. 16 The collaborative groups are detailed at the end of this article.Immune-mediated nephritis contributes to disease in systemic lupus erythematosus, Goodpasture syndrome (caused by antibodies specific for glomerular basement membrane [anti-GBM antibodies]), and spontaneous lupus nephritis. Inbred mouse strains differ in susceptibility to anti-GBM antibody-induced and spontaneous lupus nephritis. This study sought to clarify the genetic and molecular factors that may be responsible for enhanced immune-mediated renal disease in these models. When the kidneys of 3 mouse strains sensitive to anti-GBM antibody-induced nephritis were compared with those of 2 control strains using microarray analysis, one-fifth of the underexpressed genes belonged to the kallikrein gene family, which encodes serine esterases. Mouse strains that upregulated renal and urinary kallikreins exhibited less evidence of disease. Antagonizing the kallikrein pathway augmented disease, while agonists dampened the severity of anti-GBM antibody-induced nephritis. In addition, nephritis-sensitive mouse strains had kallikrein haplotypes that were distinct from those of control strains, including several regulatory polymorphisms, some of which were associated with functional consequences. Indeed, increased susceptibility to anti-GBM antibody-induced nephritis and spontaneous lupus nephritis was achieved by breeding mice with a genetic interval harboring the kallikrein genes onto a disease-resistant background. Finally, both human SLE and spontaneous lupus nephritis were found to be associated with kallikrein genes, particularly KLK1 and the KLK3 promoter, when DNA SNPs from independent cohorts of SLE patients and controls were compared. Collectively, these studies suggest that kallikreins are protective disease-associated genes in anti-GBM antibody-induced nephritis and lupus.
Objective-To examine the association of smoking with clinical and serologic features in African Americans with recent-onset rheumatoid arthritis (RA) and to explore whether this association is dependent on the presence of the HLA-DRB1 shared epitope (SE). Methods-InAfrican Americans with recent-onset RA (n = 300), we examined the association of cigarette smoking (current vs. past vs. never and pack-years of exposure) with anti-CCP antibody, rheumatoid factor (RF) (-IgM and -IgA), rheumatoid nodules, and baseline radiographic erosions using logistic and cumulative logistic regression (adjusting for SE status). We also examined for evidence of interaction between smoking status and SE for all outcomes.Results-Although there was no association with RF-IgA seropositivity, current smokers were approximately twice as likely as never smokers to have higher IgA-RF concentrations (based on tertiles; OR = 1.74; 95% CI 1.05-2.88) and nodules (OR = 2.43; 95% CI 1. 13-5.22). These associations were most pronounced in those with more than 20 pack-years of exposure. There was no association of smoking status or cumulative tobacco exposure with anti-CCP antibody, IgM-RF, or radiographic erosions. There was also no evidence of a biologic or statistical SE-smoking interaction for any of the outcomes examined.Conclusion-This is the first study to systematically examine the association of cigarette smoking with RA-related features in African Americans. Cigarette smoking is associated with both subcutaneous nodules and higher serum concentrations of IgA-RF in African Americans with RA, associations that may have important implications for long-term outcomes in this population. The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, an exclusive license (or non-exclusive for government employees) on a worldwide basis to the BMJ Publishing Group Ltd and its Licenses to permit this article to be published in Annals of Rheumatic Diseases editions and any other BMJPGL products to exploit all subsidiary rights, as set out in our license http://ard.bmjjournals.com/ifora/license.pdf. Since the first report by Vessey nearly twenty years ago 1 , cigarette smoking has been shown in numerous investigations to be associated with rheumatoid arthritis (RA) susceptibility [2][3][4][5][6][7][8][9][10] . In a national study of disease-discordant monozygotic twins, smoking was associated with a twelve-fold increased risk of RA 11 , an association that appears to be most pronounced in those with long-term exposure (> 20 years duration) 7,12,13 . The impact of smoking on RA risk also appears to be mediated by certain genetic risk factors with the HLA-DRB1 shared epitope (SE) being the most notable. In a recent case-control study, there was no significant association of smoking with seropositive RA in cases without the SE. Ever having smoked, however, was associated with a more than six-fold increased risk of anti-CCP (cyclic citrullinated peptide) antibody-positive RA among those with a s...
BackgroundChronic pancreatitis has surgical options including total pancreatectomy to control pain. To avoid surgical diabetes, the explanted pancreas can have islets harvested and transplanted. Immediately following total pancreatectomy with islet autotransplantation (TP-IAT), many islet cells die due to isolation and transplantation stresses. The percentage of patients remaining insulin free after TP-IAT is therefore low. We determined whether cotransplantation of adipose-derived mesenchymal stem cells (ASCs) from chronic pancreatitis patients (CP-ASCs) would protect islets after transplantation.MethodsIn a marginal mass islet transplantation model, islets from C57BL/6 mice were cotransplanted with CP-ASCs into syngeneic streptozotocin-treated diabetic mice. Treatment response was defined by the percentage of recipients reaching normoglycemia, and by the area under the curve for glucose and c-peptide in a glucose tolerance test. Macrophage infiltration, β-cell apoptosis, and islet graft vasculature were measured in transplanted islet grafts by immunohistochemistry. mRNA expression profiling of 84 apoptosis-related genes in islet grafts transplanted alone or with CP-ASCs was measured by the RT2 Profiler™ Apoptosis PCR Array. The impact of insulin-like growth factor-1 (IGF-1) on islet apoptosis was determined in islets stimulated with cytokines (IL-1β and IFN-γ) in the presence and absence of CP-ASC conditioned medium.ResultsCP-ASC-treated mice were more often normoglycemic compared to mice receiving islets alone. ASC cotransplantation reduced macrophage infiltration, β-cell death, suppressed expression of TNF-α and Bcl-2 modifying factor (BMF), and upregulated expressions of IGF-1 and TNF Receptor Superfamily Member 11b (TNFRSF11B) in islet grafts. Islets cultured in conditioned medium from CP-ASCs showed reduced cell death. This protective effect was diminished when IGF-1 was blocked in the conditioned medium by the anti-IGF-1 antibody.ConclusionCotransplantation of islets with ASCs from the adipose of chronic pancreatitis patients improved islet survival and islet function after transplantation. The effects are in part mediated by paracrine secretion of IGF-1, suppression of inflammation, and promotion of angiogenesis. ASCs from chronic pancreatitis patients have the potential to be used as a synergistic therapy to enhance the efficacy of islet transplantation following pancreatectomy.
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