Ikuko Hayakawa

The clinical relevance of serum antinuclear antibodies in Japanese patients with systemic sclerosis

Background  Systemic sclerosis (SSc) is a connective tissue disorder with excessive fibrosis of the skin and various internal organs. Although SSc is a heterogeneous disease, it has been reported that the particular antinuclear antibodies (ANA) are often indicative of clinical features, disease course and overall severity.

Autoantibody against matrix metalloproteinase-3 in patients with systemic sclerosis

Systemic sclerosis (SSc) is characterized by multi‐organ fibrosis with an autoimmune background. Although autoantibodies are detected frequently in SSc patients, the role of autoantibody in the development of fibrosis remains unknown. Connective tissue homeostasis is a balance between the synthesis and degradation of the extracellular matrix (ECM); ECM degradation is regulated mainly by matrix metalloproteinases (MMPs). Anti‐MMP‐1 antibody is suggested to inhibit MMP‐1 and be involved in the development of the fibrosis in SSc. However, the accumulation of various ECM components in the tissue of SSc cannot be explained by the anti‐MMP‐1 antibody alone. In this study, we examined the presence  or  levels of antibody to MMP‐3, a protein which degrades various ECM components relevant to SSc fibrosis. Enzyme‐linked immunosorbent assay (ELISA) using human recombinant MMP‐3 revealed that IgG anti‐MMP‐3 autoantibody levels were elevated significantly in the sera from SSc patients, but not in patients with active systemic lupus erythematosus or dermatomyositis. IgG and IgM anti‐MMP‐3 antibody levels were significantly higher in diffuse cutaneous SSc, a severe form, than those in limited cutaneous SSc. Consistently, IgG anti‐MMP‐3 antibody levels correlated significantly with fibrosis of the skin, lung and renal blood vessels. The presence of IgG anti‐MMP‐3 autoantibody in sera from SSc patients was confirmed by immunoblotting analysis. Remarkably, MMP‐3 activity was inhibited by IgG anti‐MMP‐3 antibody. These results suggest that anti‐MMP‐3 antibody is a serological marker that reflects the severity of SSc and also suggest that it may contribute to the development of fibrosis by inhibiting MMP‐3 activity and reducing the ECM turnover.

Anti-DNA topoisomerase II α autoantibodies in Japanese patients with systemic sclerosis

The pathogenesis and etiology of systemic sclerosis (SSc) remain unknown, but the presence of several autoantibodies is recognized as one of its prominent features. The clinical significance of anti-DNA topoisomerase II α antibody (anti-topo II α Ab) remains unknown in Japanese patients with SSc. To determine the prevalence and clinical correlation of anti-topo II α Ab in Japanese patients with SSc. Serum samples were obtained from 103 Japanese patients with SSc. Control serum samples were obtained from 43 healthy Japanese volunteers. Anti-topo II α Abs were determined by enzyme linked-immunosorbent assay.IgG anti-topo II α Ab levels were significantly increased in SSc patients (n=103) compared to normal controls (n=43; P<0.005). IgG or IgM anti-topo II α Ab was detected in 19% (20/103) of SSc patients when absorbance values higher than the mean+2SD of control serum samples were considered positive. By contrast, IgG or IgM anti-topo II α Ab was observed in only 7% (3/43) of healthy individuals. The presence of pulmonary fibrosis was more frequently detected in SSc patients with IgG anti-topo II α Ab than those without the Ab (P<0.05). Moreover, % DLco and % VC were significantly decreased in SSc patients with anti-topo II α Ab relative to those without the Ab (P<0.05 and P<0.01, respectively). The elevated levels of both erythrocyte sedimentation rate and C-reactive protein were also more frequently observed in SSc patients positive for IgG anti-topo II α Ab (P<0.005). The results of the present study indicate that anti-topo II α Ab represent one of the autoantibody specificities detected on SSc patients and may be regarded a serological marker of pulmonary fibrosis in Japanese patients with SSc.

Antigen specificity of antihistone antibodies in connective tissue disease patients with anti-U1RNP antibodies

To determine the prevalence of antibodies to individual histone components in collagen disease patients with anti-U1RNP antibodies. Serum samples were examined by enzyme-linked immunosorbent assay. Patients with mixed connective tissue disease (MCTD) and systemic sclerosis (SSc) showed similar levels and patterns of antihistone antibody (AHA) reactivities to individual histones: IgG responses to H2B or H3 and IgM responses to H2B were highest. However, both IgG and IgM AHAs against outer portion of chromatin (H1, H2A, or H2B) were generally higher in SLE compared with other diseases. SLE or SSc patients with anti-U1RNP antibodies showed generally higher AHA levels than in those without them. Thus, the pattern of reactivities to each histone component was dependent on the disease, while the intensity was dependent on both the disease and anti-U1RNP antibodies. The antigenic stimulus in SLE may be different from other connective tissue diseases and is more likely to be native chromatin.