These results suggest that a GIMAP cluster is a novel susceptibility locus for BD, which is involved in T-cell survival, and T-cell aberration can contribute to the development of BD.
Z39Ig is a transmembrane protein containing two Ig homology domains with unknown functions. Immunohistochemical analyses of human carotid atherosclerotic plaques detected Z39Ig staining in areas rich in foamy macrophages. Z39Ig staining was also observed in macrophages in the lining layers and sublining areas of rheumatoid arthritis synovium. Z39Ig staining in the osteoarthritis synovium was restricted to macrophages in the lining layers. To identify the role(s) of Z39Ig in the function of macrophages, we used human monocytic cell lines TF-1A (Z39Ig-negative) and THP-1 (Z39Ig-positive). The expression of Z39Ig was induced in TF-1A cells ,when they were differentiated into macrophages by treatment with PMA. The stimulation of PMA-treated TF-1A or THP-1 cells with immobilized anti-Z39Ig mAb induced the secretion of IL-8 and matrix metalloproteinase (MMP)-9, which was dependent on NF-kappaB activation. These data indicate that the macrophage Z39Ig is involved in the pathogenesis of inflammatory diseases through chemokine induction, which will promote the migration of inflammatory cells into the lesion area, and MMP-9 induction, which will contribute to cartilage destruction or extracellular matrix degradation.
The enhanced differentiation and activation of osteoclasts (OCs) in the inflammatory arthritis such as rheumatoid arthritis (RA) and gout causes not only local bone erosion, but also systemic osteoporosis, leading to functional disabilities and morbidity. The induction and amplification of NFATc1, a master regulator of OC differentiation, is mainly regulated by receptor activator of NF-κB (RANK) ligand-RANK and calcium signaling which are amplified in the inflammatory milieu, as well as by inflammatory cytokines such as TNFα, IL-1β and IL-6. Moreover, the predominance of CD4 + T cell subsets, which varies depending on the condition of inflammatory diseases, can determine the fate of OC differentiation. Anti-citrullinated peptide antibodies which are critical in the pathogenesis of RA can bind to the citrullinated vimentin on the surface of OC precursors, and in turn promote OC differentiation and function via IL-8. In addition to adaptive immunity, the activation of innate immune system including the nucleotide oligomerization domain leucine rich repeat with a pyrin domain 3 inflammasome and TLRs can regulate OC maturation. The emerging perspectives about the diverse and close interactions between the immune cells and OCs in inflammatory milieu can have a significant impact on the future direction of drug development.
BackgroundAntineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides (AAV) are necrotizing small-vessel vasculitides in conjunction with autoantibodies to neutrophil constituents. Diffuse alveolar hemorrhage (DAH) and renal involvement are the most serious manifestations, and higher five factor score (FFS) has been associated with higher mortality rate. Although the introduction of cyclophosphamide and corticosteroids has changed the natural history of disease from an almost fatal condition to a relapsing and remitting one with greatly increased survival, patients with AAV still have a 9-fold increased risk of death in the first year of disease. Furthermore, reported causes of death (COD) and risk factors for mortality vary between studies, which indicate the need of further investigation.ObjectivesTo investigate the COD and risk factors for mortality in patients with AAV.MethodsA retrospective study was conducted in 44 patients with microscopic polyangiitis (MPA) and 12 granulomatosis with polyangiitis (GPA) from January 1999 to December 2011. All patients fulfilled the Chapel Hill Consensus Conference 1992 definition and Sorensen's diagnostic criteria for MPA and GPA. We reviewed medical records of patients including basic demographic characteristics, cumulative clinical features, treatment agents, and causes of death. The primary COD was defined as the main clinical and pathological process directly responsible for death and then categorized into 3 groups: vasculitis-related, vasculitis-unrelated, and unknown.ResultsRenal involvement and DAH were observed in 73.2% (41/56), and 30.4 (17/56), respectively, in all the patients with MPA or GPA. The mortality rate was 41.1% (23/56) with 5 deaths (41.6%) in patients with GPA and 18 (40.9%) with MPA. Among the significant risk factors for mortality on univariate analysis, which include DAH, renal involvement, ≥4 organ involvements, ≥2 FFS scores, and ≥4 treatment modalities, a multivariate regression analysis identified DAH as an independent predicting factor (HR, 10.28; 95% CI, 2.58–40.56; p<0.001). In an analysis of COD, two deaths (8.6%) were related to vasculitis, while 19 (82.6%) were related to infection. The most common COD was pneumonia (17/23, 73.9%) which, in turn, was associated with DAH (OR, 27.18; 95% CI, 4.30 - 171.80; p <0.001) and ≥4 organ involvement (OR, 7.62; 95% CI, 1.54 - 37.71; p =0.013) as independent risk factors. Bacteria were the most frequent microorganisms causing pneumonia (n=43, 68.2%), followed by fungi (n=8, 12.7%) and Pneumocyctis jirovecii (n=7, 11.1%). Most frequently isolated bacteria were Acinetobacter baumanii (6 cases), and Staphylococcus aureus (MRSA, 6 cases). The mean number of isolated pathogens in patients with pneumonia was 3.33 ±2.11. There were no significant difference in the mean number of pathogens between patients who survived and dead (3.00±0.00 vs. 3.37±2.24).ConclusionsThe result of present study implicated that early intervention of pulmonary infection may be critical to increase survival rates in AAV ...
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