Type B acute aortic dissection (AAD) spares the ascending aorta and is optimally managed by medical therapy in the absence of complications. However, patients with enhanced inflammation sometimes present with aortic enlargement, thereby facing undesirable outcomes. Thus, a better understanding of the molecular and cellular mechanisms involved in AAD-associated inflammatory processes and the requirement for a novel therapeutic approach for patients with type B AAD are unmet clinical needs. This study showed that dissection per se induced neutrophil-chemoattractant chemokine expression in the aortic tunica adventitia, possibly by mechanical injury and stretching followed by pseudolumen formation. Subsequent systemic changes in chemokine-dependent signaling caused neutrophilia and massive neutrophil accumulation in the dissected aorta, thereby leading to aortic enlargement and rupture via interleukin-6 production. Importantly, temporal and spatial dynamics of inflammatory cytokine and chemokine elevation, as well as leukocyte recruitment, were consistent between rodents and humans. Our study provides a new mechanistic insight into neutrophil-mediated adventitial inflammation after AAD and implicates CXCR2- or interleukin-6 neutralization as novel therapeutic strategies to prevent large-artery complications, including aneurysm formation and rupture, in patients with type B AAD.

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  It has long been suggested that various aspects of the immune system is affected by the activity of the nervous system. However, how the inputs from the nervous system are converted into the outputs from the immune system had been largely unclear. Studies in the last decade revealed the cellular and molecular basis by which inputs from the autonomic nervous system control the development and functions of immune cells. The principal autonomic neurotransmitters, acetylcholine and noradrenaline, are involved in immune regulation in the context of inflammation through various molecular pathways. Circadian rhythm in the activity of the autonomic nervous system produces fluctuations of immune functions during a day. This review integrates the current knowledge about the autonomic regulation of inflammatory responses and provide therapeutic implications for inflammatory diseases.

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  Development of acute experimental autoimmune encephalomyelitis (EAE) depends on Th17 cells expressing the nuclear factor NR4A2, which we have previously reported to be upregulated in peripheral blood T cells from patients of multiple sclerosis (MS). EAE induced in mice lacking NR4A2 in T cells showed a great reduction in Th17-mediated acute symptoms, whereas a late-onset disease independent of NR4A2 was still inducible. We identified cytotoxic T-cell-like CD4+ T cells expressing the T-box transcription factor Eomesodermin (Eomes) as a pathogenic component for the development of the late-onset disease. Furthermore, T cell-specific deletion of the Eomes gene or Eomes-specific RNA interference in vivo remarkably ameliorated the late-onset EAE. Intriguingly, similar Eomes-expressing CD4+ T cells are increased in the peripheral blood and cerebrospinal fluid only from patients with secondary-progressive MS accompanied by neurodegenerative symptoms, but not in relapsing-remitting MS. Mechanistic analysis revealed that granzyme B was secreted by Eomes-expressing CD4+ T cells and the activation of protease-activated receptor-1 by granzyme B is involved in the neuroinflammation observed in the late-onset EAE.

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  CD4⁺ T cells play central roles to appropriate protection against pathogens. While, they can also be pathogenic driving inflammatory diseases. Besides the classical model of differentiation of T helper 1 (Th1) and Th2 cells, various CD4⁺ T cell subsets, including Th17, Th9, T follicular helper (Tfh) and T regulatory (Treg) cells, have been recognized recently. In this review, we will focus on how these various CD4⁺ T cell subsets contribute to the pathogenesis of immune-mediated inflammatory diseases. We will also discuss various unique subpopulations of T helper cells that have been identified. Recent advancement of the basic immunological research revealed that T helper cells are plastic than we imagined. So, we will focus on the molecular mechanisms underlying the generation of the plasticity and heterogeneity of T helper cell subsets. These latest finding regarding T helper cell subsets has pushed us to reconsider the etiology of immune-mediated inflammatory diseases beyond the model based on the conventional Th1/Th2 balance. Toward this end, we put forward another model, “the pathogenic Th population disease induction model”, as a possible mechanism for the induction and/or persistence of immune-mediated inflammatory diseases.

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  Rapid development of fluorescent imaging techniques enables us to understand cellular dynamics in vivo. We have originally established an advanced imaging system for visualizing living bone tissues with intravital two-photon microscopy. By means of the system, we have recently succeeded in visualization of the in vivo behavior of living mature osteoclasts on the bone surface, and identified different functional subsets of osteoclasts in terms of their motility and function, i.e., ‘static – bone resorptive’ and ‘moving – non resorptive’. Pathological conditions changed the composition of these populations as well as the total number of mature osteoclasts. We also found that RANKL-bearing Th17 cells could control bone resorption of mature osteoclasts, demonstrating novel actions of Th17. Furthermore, we have also developed the imaging system to visualize bone destruction by osteoclasts in arthritic joints using intravital two-photon microscopy. In this review, we summarize the latest data of intravital imaging of osteoclast dynamics, and also discuss its further application.

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Background: In Japan, familial Mediterranean fever (FMF) is a rare cause of fever of unknown origin (FUO). However, we experienced an extraordinary number of FMF cases over 3 years. This suggests that many patients with FMF remain misdiagnosed in Japan. This study examines the clinical picture of FMF to assist Japanese clinicians in daily practice dealing with FUO.
Patients and Methods: Three years of medical records were reviewed, and 38 patients with FMF or suspected FMF were collected from our patient database. We applied the Tel-Hashomer criteria to those patients.
Results: Of the 38 patients, 30 were classified as having FMF in this investigation. The mean patient age was 27.8 years. MEFV gene mutations were detected in 14 patients. Three cases were colchicine-resistant.
Conclusion: Clinicians should recognize the pattern of short, spontaneously resolving attacks of fever with fever-free intervals, especially when they see patients with recurrent FUO in the outpatient setting.

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  Anti-aminoacyl-tRNA synthetase (ARS) antibody is one of the myositis-specific autoantibodies to make a diagnosis of polymyositis (PM) and dermatomyositis (DM). Recently a new enzyme-linked immunosorbent assay (ELISA) kit of concurrently detected anti-ARS antibodies (anti-Jo-1, anti-PL-7, anti-PL-12, anti-EJ and anti-KS) have become to measure in the clinical setting. To evaluate the reliability of this ELISA kit, we measured anti-ARS antibodies in 75 PM and DM patients using by this ELISA assay and compared them with the results by RNA immunoprecipitation assay. Between the measurements of anti-PL-7, anti-PL-12, anti-EJ and anti-KS autoantibodies by ELISA assay and RNA-IP assay, the concordance rate of reproducibility is 95.1% and the positive agreement rate is 90.9% and negative agreement rate is 96.0% and kappa statistic is 0.841. Between the measurements of existing anti-Jo-1 antibody ELISA kit and anti-ARS antibody ELISA kit, the concordance rate of reproducibility is 96.9%, the positive agreement rate is 100%, negative agreement rate is 96.1% and kappa statistic is 0.909. The lung involvement in patients with PM and DM patients are positive of anti-ARS antibodies and anti-melanoma differentiation associated gene5 (MDA5) antibody at a rate around 70%. Then most life-threatening ILD with anti-MDA5 positive clinically amyopathic dermatomyositis patients could be highly guessed when anti-ARS antibodies are negative.

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  A 15-year-old young woman received the Human papillomavirus (HPV) vaccines. Following the second HPV vaccination, intermittent fever, myalgia, arthritis and malar rash developed, and she was admitted to our hospital. Laboratory studies showed positive results for antinuclear antibody, anti-dsDNA antibody and anti-Sm antibody. Systemic lupus erythematosus (SLE) was diagnosed according to the Systemic Lupus International Collaborative Clinics 2012. Magnetic resonance imaging showed abnormal hyperintense areas in the fascia, and en bloc biopsy showed fasciitis. Treatment with prednisolone resulted in an amelioration of the symptoms. Reportedly, SLE developed after HPV vaccinations in some patients. Most such patients have a past or family history of autoimmune disease and presented SLE symptoms after the second vaccination. We describe herein a patient in whom SLE developed in association with HPV vaccination.

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  Antisynthetase syndrome is characterized by the presence of anti-aminoacyl-tRNA synthetase antibodies and characteristic clinical features. We report an anti-EJ antibody-positive case presenting an ILD with slight hyperkeratotic skin changes on the fingertips that appeared simultaneously with respiratory symptoms. We suspected those skin changes of a disease manifestation of antisynthetase syndrome, and thus investigated anti-synthetase antibodies. This case implies that broader spectrum of the patients should fall in antisynthetase syndrome even though the present diagnostic criteria call for mechanic's hand as a skin manifestation. Careful examination of the finger skin and antibody testing should lead to a proper understanding of the pathological processes.

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