Rheumatoid arthritis (RA) is a systemic autoimmune disease of unknown etiology, characterized by chronic joint inflammation that often leads to joint destruction. Diagnosis of RA is currently based on the revised classification criteria of the American College of Rheumatology (ACR) ; however, it remains imprecise, especially early in the course of disease. Rheumatoid factor (RF) has been widely used in clinical practice as a useful serological marker for diagnosis of RA. Although RF is the only serological test in the criteria of the ACR, its specificity is limited since RF can be also detected in other rheumatic diseases. Because the current therapeutic strategies in RA employ increasingly aggressive regimens from early stage of the disease, more specific serological markers than RF are desirable. Recently, anti-cyclic citrullinated peptide (anti-CCP) antibodies have attracted attention as a useful marker for the diagnosis of RA with high specificity. In addition to the diagnostic properties, anti-CCP antibodies showed to be a good prognostic marker for joint destructions. In this review, we will explain about the clinical usefulness of anti-CCP antibodies for the daily practice of RA.

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  Genesis of antinuclear antibodies is one of the most important immunological abnormalities that are closely associated with clinical manifestations, disease activity, and prognosis of systemic autoimmune diseases. Previous reports indicated that autoreactive T cells have critical roles not only in antinuclear antibody production but also in organ damages. Recently, the possible molecules that are involved in the mechanism of antinuclear antibody production have been determined by using lupus-prone mice. Target treatment against the key molecules associated with autoreactive T cells and B cells may be the useful therapeutic strategy for systemic autoimmune diseases along with the suppression of disease-specific antinuclear antibody production.

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  Anti-DNA antibody is a characteristic feature of systemic lupus erythematosus (SLE) and plays an important role in pathogenesis of lupus nephritis. However, the mechanism of anti-DNA antibody production, which may directly link to the etiology of SLE, remains uncertain. Mammalian DNA alone is not immunogenic. However, some anti-DNA antibodies cross-react with self antigens, and immunization of mice with a certain peptide could induce anti-DNA antibodies. These facts raise a question as to whether an antigenic trigger of anti-DNA antibodies production is DNA itself. Therefore, molecular mimicry of DNA by non DNA antigen is a possibility for the initial production of anti-DNA antibodies. We found that the human monoclonal nephritogenic anti-DNA antibody, O-81, specifically bound to an endoplasmic reticulum stress response protein, Herp. This suggests that lupus nephritogenic anti-DNA antibody cross-react with Herp and an epitope on Herp mimics DNA. Each time cells receive stress (for example, viral infection), the synthesis of Herp protein is induced. If the epitope is immunogenic, repetitive cell stress can be a trigger of anti-DNA antibodies production.

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  The pathogenetic roles of autoantibodies remain unknown in systemic sclerosis (SSc). CD19, a cell-surface critical signal transduction molecule of B lymphocytes, augments signaling through B cell antigen receptor and CD19 overexpression in mice induces various autoantibody production. Peripheral B cells from SSc patients exhibit 20%-increase in CD19 expression. Furthermore, B cells from a tight-skin (TSK) mouse, a genetic murine model of SSc, show augmented signaling through CD19. The deficiency of CD19 expression in TSK mice results in inhibition of autoantibody production, reduced skin fibrosis, and inhibition of augmented IL-6 production by splenic B cells. Collectively, a new model that could explain the relationship between autoantibody and the development of fibrosis is proposed. CD19 overexpression observed in SSc patients breaks down peripheral tolerance of B cells, which results in autoantibody production. Furthermore, it is also possible that in vivo chronic B cell activation probably due to CD19 overexpression results in the development of fibrosis through production of fibrogenic cytokines, such as IL-6. This model indicates that B cells or CD19 would be potential therapeutic targets in SSc.

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  Polymyositis/Dermatomyositis (PM/DM) is a chronic inflammatory disorder that culminates in injury to the skin and muscle and, sometimes, is accompanied by interstitial lung disease (ILD). A number of autoantibodies are associated with myositis, including those specific for aminoacyl-tRNA synthetase (anti-ARS), signal recognition particle (anti-SRP), and Mi-2. These autoantibodies have proven to be useful in the diagnosis and classification of the diseases and are predictive of prognosis.
  It has been known that certain patients may have typical DM skin manifestations without clinical evidence of myositis for at least 2 years (Clinically Amyopathic DM ; C-ADM). Although classical myositis-related antibodies are well known, specificities related to C-ADM have not been examined in detail.
  Therefore, we have examined sera from 15 Japanese patients with C-ADM to identify additional autoantibodies associated with this disease. Eight sera of C-ADM patient recognized a polypeptide of approximately 140 kDa and we named this new antibody specificity anti-CADM-140. Anti-CADM-140 antibodies were detected in 8 of 42 patients with DM, but not in patients with other connective tissue diseases or idiopathic pulmonary fibrosis. It is noteworthy that DM patients with anti-CADM-140 had significantly more rapidly progressive ILD when compared to patients without anti-CADM-140 (50% vs 6%, P=0.008). Further studies of the pathogenicity of these autoantibodies specificity may provide insight into the pathogenic mechanisms of PM/DM accompanied by rapidly progressive ILD.

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  Myeloperoxidase (MPO)-specific anti-neutrophil cytoplasmic antibodies (MPO-ANCA) are involved in the development of vasculitis microscopic polyangiitis, a systemic vasculitis etc. We have showed a correlation of MPO-ANCA epitopes in vasculitis concerning contribution of N and C terminus of MPO to severity of the diseases. On the other hand, a role of activated neutrophils in inflammatory nephritis renal lesions using SCG/Kj mice. In the phase of nephritis with a low grade of proteinuria, the spontaneous release of MPO from peripheral neutrophils increased, indicating that neutrophils are activated and contribute to the development of active crescentic lesions in SCG/Kj mice. In addition, we have investigated that mice having CADS/CAWS-induced vasculitis also are good model animals for the analysis of the production of MPO-ANCA. Furthermore, we have clarified that MPO is a major antigen for MPO-ANCA production using MPO knock mice.

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  Good syndrome, characterized by both thymoma and hypogammaglobulinemia, is a rare immunodeficient disorder. We experienced a case of Good syndrome accompanied by myasthenia gravis (MG). A 58-year-old man was admitted to our hospital because of muscle weakness and fatigability. Based on the presence of anti-acetylcholine receptor (AChR) antibody and thymoma, he was diagnosed as having MG. Peripheral blood lymphocyte count was normal, but gammaglobulin levels were markedly decreased (IgG 283 mg/dl, IgA 17 mg/dl, IgM 1 mg/dl). Clinical remission of MG was achived by thymectomy followed by high-dose corticosteroids. Despite monthly intravenous immunoglobulin supplementation, he suffered from repeated respiratory tract infections and candidiasis. Body CT revealed adrenal tumor and pancreatic cancer with liver metastasis, and he died of bacterial pneumonia. Immunological evaluations showed complete lack of CD19+ B cell in the peripheral blood and responses of peripheral blood mononuclear cells to mitogens. Peripheral blood T cells responded to a suboptimal concentration of a recombinant AChR fragment : this pattern of AChR-induced T cell response was typical of MG patients. We failed to detect IgG autoantibodies reactive with B cells in his serum. Patients with Good syndrome represent imbalance of immune responses, leading to both immunodeficiency and autoimmunity.

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