related to differential promoter demethylation. CD70 on bystander CD4(+)CD28(-) T cells functioned by lowering the threshold for T cell activation; admixture of CD4(+)CD28(-) T cells augmented TCR-induced responses of autologous naive CD4(+)CD28(+) T cells, particularly of low-avidity T cells. The data support a model in which CD70 expressed on T cells causes degeneracy in T cell responses and undermines tolerance mechanisms that normally control T cell autoreactivity."

Skewed distribution of proinflammatory CD4+CD28null T cells in rheumatoid arthritis. AE Fasth, O Snir, AA Johansson, B Nordmark, A Rahbar, E Af Klint, NK Björkström, AK Ulfgren, RF van Vollenhoven, V Malmström, C Trollmo. Arthritis Res Ther 2007;9(5):R87. "CD4+CD28null T cells were infrequent in the synovial membrane and synovial fluid, despite significant frequencies in the circulation. Strikingly, the dominant TCR-Vβ subsets of CD4+CD28null T cells in peripheral blood were often absent in synovial fluid. CD4+CD28null T cells in blood and synovial fluid showed specificity for HCMV antigens, and their presence was clearly associated with HCMV seropositivity but not with anti-citrullinated protein antibodies in the serum or synovial fluid, nor with erosive disease."

cast 03-08-08