B cells positively regulate immune responses through antibody production and optimal CD4⁺ T cell activation. However, a specific and functionally important subset of B cells can also negatively regulate immune responses in mouse autoimmunity and inflammation models. The lack or loss of regulatory B cells has been demonstrated by exacerbated symptoms in experimental autoimmune encephalitis, chronic colitis, contact hypersensitivity, collagen-induced arthritis, and non-obese diabetic mouse models. We have recently found that IL-10-producing regulatory B cells predominantly localize within a rare CD1d^hiCD5⁺ B cell subset that shares cell surface markers with both B-1 and marginal zone B cells. We have labeled this specific subset of regulatory B cells as B10 cells to highlight that these rare CD1d^hiCD5⁺ B cells only produce IL-10 and are responsible for most IL-10 production by B cells, and to distinguish them from other regulatory B cell subsets that may also exist. This review focuses on the recent progress in this field and the exciting opportunities for understanding how this unique B cell subset influences diverse immune functions.

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  There are two subclasses of IgA, IgA1 and IgA2, and its heavy chains are encoded by two different genes, α1 and α2 genes. These two subclasses play important roles in the first line of defense, and the amount ratio of these molecules in secretions varies. IgA deficiency (IgAD) is the most common immunodeficiency, however the pathogenesis in most cases of IgAD is unknown. The class switch disorder in IgA producing B lymphocytes is one of the important factors in IgAD patients. The decreased expression levels of Iα germline transcripts before a class switch may be the cause of selective IgAD. The α1 and α2 gene expression levels are low in most IgAD patients. Using RT-PCR method in which α1 and α2 mRNAs can be separately evaluated, we identified the second case of α1 gene deletion in Japan. Longitudinal change in the serum IgA of the patient with α1 gene deletion showed the pattern of the partial IgAD. Patients with α1 gene deletion can be considered as having partial IgAD.

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  TNF inhibitors, infliximab, etanercept and adalimumab, and tocilizumab are available in Japan and have been successful at improving the signs and symptoms of RA and, thereby, have set a new standard for disease control of RA and have the potential to protect joints from structural damage or to improve quality of life and mortality. However, the rate of successful induction of remission was about 30% and the treatment strategies for the patients who do not respond to these biologics should be established. Randomized clinical trials targeting T or B lymphocytes have been conducted in addition to the new anti-TNF blockers like golimumab or certolizumab pegol. Anti-CD20 antibodies such as rituximab (chimeric), ocrelizumab (humanized), ofatuzumab (full human) demonstrated effectiveness to the patients who do not respond to TNF blockers. CTLA-4 Ig, which can transduce negative signal into T lymphocytes in the co-stimulatory pathway, has also showed a good response to refractory RA. Furthermore, low molecular agents such as Jak (Janus kinase) 3 or syk (spleen tyrosine kinase) inhibitors demonstrated rapid and strong suppression of synovitis and are thought to be new candidates for the drugs to overcome refractory RA.

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  Tissue fibrosis is a common cause of organ failure. Consequently, elucidation of the mechanisms underlying both the initiation and progression of fibrosis is an essential step toward establishing new therapeutic strategies for the treatment of organ failure. Fibroblasts are the principal effectors mediating fibrosis and their heterogeneous origins, including epithelial-mesenchymal transition (EMT), bone marrow-derived cell or fibrocyte, and endothelial-mesenchymal transison (EndMT), have been demonstrated. Chronic hypoxia has been proposed as an important microenviromental factor in the development of tissue fibrosis. Recently, we reported that hypoxia induces EMT in renal tubular epithelial cells through activation of hypoxia-inducible factor-1α (HIF-1α). Using the Cre-loxP mediated gene targeting of HIF-1α or VHL which acts as a ubiquitin ligase to promote degradation of HIF-1α, we showed that HIF-1α plays a key role in the progression of renal fibrosis. As a large number of molecules that contribute to the induction of fibrosis have been identified, and their signal transduction pathway has been characterized, these fibrosis-related molecules have been proposed as therapeutic targets. EMT antagonists, TGF-β signal modulator, and HIF-1α inhbitor could be useful for the treatment of fibrosis.

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  Recent advance of molecular biology and immunology contributes to the development biologics such as anti-TNFα agent in the treatment for inflammatory bowel disease (IBD). Although therapeutic strategy of IBD has not been changed for a long time, success of Infliximab, first anti-TNFα agent, now changes therapeutic strategy of IBD dramatically. Top-down strategy has been considered to improve patients' natural history in the therapy for Crohn's disease as well as in rheumatoid arthritis. Infliximab also has been expected as a promising medicine for pediatric Crohn's disease. Furthermore, Infliximab has been approved for the therapy of ulcerative colitis. These tremendous successes of Infliximab have encouraged us to develop other anti-TNF agents and other biologics. In this review, we describe current topics of biologics in IBD treatment and discuss future direction.

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  Background: Eosinophils play an important role in allergic responses. Eotaxin is a CC chemokine that promotes the selective recruitment of eosinophils. This study was performed to investigate the significance of eotaxin in pediatric food allergies.
  Methods: The study population included 35 patients with food allergy, 18 patients with atopic dermatitis but without food allergy, and 19 age-matched non-allergic controls. Eotaxin-1 and eotaxin-3 levels in plasma were assayed by enzyme-linked immunosorbent assay. Simultaneously, eosinophil counts in peripheral blood and serum immunoglobulin E (IgE) values were assessed.
  Results: Plasma eotaxin-1 levels were 93.6±33.4 pg/ml in patients with food allergy, 78.0±31.8 pg/ml in patients with atopic dermatitis, and 60.4±15.7 pg/ml in controls. Differences between the food allergy and control groups were significant (P<0.001). Circulating eosinophil counts in patients with food allergy were higher than those in controls (5.84±9.46×10⁹/l vs. 1.20±1.11×10⁹/l, P<0.001). Nevertheless, eotaxin-1 levels in children with food allergy were not correlated with eosinophil counts or serum IgE levels. There were no significant differences in eotaxin-3 levels between the 3 groups.
  Conclusion: Plasma levels of eotaxin-1 were elevated in children with food allergy. The pathophysiological relevance of the increase in eotaxin is discussed.

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  Behcet's disease (BD) is a polysymptomatic and recurrent systemic vasculitis with a chronic course and unknown cause. Erosive arthropathy is extremely rare. We report a 52-year-old female patient with BD demonstrating bone erosion of the sternocostal joint.

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  The patient was a 63-year-old woman. She was admitted to our hospital with acute renal failure and multiple mononeuritis in 2002. She was diagnosed as microscopic polyangiitis based on positive for MPO-ANCA. Remission was induced by combination therapy with methylprednisolone pulse therapy and plasma exchange. Because condition of the disease was stable, prednisolone was discontinued from August 2006. Elevation of serum creatinine and microscopic hematuria was detected in November 2007. Fever and dyspnea occurred in January 24 2008. Elevation of CRP and serum creatinine was found, and infiltration in bilateral lung was noted on chest X-ray. She was admitted on the same day. After admission, she presented with hemosputum and exacerbation of dyspnea. Chest CT revealed diffuse consolidation and ground glass opacity, and MPO-ANCA converted to be positive. Diagnosis of diffuse alveolar hemorrhage and rapidly progressive glomerulonephritis with microscopic polyangiitis was made, and she was managed by artificial respirator and CHDF in ICU. Combination therapy with steroid pulse therapy and plasma exchange re-induced remission. Mizoribine was administrated as maintenance therapy with oral prednisolone.

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  The therapeutic efficacy of corticosteroids and immunosuppressants on secretary glands of children with Sjögren syndrome was investigated examining the lip-biopsy specimen on both lymphocyte infiltration and fibrosis. Six children with primary Sjögren syndrome and two children with lupus-associated secondary Sjögren syndrome were evaluated according to the intensity of therapy. The shorter the term of medications of corticosteroids and immunosuppressants were, the lesser the extents of lymphocyte infiltration and fibrosis were, and the lower the doses of medications were, the lesser the efficacy was. Thus, in childhood Sjögren syndrome, appropriate corticosteroids and immunosuppressants may provide the suppressive effects on the progressive inflammatory destruction of secretary glands. Further evaluation with more patients is needed to determine the inclusion criteria of these treatments for sicca syndrome, especially in cases with no other organ involvement.

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