Mizuho Matsunawa

Correlation of CX3CL1 and CX3CR1 Levels with Response to Infliximab Therapy in Patients with Rheumatoid Arthritis

Objective. To examine the relation between serum chemokine levels and patient responsiveness to infliximab, and the influence of infliximab administration on serum chemokine levels. Methods. Serum levels of the chemokines CX3CL1, CXCL8, CCL3, and CXCL10 were quantified prior to (at baseline) and after 30 weeks of treatment with infliximab in 20 patients using enzyme-linked immunosorbent assays. Disease status was assessed using the Disease Activity Score (DAS28). The response to infliximab was classified according to the European League Against Rheumatism (EULAR) response criteria. Results. By 30 weeks, infliximab produced a significant overall reduction in DAS28 among the 20 patients with RA, although only 12 achieved a good to moderate response based on EULAR response criteria. A significant reduction in CX3CL1 was seen in the responsive group, although infliximab treatment had no significant effect on the serum levels of the other 3 chemokines. Comparison of patients with lower (< 2000 pg/ml) and higher (≥ 2000 pg/ml) basal CX3CL1 levels revealed that DAS28, erythrocyte sedimentation rate, C-reactive protein, and CX3CL1 levels were all significantly diminished by infliximab in RA patients with lower basal CX3CL1 levels, but not in those with higher basal levels. In addition, cell-surface expression of CX3CR1 protein in peripheral blood CD8+CD3+ T cells and mRNA expression of CX3CR1 in lymphocytes were both significantly downregulated after infliximab treatment in the responsive group. Conclusion. Our results suggest that the CX3CL1-CX3CR1 system in patients with active RA may be sensitive to anti-tumor necrosis factor-α therapy, and confirm that CX3CL1 plays a crucial role in the pathogenesis of RA.

Enhanced expression of interferon-inducible protein 10 associated with Th1 profiles of chemokine receptor in autoimmune pulmonary inflammation of MRL/lpr mice

MRL/Mp-lpr/lpr (MRL/lpr) mice spontaneously develop systemic lupus erythematosus (SLE)-like disease. The natural history of the pulmonary involvement and the underlying mechanism of leukocyte infiltration into the lungs of MRL/lpr mice and SLE patients remains elusive. We aimed to investigate the expression profiles of chemokines and chemokine receptors in the lung of the SLE-prone mouse. We examined the correlation between lung inflammation and expression of IP-10 (interferon-γ-inducible protein 10), a CXC chemokine, and TARC (thymus- and activation-regulated chemokine), a CC chemokine, in MRL/lpr mice, MRL/Mp-+/+ (MRL/+) mice, and C57BL/6 (B6) control mice. The extent of cell infiltration in the lung was assessed histopathologically. Reverse transcriptase PCR showed up-regulation of IP-10 mRNA expression in the lungs (P < 0.05) of MRL/lpr mice, in comparison with MRL/+ or B6 mice. The increase paralleled increased expression of a specific IP-10 receptor, CXCR3, and correlated with the degree of infiltration of mononuclear lymphocytes. In contrast, lung expression of TARC and its specific receptor, CCR4, were suppressed in MRL/lpr mice. Immunohistology showed that macrophage-like cells were the likely source of IP-10. Flow cytometric analyses revealed that the CXCR3-expressing cells were mainly infiltrating CD4 T cells and macrophages, which correlated with the degree of mononuclear lymphocyte infiltration. Recent data suggest that Th1 cells and Th1-derived cytokines play an important role in the development of SLE-like disease in MRL/lpr mice. Our results suggest that IP-10 expression in the lung is involved, through CXCR3, in the pathogenesis of pulmonary inflammation associated with migration of Th1 cells.

Tacrolimus-induced lung injury in a rheumatoid arthritis patient with interstitial pneumonitis

A 74-year-old woman was experiencing rheumatoid arthritis complicated with interstitial pneumonitis (IP), and tacrolimus treatment was started. She presented with dyspnea. Chest X-ray and computed tomography (CT) showed ground-glass opacity and IP. Although tacrolimus was stopped, she died of respiratory failure. At autopsy, both the upper and lower lung fields showed usual IP and the organizing stage of diffuse alveolar damage. The former is common, but the latter is uncommon, suggesting tacrolimus may cause severe alveolar damage.

Increased serum levels of macrophage migration inhibitory factor (MIF) in patients with microscopic polyangiitis

Objective To test the hypothesis that macrophage migration inhibitory factor (MIF) is involved in the disease activity of systemic vasculitis. Methods Patients with systemic vasculitis were divided into three groups based on the size of the affected vessels. Microscopic polyangiitis (MPA) was considered as small vessel vasculitis (SVV), polyarteritis nodosa as medium-sized vessel vasculitis (MVV), and giant cell arteritis and Takayasu arteritis as large vessel vasculitis (LVV). Sera from patients with systemic vasculitis and healthy individuals were collected, and MIF levels were measured using an enzyme-linked immunosorbent assay. Disease activity of vasculitis was assessed using the Birmingham Vasculitis Activity Score (BVAS). Results Serum MIF levels were significantly higher in the vasculitis patients than in healthy individuals. Among the vasculitis patients, MIF levels were significantly higher in patients in the SVV group (median; 4161.7 pg/ml) than in the other groups (MVV; 1443.2 pg/ml and LVV; 1576.7 pg/ml). In patients with MPA, a positive correlation was observed between serum MIF levels and CRP levels and disease activity (BVAS). Notably, serum MIF levels were significantly diminished after clinical improvement. Conclusions Our findings suggest that MIF may have an important role in small vessel vasculopathy and serve as a useful serologic marker of MPA disease activity.

Rheumatoid Arthritis Patients with Sjogrens Syndrome are More Prone to Depression than Patients with Rheumatoid Arthritis or Sjogrens Syndrome Alone

Although depression is known to be an important complication in patients with rheumatoid arthritis (RA) or Sjogrens syndrome (SS), at present little is known about the mental states of RA patients who also have SS. To address that issue, we recently used a standardized questionnaire, the self-rating depression scale (SDS), to compare the mental states of patients with RA alone and those with RA complicated by SS. There were no significant differences between the two groups with respect to age, sex, arthralgia, patient global assessment or dosage of steroid. On the other hand, the SDS scores of RA patients with SS were significantly higher than those of RA patients without SS. Among the twenty items on the SDS questionnaire, RA patients with SS complained of “constipation” significantly more often than RA patients without SS. Collectively, our findings suggest SS exacerbates depression in RA patients. In discussing our findings, we describe the features of the depression seen in patients with RA, SS and RA with secondary SS, and make comparisons among these three groups.

Critical Involvement of Cytokines and Chemokines in the Pathogenesis of Rheumatoid Vasculitis

Vasculitis in rheumatoid arthritis (rheumatoid vasculitis) has a heterogeneous clinical presentation that includes skin disorders, neuropathy, eye symptoms and systemic inflammation. The molecular mechanisms underlying rheumatoid vasculitis are not fully understood; however, the importance of a chronic imbalance of the cytokines and chemokines involved in orchestrating inflammatory responses is well established in patients with rheumatoid arthritis, and similar dysregulation of these mediators has been suggested to occur in patients with rheumatoid vasculitis. In the present review, we discuss the involvement of cytokines and chemokines in the pathogenesis of rheumatoid vasculitis and evaluate their utility as laboratory parameters of active vasculitic disease. Also the involvement of adhesion molecules is discussed.

Clinical Relevance of Cytokines and Inflammatory Molecules in Rheumatoid Vasculitis

Rheumatoid vasculitis (RV) is an uncommon but severe complication of rheumatoid arthritis (RA) that can cause skin disorders, such as rash, cutaneous ulcerations and gangrene, neuropathy, eye symptoms, and systemic inflammation. Although the molecular mechanisms underlying RV in RA are unclear, it is well known that a chronic imbalance in the expression of chemokines and proinflammatory cytokines is important for orchestrating inflammatory responses in RA patients, and similar dysregulation of cytokines and other inflammatory molecules, such as adhesion molecules, has been suggested to occur in patients with RV. Recently, we reported elevated levels of the soluble form of CX3CL1, which is a newly described membrane-bound CX3C chemokine, in the serum of patients with RV. In the present review, we discuss the involvement of cytokines and inflammatory molecules in the pathogenesis of RV and evaluate their significance as useful laboratory parameters of active vasculitis disease.

Expression and Function of Cytokines and Chemokines in Neuropsychiatric Related Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multi-organ damage, and the neuropsychiatric complications of SLE (NPSLE) are associated with increased morbidity and mortality. In general, the diagnosis of NPSLE is difficult, because no single laboratory marker or imaging modality has been found which can serve as a gold standard, and the diagnosis is thus primarily clinical. The pathogenesis of NPSLE has not been fully elucidated. Focal symptoms are thought to more likely result from vascular lesions, whereas diffuse manifestations are more likely related to autoantibody- or cytokine-mediated impairment of neuronal function. However recent progress has provided evidence that a number of cytokines and chemokines, as well as autoantibodies, may be involved in the neuropsychiatric manifestations of SLE, because certain repertoires of cytokines/chemokines are detectable in the central nervous system of NPSLE patients during active disease. In addition, we have recently shown elevated levels of the soluble form of fractalkine, which is a newly described membrane-bound CX3C chemokine, in the cerebrospinal fluid of patients with active NPSLE. This review will discuss the involvement of cytokines and chemokines in the pathogenesis of NPSLE and the evaluation of their significance as a useful laboratory parameter of active neuropsychiatric disease.