Increased Lymphocyte Infiltration in Rheumatoid Arthritis Is Correlated with an Increase in LTi-like Cells in Synovial Fluid

Abstract

In this study, we compared the immune cell populations in rheumatoid arthritis (RA) synovial fluid, which shows lymphoid tissue-like structure, with those in tonsils, which are normal secondary lymphoid tissues. Firstly, we found that CD4-CD11b+ macrophages were the major population in RA synovial fluid and that B cells were the major population in tonsils. In addition, synovial fluid from patients with osteoarthritis, which is a degenerative joint disease, contained CD4+CD11b+ monocytes as the major immune cell population. Secondly, we categorized three groups based on the proportion of macrophages found in RA synovial fluid: (1) the macrophage-high group, which contained more than 80% macrophages; (2) the macrophage-intermediate group, which contained between 40% and 80% macrophages; and (3) the macrophage-low group, which contained less than 40% macrophages. In the macrophage-low group, more lymphoid tissue inducer (LTi)-like cells were detected, and the expression of OX40L and TRANCE in these cells was higher than that in the other groups. In addition, in this group, the suppressive function of regulatory T cells was downregulated. Finally, CXCL13 expression was higher in RA synovial fluid than in tonsils, but CCL21 expression was comparable in synovial fluid from all groups and in tonsils. These data demonstrate that increased lymphocyte infiltration in RA synovial fluid is correlated with an increase in LTi-like cells and the elevation of the chemokine expression.

OX40, OX40L and Autoimmunity: a Comprehensive Review

“…Coeliac disease OX40-positive lymphocytes present in disease but not control duodenal biopsies [27]; peripheral OX40 expression not affected [152] Rheumatoid arthritis Increased OX40-positivity on lymphocytes in synovial fluid from inflamed joints [26,153,123,154,110] OX40L expression on sublining layer of sinovium from inflamed joints [123,155] Reduced sOX40 [110] Increased sOX40L with correlation with autoantibody status [110] Inflammatory myositis OX40 expression present in inflammatory myopathies but not controls [156,157] OX40L seen on T cells, B cells, macrophages and myeloid dendritic cells in inflammatory myopathies but not controls [156] Uveitis Multiple OX40-positive infiltrating lymphocytes from ciliary bodes of eyes enucleated for uveitis [139] Type 1 Diabetes Mellitus Increased proportion of CD4+ cells positive in peripheral blood of newly diagnosed paediatric cases [106] Systemic sclerosis Elevated serum sOX40 concentrations in comparison with SLE and healthy controls [109] Graves' Thyroiditis Increased OX40-positivity of circulating CD4+ T cells in patients with anti-TSHR antibodies [112,158,159] Increased OX40L-positivity of circulating CD4+ T cells in patients with anti-TSHR antibodies [112] Elevations of sOX40L [48] Multiple sclerosis Reduction in OX40+CD26+ peripheral CD4+ T cells correlating with clinical response after treatment with natalizumab [104] OX40 expressed in MS brain and cord sections [126] Neuromyelitis optica Increased OX40 positivity of pathological brain specimens [126] Sjögren syndrome Increased OX40 expression on peripheral T cells [160] Increased OX40L expression on peripheral B cells and monocytes [160] Myasthenia gravis Increased thymic OX40 staining around germinal centres [161] OX40L present in myasthenia gravis thyroid but not control [161] Increased OX40-staining on peripheral CD4+ T cells [105] Granul...…”

Chronic Inflammation: A Common Promoter in Tertiary Lymphoid Organ Neogenesis

“…In human non-small cell lung cancer, tumor NCR + ILC3 might contribute to tumor-associated TLOs by interacting with both tumor cells and tumor fibroblasts (93). Enhanced lymphocyte infiltrations in rheumatoid arthritis synovial fluid and murine intestine are believed to correlate with increased expression of TNF-related activation-induced cytokine by LTi-like cells (94,95). Bone marrow derived M1 macrophages has been reported to act as LTi cells and crosstalk with VSMCs, and then initiated TLO formation in a LTβR-independent manner (96).…”

Proinflammatory M1 Macrophages Inhibit RANKL-Induced Osteoclastogenesis

“…However, in the context of bone lytic diseases involving chronic inflammation, such as periodontitis and rheumatoid arthritis, infiltrations of not only B and T cells but also of macrophages are observed (6,7). It is true that macrophages are the most abundant immune cells found in the synovial membrane in osteoarthritis (8) and in synovial fluid in rheumatoid arthritis (9), outnumbering T and B cells. Therefore, it is plausible that osteoclast differentiation is affected by local factors produced by infiltrating lymphocytes, especially macrophages.…”