Chronic granulomatous disease (CGD) is a primary immunodeficiency (PID) characterized by the inability of phagocytes to produce reactive oxygen intermediates (ROIs) due to a defect in the NADPH oxidase complex. Recent studies have revealed that ROIs are involved in inflammatory signaling in phagocytes, illuminating the underlying mechanisms of hyper-inflammation in CGD. CGD patients frequently suffer from CGD-associated bowel inflammation, granuloma, and life-threatening infections. Based on the discovery of the regulatory function of ROIs in the immune response, therapeutic methods for excessive inflammation focusing on inflammatory cytokines are being developed for CGD. Although hematopoietic stem cell (HSC) transplantation (HSCT) is a curative therapy for CGD, successful transplants greatly depend on HSC source selection and the degree of matching of potential donors. Gene therapy trials for PID have been performed on over 120 patients with no HLA identical donor for HSCT, and have demonstrated clinical benefits. Genotoxicity in HSC gene therapy trials has expanded our knowledge on the mechanisms of vector-associated clonal expansion of gene-modified cells, which will advance gene therapy development using self-inactivating retrovirus and lentivirus vectors. We will discuss the complications of HSCT for CGD. We will then outline the status of gene therapy approaches in the treatment of CGD.

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  Revertant somatic mosaicism has been described in an increasing number of genetic disorders including primary immunodeficiency diseases. Both back mutations leading to restoration of wild-type sequences and second-site mutations resulting in compensatory changes have been demonstrated in mosaic individuals. Recent studies identifying revertant somatic mosaicism caused by multiple independent genetic changes further support its frequent occurrence in primary immunodeficiency diseases. Revertant mosaicism acquires a particular clinical relevance because it may lead to selective growth advantage of the corrected cells, resulting in improvement of disease symptoms or atypical clinical presentations. This phenomenon also provides us unique opportunities to evaluate the biological effects of restored gene expression in different cell lineages. Here we review the recent findings of revertant somatic mosaicism in primary immunodeficiency diseases and discuss its clinical implications.

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  The prognosis of connective tissue disease (CTD)-associated pulmonary arterial hypertension (PAH) is so poor that early therapeutic intervention is advisable. Borderline PAH (21-24 mmHg mean pulmonary arterial pressure) is a concept created to distinguish cases that would become definite PAH. It is controversial whether borderline PAH cases with no symptoms should be treated, but therapeutic intervention in the case of borderline PAH is justified when systemic sclerosis (SSc) is in the background, because SSc-associated PAH shows an especially poor prognosis compared to PAH associated with other CTDs, while 42-55% of SSc-associated borderline PAH cases become definite PAH within several years. However, cautious attention should be paid when pulmonary vasodilators are administered to SSc-associated PAH cases, because complications caused by SSc such as lung lesions, left heart diseases and pulmonary venous lesions can be obstacles to the success of the therapy. There is very little evidence of the efficacy of therapeutic intervention in borderline PAH. Clinical trials should be planned.

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  Recently a new pathogenic mechanism for autoantibody production was proposed. Misfolded proteins bind to MHC class II in the endoplasmic reticulum and are processed to be presented at the cell surface. Misfolded proteins are not trimmed to peptides, but are presented as they are together with MHC class II molecules. Such misfolded protein/MHC class II complex can stimulate B cells, but not T cells, and will induce autoantibody production. One of such examples is the case of IgG heavy chain (IgGH). HLA class II can bind IgGH and presents it to the cell surface. Such IgGH/HLA class II complex can be recognized by rheumatoid factor. Surprisingly, RA susceptible HLA class II alleles can present IgGH efficiently, but RA resistant HLA class II alleles cannot. Therefore susceptibility to certain autoimmune diseases may be determined by the affinity of misfolded autoantigens to certain HLA class II alleles. Such new autoimmune mechanisms may explain the unexplained autoantibody production mechanisms.

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  Neuromyelitis optica (NMO) has been revealed the difference in the pathology of multiple sclerosis since the anti-aquaporin 4 (AQP4) antibody associated with NMO has been found. The clinical epidemiological study has been reviewed, NMO-related patient number in Japan is estimated to be about 4400 people. The antibody-positive patients against myelin-oligodendrocyte glycoprotein (MOG) are present in anti-AQP4 antibody-negative NMO patients. These patients have a characteristic with high frequency of optic neuritis and good response to therapy. In addition, by research in recent years, a new treatment such as anti-IL-6 therapy or anti-complement therapy has been attempted to NMO.

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  Systemic sclerosis (SSc) is a multisystem connective tissue disease featured by immune abnormalities, vasculopathy and resultant fibrosis of the skin and various internal organs. Although the pathogenesis of SSc remains incompletely elucidated, it is currently accepted that this disease is caused by the complex interplay between hereditary and environmental factors. The deficiency of transcription factor Fli1, which is epigenetically suppressed in SSc dermal fibroblasts, potentially causes SSc-like phenotypical alteration in various cell types such as fibroblasts, endothelial cells, and macrophages, suggesting that Fli1 is a predisposing factor of SSc. KLF5 is another transcription factor which is suppressed in SSc dermal fibroblasts through an epigenetic mechanism. Importantly, double heterozygous mice for Fli1 and KLF5 develop three cardinal features of SSc, including immune abnormalities, vasculopathy and fibrosis. Therefore, these two transcription factors are likely to be critical predisposing factors regulating the development of SSc. Given that potential disease modifying drugs, bosentan and imatinib, reverse the expression and transcriptional activity of Fli1, the studies on the pathological process of double heterozygous mice and the impact of these transcription factors on various cell types may provide a new clue to further understand the pathogenesis of SSc leading to the development of new therapies.

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  We herein described the long-term administration of tocilizumab (TCZ) to a patient with rheumatoid arthritis (RA) complicated by three vessel coronary artery disease and severe heart failure (HF). A 41-year-old male was admitted to our hospital with exacerbated RA and congestive HF. Cardiac ultrasonography revealed diffuse hypokinesis with a left ventricular ejection fraction (LVEF) of 16.8% and New York Heart Association (NYHA) class III/IV HF. Swelling and tenderness were noted in most of his joints. Methotrexate (MTX) was initiated during his hospitalization and TCZ was introduced 6 months later. Our patient has been treated with MTX and TCZ for five years without any adverse events, and RA and HF have remained stable. Although it may be anecdotal, we suggest that TCZ may be used as a treatment option in patients with RA complicated by severe HF.

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