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Autoimmune Inflammatory Disease (autoimmune + inflammatory_disease)
Selected AbstractsHeritability of vasculopathy, autoimmune disease, and fibrosis in systemic sclerosis: A population-based studyARTHRITIS & RHEUMATISM, Issue 7 2010Tracy Frech Objective To investigate the familiality of systemic sclerosis (SSc) in relation to Raynaud's phenomenon (RP) (a marker of vasculopathy), other autoimmune inflammatory disease, and fibrotic interstitial lung disease (ILD). Methods A genealogic resource, the Utah Population Database (UPDB), was used to test heritability of RP, other autoimmune disease, and ILD. Diseases were defined by International Classification of Diseases, Ninth Revision codes and identified from statewide discharge data, the University of Utah Health Science Center Enterprise Data Warehouse, and death certificates and were linked to the UPDB for analysis. Familial standardized incidence ratio (FSIR), relative risks (RRs) to first-, second-, third-, and fourth-degree relatives for SSc, RP, other autoimmune disease, and ILD (with 95% confidence intervals [95% CIs]), and population attributable risk (PAR) were calculated. Results A software kinship analysis tool was used to analyze 1,037 unique SSc patients. Fifty SSc families had significant FSIRs, ranging from 2.07 to 17.60. The adjusted PAR was ,8%. The RRs were significant for other autoimmune disease in the first-degree relatives (2.49 [95% CI 1.99,3.41], P = 2.42 × 10,15) and second-degree relatives (1.48 [95% CI 1.34,2.39], P = 0.002), for RP in first-degree relatives (6.38 [95% CI 3.44,11.83], P = 4.04 × 10,9) and second-degree relatives (2.39 [95% CI 1.21,4.74], P = 0.012), and for ILD in first-degree relatives (1.53 [95% CI 1.04,2.26], P = 0.03), third-degree relatives (1.47 [95% CI 1.18,1.82], P = 0.0004), and fourth-degree relatives (1.2 [95% CI 1.06,1.35], P = 0.004). Conclusion These data suggest that SSc pedigrees include more RP, autoimmune inflammatory disease, and ILD than would be expected by chance. In SSc pedigrees, genetic predisposition to vasculopathy is the most frequent risk among first-degree relatives. [source] The Critical Role of IL-12p40 in Initiating, Enhancing, and Perpetuating Pathogenic Events in Murine Experimental Autoimmune NeuritisBRAIN PATHOLOGY, Issue 4 2002Lei Bao Interleukin 12 (IL-12) is a proinflammatory cytokine with important immunoregulatory activities and is critical in determining the differentiation and generation of Th1 cells. For the present study, we investigated the role of endogenous IL-12 in the pathogenesis of experimental autoimmune neuritis (EAN), which is a CD4+ T-cell mediated autoimmune inflammatory disease of the peripheral nervous system. EAN is used as an animal model for Guillain-Barré syndrome of humans. Here, EAN was established in IL-12 p40 deficient mutant (IL-12 -/- ) C57BL/6 mice by immunization with P0 peptide 180,199, a purified component of peripheral nerve myelin, and Freund's complete adjuvant. In these IL-12 -/- mice the onset of clinical disease was delayed, and the incidence and severity of EAN were significantly reduced compared to that in wild-type mice. The former group's clinical manifestations were associated with less P0-peptide 180,199 induced secretion of interferon-, (IFN-,) by splenocytes in vitro and low production of anti-P0-peptide 180,199 IgG2b antibodies in serum. Fewer IFN-, and TNF-, producing cells, but more cells secreting IL-4, were found in sciatic nerve sections from IL-12 -/- mice, consistent with impaired Th1 functions and response. However, the IL-12 deficiency appeared not to affect P0 peptide 180,199-specific T-cell proliferation. These results indicate that IL-12 has a major role in the initiation, enhancement and perpetuation of pathogenic events in EAN by promoting a Th1 cell-mediated immune response and suppressing the Th2 response. This information augments consideration of IL-12 as a therapeutic target in Guillain-Barré syndrome and other T-cell-mediated autoimmune diseases. [source] Serum chemokine profile in patients with bullous pemphigoidBRITISH JOURNAL OF DERMATOLOGY, Issue 3 2007H. Nakashima Summary Background, Bullous pemphigoid (BP) is an autoimmune inflammatory disease causing blister formation at the dermoepidermal junction. Cutaneous infiltration of activated CD4+ T cells and eosinophils is an early event in blister formation during the disease process, suggesting that the trafficking of circulating leucocytes through the sites of inflammation is crucial in the pathogenesis of the disease. While the accumulated evidence suggests that some cytokines are involved in the pathogenesis, there have been few reports about serum chemokine profiles in patients with BP. Objectives, To determine serum profiles of various chemokines and their clinical association in patients with BP. Methods, Concentrations of 10 chemokines , interferon (IFN)- , -inducible protein-10 (IP-10), monokine induced by IFN- , (MIG), macrophage inflammatory protein (MIP)-1,, MIP-1,, RANTES, eotaxin, monocyte chemoattractant protein (MCP)-1, MCP-2, MCP-3 and growth-regulated oncogene- ,, were measured in serum samples from 38 patients with BP, 16 with pemphigus vulgaris (PV) and 17 normal controls using a sandwich immunoassay-based multiplex protein array system. Results, While there was no significant increase in any serum chemokine levels in patients with PV, serum levels of IP-10 and MCP-1 were significantly increased in patients with BP compared with healthy controls. Furthermore, serum levels of IP-10, MIG, MCP-1 and eotaxin in patients with BP increased significantly with disease severity as determined by the area affected. Conclusions, These observations suggest that an elaborately orchestrated network of chemokines, especially MCP-1 and IP-10, contributes to the pathomechanism of BP. [source] Interleukin-7 promotes the survival of human CD4+ effector/memory T cells by up-regulating Bcl-2 proteins and activating the JAK/STAT signalling pathwayIMMUNOLOGY, Issue 3 2010Nizar Chetoui Summary Interleukin-7 (IL-7) is a crucial cytokine involved in T-cell survival and development but its signalling in human T cells, particularly in effector/memory T cells, is poorly documented. In this study, we found that IL-7 protects human CD4+ effector/memory T cells from apoptosis induced upon the absence of stimulation and cytokines. We show that IL-7 up-regulates not only Bcl-2 but also Bcl-xL and Mcl-1 as well. Interleukin-7-induced activation of the janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling pathway is sufficient for cell survival and up-regulation of Bcl-2 proteins. In contrast to previous studies with naive T cells, we found that IL-7 is a weak activator of the phosphatidylinositol 3 kinase (PI3K)/AKT (also referred as protein kinase B) pathway and IL-7-mediated cell survival occurs independently from the PI3K/AKT pathway as well as from activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway. Considering the contribution of both IL-7 and CD4+ effector/memory T cells to the pathogenesis of autoimmune diseases such as rheumatoid arthritis and colitis, our study suggests that IL-7 can contribute to these diseases by promoting cell survival. A further understanding of the mechanisms of IL-7 signalling in effector/memory T cells associated with autoimmune inflammatory diseases may lead to potential new therapeutic avenues. [source] Interleukin-12 P40 induces the expression of TNF-, in microglia and macrophagesJOURNAL OF NEUROCHEMISTRY, Issue 2002M. Jana Recently, it has been found that overproduction of IL-12 can be dangerous to the host as it is involved in the pathogenesis of a number of autoimmune inflammatory diseases such as multiple sclerosis. It is composed of two different subunits , p40 and p35. Expression of p40 mRNA but not that of p35 mRNA in excessive amount in the CNS of patients with Multiple Sclerosis (MS) suggests that IL-12 p40 may have a role in the pathogenesis of the disease. The present study was undertaken to explore the role of p40 in the expression of TNF-, in microglia. Interestingly, we have found that IL-12 p70, p402 (the p40 homodimer) and p40 (the p40 monomer) dose-dependently induced the production of TNF-, in BV-2 microglial cells. This induction of TNF-, production was accompanied by an induction of TNF-, mRNA. In addition to BV-2 glial cells, p70, p402 and p40 also induced the production of TNF-, in mouse primary microglia and peritoneal macrophages. Since the activation of both NF-,B and C/EBPb is important for the expression of TNF-, in microglial cells, we investigated the effect of p40 on the activation of NF-,B as well as C/EBPb. Activation of NF-,B as well as C/EBPb by p40 and inhibition of p40-induced expression of TNF-, by Dp65, a dominant-negative mutant of p65, and DC/EBPb, a dominant-negative mutant of C/EBPb, suggests that p40 induces the expression of TNF-, through the activation of NF-,B and C/EBPb. This study delineates a novel role of IL-12 p40 in inducing the expression of TNF-, in microglial cells which may participate in the pathogenesis of neuroinflammatory diseases. Acknowledgements:, This study was supported by NIH grants (NS39940 and AG19487). [source] | ||||||||||