Subject(s)
Immunity, Cellular , Immunity, Humoral , Lymphoproliferative Disorders/immunology , Child , Humans , Lymphoproliferative Disorders/genetics , Lymphoproliferative Disorders/pathology , Male , Signaling Lymphocytic Activation Molecule Associated Protein/genetics , Signaling Lymphocytic Activation Molecule Associated Protein/immunologyABSTRACT
T cell lymphopenia results in peripheral homeostatic expansion to maintain the T cell immune system, which is termed lymphopenia-induced proliferation (LIP). LIP is a potential risk for expanding autoreactive clones to become pathogenic in human and murine autoimmune diseases. However, the ontogeny of T cells that induce autoantibody production by autoreactive B cells in LIP remains unclear. Transfer of CD4+CD25- conventional T (Tc) cells into T-cell-deficient athymic nude mice has been previously reported as a LIP-induced autoimmune model which develops organ-specific autoimmune diseases and systemic antinuclear antibodies (ANAs). We show here that via LIP in this model, Tc cells proliferated and differentiated into PD-1+CXCR5-/dim B-helper T cells, which promoted splenic germinal center (GC) formation, provided help for autoantibody-producing B cells, and had distinctive features of follicular helper T (Tfh) cells except that they do not express high CXCR5. Intestinal microbiota were essential for their generation, since depletion of them in recipient mice by antibiotics resulted in a reduction of LIP-induced PD-1+CXCR5-/dim B-helper T cells and an amelioration of autoimmune responses. Our findings will contribute to the elucidation of the mechanism of lymphopenia-induced autoimmunity and autoantibody production, and will pave the way for microbiota-targeted novel therapeutic approaches to systemic autoimmune diseases.
Subject(s)
Autoimmunity , B-Lymphocytes/immunology , Gastrointestinal Microbiome , Lymphopenia/immunology , Lymphopenia/microbiology , Programmed Cell Death 1 Receptor/metabolism , Receptors, CXCR5/metabolism , T-Lymphocytes, Helper-Inducer/immunology , Animals , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Antibodies, Antinuclear , Antibody Formation , Antigens/metabolism , Antigens, CD/metabolism , Autoantibodies/immunology , Cell Differentiation , Cell Proliferation , Feces/microbiology , Gastritis/drug therapy , Gastritis/immunology , Gastritis/microbiology , Germinal Center/metabolism , Immunoglobulin Class Switching , Lymphopenia/pathology , Mice, Inbred BALB C , Mice, Nude , Receptors, Antigen, T-Cell/metabolism , Spleen/pathologyABSTRACT
OBJECTIVES: Cellular fibronectin (cFn) has been implicated in the pathogenesis of rheumatoid arthritis (RA), and we previously demonstrated the presence of citrullinated cFn in rheumatoid synovial tissues. The present study aimed to investigate whether citrullinated cFn can be detected in the plasma or synovial fluid of RA patients. METHODS: Twenty-five rheumatoid arthritis synovial fluid (RASF), seven osteoarthritis synovial fluid (OASF) and 12 plasma samples from RA patients were examined. Citrullination of cFn was determined by immunoprecipitation (IP), western blotting and enzyme-linked immunosorbent assay (ELISA), in which peptidyl-citrulline within cFn was detected using a specific anti-cFn monoclonal antibody in combination with anti-modified citrulline antibody after chemical modification. RESULTS: Levels of citrullination associated with cFn, as determined by ELISA, were significantly higher in RASF than in OASF samples. IP and western blotting detected citrullinated cFn in RASF but not in plasma samples from RA patients. Levels of total cFn were elevated in RASF compared with OASF, and 24 out of 25 RASF samples were positive for anti-CCP antibody. However, no correlation was observed between levels of citrullinated cFn and those of total cFn or anti-CCP antibody in RASF. On the other hand, a significant positive correlation was observed between the levels of matrix metalloproteinase-3 (MMP-3) and cFn citrullination in RASF. CONCLUSIONS: Citrullinated cFn appears to be produced within the affected joint and might be involved in the pathogenesis of rheumatoid synovitis.
Subject(s)
Arthritis, Rheumatoid/metabolism , Autoantibodies/analysis , Fibronectins/metabolism , Peptides, Cyclic/immunology , Synovial Fluid/metabolism , Arthritis, Rheumatoid/immunology , Humans , Osteoarthritis/immunology , Osteoarthritis/metabolism , Synovial Fluid/chemistry , Synovial Fluid/immunologySubject(s)
Adrenal Cortex Hormones/adverse effects , Arthritis, Rheumatoid/drug therapy , Calcinosis/chemically induced , Finger Joint/diagnostic imaging , Arthritis, Rheumatoid/diagnostic imaging , Artifacts , Calcinosis/diagnostic imaging , Female , Humans , Injections, Intra-Articular , Middle Aged , Ultrasonography, Doppler, ColorABSTRACT
To assess the long-term safety and efficacy of tacrolimus (TAC) used in combination with oral methotrexate (MTX) in patients with rheumatoid arthritis (RA) whose disease remains active despite treatment with MTX alone. The clinical courses of 24 RA patients who received TAC added to MTX from a single center were analyzed retrospectively. The disease activity was evaluated by the DAS28-ESR(3) every 12 months after the addition of TAC, and side effects were evaluated for 3 years. At 3 years after starting the treatment, TAC was still being used by 19 patients (79 %). The causes of discontinuation were an inadequate response (3 cases), oral ulcers and elevation of creatinine (1 case), and worsening of interstitial pneumonia (1 case). No death was registered. The DAS28-ESR(3) was decreased from 4.81 to 3.41 after 3 years of treatment. The doses of prednisolone were decreased from 5.1 mg/day to 3.2 mg/day after 3 years. In patients whose active RA persists despite treatment with MTX, TAC in combination with MTX is safe and well tolerated and provided clinical benefit for a long time in this single-center retrospective study. Further studies are required to confirm the safety and efficacy of this combination therapy.
