A Four-Step Model for the IL-6 Amplifier, a Regulator of Chronic Inflammations in Tissue-Specific MHC Class II-Associated Autoimmune Diseases

It is commonly thought that autoimmune diseases are caused by the breakdown of self-tolerance, which suggests the recognition of specific antigens by autoreactive CD4+ T cells contribute to the specificity of autoimmune diseases (Marrack et al., 2001; Mathis and Benoist, 2004). In several cases, however, even for diseases associated with class II major histocompatibility complex (MHC) alleles, the causative tissue-specific antigens recognized by memory/activated CD4+ T cells have not been established (Mocci et al., 2000; Skapenko et al., 2005). Rheumatoid arthritis (RA) and arthritis in F759 knock-in mice (F759 mice) are such examples (Atsumi et al., 2002; Brennan et al., 2002; Falgarone et al., 2009). These include associations with class II MHC and CD4 molecules; increased numbers of memory/activated CD4+ T cells; and improved outcomes in response to suppressions and/or deficiencies in class II MHC molecules, CD4+ T cells, and the T cell survival cytokine IL-7. Regarding the development of arthritis in F759 mice, it is not only the immune system, but also non-immune tissue that are involved, indicating that the importance of their interactions (Sawa et al., 2006, 2009; Ogura et al., 2008; Hirano, 2010; Murakami et al., 2011). Furthermore, we have shown that local events such as microbleeding together with an accumulation of activated CD4+ T cells in a manner independent of tissue antigen-recognitions induces arthritis in the joints of F759 mice (Murakami et al., 2011). For example, local microbleeding-mediated CCL20 expression induce such an accumulation, causing arthritis development via chronic activation of an IL-17A-dependent IL-6 signaling amplification loop in type 1 collagen+ cells that is triggered by CD4+ T cell-derived cytokine(s) such as IL-17A, which leads to the synergistic activation of STAT3 and NFκB in non-hematopoietic cells in the joint (Murakami et al., 2011). We named this loop the IL-6-mediated inflammation amplifier, or IL-6 amplifier for short (Ogura et al., 2008; Hirano, 2010; Murakami et al., 2011). Thus, certain class II MHC-associated, tissue-specific autoimmune diseases, including some RA subtypes, may be induced by local events that cause an antigen-independent accumulation of effector CD4+ T cells followed by the induction of the IL-6 amplifier in the affected tissue. In other words, in certain cases, the target tissue itself may determine the specificity of the autoimmune disease via activation of the IL-6 amplifier. To explain this hypothesis, we have proposed a four-step model for MHC class II-associated autoimmune diseases (Murakami et al., 2011): (1) T cell activation regardless of antigen specificity; (2) local events inducing a tissue-specific accumulation of activated T cells; (3) transient activation of the IL-6 amplifier; and (4) enhanced sensitivity to cytokines in the target tissue. The interaction of these events results in chronic activation of the IL-6 amplifier and subsequent manifestation of autoimmune diseases. Thus, the IL-6 amplifier, which is chronically activated by these four events, is a critical regulator of chronic inflammations in tissue-specific MHC class II-associated autoimmune diseases

Gateway Reflex: A Neuro-Immune Crosstalk for Organ-Specific Disease Development

Homeostasis of the central nervous system (CNS) is strictly regulated by a unique structure of blood vessels, the blood-brain barrier (BBB). Experimental and clinical evidence has revealed that abnormalities in the BBB in chronic inflammatory diseases such as multiple sclerosis (MS). By using an animal model of MS, we identified novel neuro-immune crosstalk to explain how pathogenic immune cells enter the CNS to disrupt its homeostasis, a phenomenon we named the gateway reflex. Regional neural inputs such as gravity, electricity, pain or chronic stress cause specific neural activation to create a gateway of immune cells, particularly pathogenic ones, at specific blood vessels. Moreover, the recently discovered stress-induced gateway reflex uncovered a stress-induced neural link between the brain, gastrointestine, and heart. Thus, the gateway reflex is critical for the homeostasis of various organs, and aberrant activation of neural pathways by the gateway reflex disrupts normal organ homeostasis. The inflammatory reflex is another mechanism for local neuro-immune interactions. It potently exerts a cholinergic anti-inflammatory effect on various disease conditions. In this section, we discuss emerging roles for local neuro-immune interactions, with a special focus on the gateway reflex

Non-Equilibrium Ionization States of GRB Environments

Iron spectral features are thought to be the best tracer of a progenitor of gamma-ray bursts (GRBs). The detections of spectral features such as an iron line and/or a Radiative Recombination edge and Continuum (RRC) were reported in four X-ray afterglows of GRBs. However their properties were different each other burst by burst. For example, Chandra observation of GRB 991216 reported both the strong H-like iron line together with its RRC. On the contrary, Yoshida et al. (2001) report only a detection of the strong RRC in GRB 970828 with ASCA. Since it is difficult to produce the strong RRC, we have to consider special condition for the line and/or the RRC forming region. In this paper, we point out a possibility of a ``non-equilibrium ionization state'' for the line and the RRC forming region.Comment: 10pages, 2figures. Accepted for ApJL. This is a companion paper by A.Yoshida et. a

Pericardial Effusion in Association With Periodontitis: Case Report and Review of 8 Patients in Literature

Periodontal diseases are well-known background for infective endocarditis. Here, we show that pericardial effusion or pericarditis might have origin also in periodontal diseases. An 86-year-old man with well-controlled hypertension and diabetes mellitus developed asymptomatic increase in pericardial effusion. Two weeks previously, he took oral new quinolone antibiotics for a week because he had painful periodontitis along a dental bridge in the mandibular teeth on the right side and presented cheek swelling. The sputum was positive for Streptococcus species. He was healthy and had a small volume of pericardial effusion for the previous 5 years after drug-eluting coronary stents were inserted at the left anterior descending branch 10 years previously. The differential diagnoses listed for pericardial effusion were infection including tuberculosis, autoimmune diseases, and metastatic malignancy. Thoracic to pelvic computed tomographic scan demonstrated no mass lesions, except for pericardial effusion and a small volume of pleural effusion on the left side. Fluorodeoxyglucose positron emission tomography disclosed many spotty uptakes in the pericardial effusion. The patient denied pericardiocentesis, based on his evaluation of the risk of the procedure. He was thus discharged in several days and followed at outpatient clinic. He underwent dental treatment and pericardial effusion resolved completely in a month. He was healthy in 6 years until the last follow-up at the age of 92 years. We also reviewed 8 patients with pericarditis in association with periodontal diseases in the literature to reveal that periodontal diseases would be the background for developing infective pericarditis and also mediastinitis on some occasions