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

Safety and Efficacy of Tocilizumab for the Treatment of Rheumatoid Arthritis

Because of the pathological role of IL-6 in rheumatoid arthritis (RA), tocilizumab (TCZ), a humanized anti-IL-6 receptor monoclonal antibody, was expected to improve inflammation and joint destruction of RA. Indeed, randomized clinical trials demonstrated the clinical efficacy of TCZ as monotherapy or combined with methotrexate (MTX) for RA patients with inadequate responses to disease-modifying antirheumatic drugs, MTX or tumor necrosis factor (TNF) inhibitors. Although long-term tolerability for TCZ is superior to that for TNF inhibitors, information regarding the potency of drug free remission of TCZ is limited at present. In terms of its safety profile, the general risk of infection when using TCZ is comparable to that of TNF inhibitors. TCZ has some advantage in RA patients who can not use MTX and are non-responders to TNF inhibitors. In conclusion, TCZ is one of the most prospective next generation biologics for the treatment of RA

Factors Affecting Catecholamines in Caregivers of Patients with Dementia

Background: Caregivers of dementia patients have significantly higher levels of serum IL-6 and CRP compared to non-caregivers, and the accumulation of everyday stressors reportedly promotes the induction of inflammatory markers. However, few studies have identified factors that affect catecholamine levels in caregivers who experience a combination of physical and mental stress from caregiving. Purpose: This study aimed to identify physical factors that impact catecholamine levels in caregivers of dementia patients. Methods: Participants were elderly caregivers living together with elderly Alzheimer’s-type dementia patients. We performed logistic regression analysis, with levels of adrenaline, noradrenaline, and dopamine (indicators of catecholamine) as dependent variables. Results: Caregiver BMI had a significant impact on adrenaline levels (OR: 0.792; 95%CI: 0.654-0.960) and noradrenaline levels (OR: 1.210; 95%CI: 1.009-1.451), whereas age had a significant impact on dopamine levels (OR: 1.162; 95%CI: 1.019- 1.324). Discussion: While caregiver BMI significantly impacted adrenaline and noradrenaline levels, the mechanism underlying these relationships is unclear. One possibility is that obesity (BMI) and a rise in sympathetic nerve activity contributed to hypertension. Our findings suggest that chronic stress in elderly caregivers may potentially impair the dopaminergic activation system in the brain. Conclusion: There is a need to identify factors which increase BMI in caregivers. Future studies aimed at gaining a better understanding of the lifestyle habits of caregivers and intervention studies aimed at reducing their BMI are warrante

Heteroepitaxial growth and optoelectronic properties of layered iron oxyarsenide, LaFeAsO

Epitaxial thin films of LaFeAsO were fabricated on MgO (001) and mixed-perovskite (La, Sr)(Al, Ta)O3 (001) single-crystal substrates by pulsed laser deposition using a Nd:YAG second harmonic source and a 10 at.% F-doped LaFeAsO disk target. Temperature dependences of the electrical resistivities showed no superconducting transition in the temperature range of 2-300 K, and were similar to those of undoped polycrystalline bulk samples. The transmittance spectrum exhibited a clear peak at ~0.2 eV, which is explained by ab-initio calculations.Comment: Submission: 31st July 2008, Accepted for publication in Appl. Phys. Let