Search

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with genetic and environmental contributions. Hallmarks of the disease are the appearance of immune complexes (IC) containing autoreactive Abs and TLR-activating nucleic acids, whose deposition in kidney glomeruli is suspected to promote tissue injury and glomerulonephritis (GN). Here, using a mouse model based on the human SLE susceptibility locus TNFAIP3-interacting protein 1 (TNIP1, also known as ABIN1), we investigated the pathogenesis of GN. We found that GN was driven by TLRs but, remarkably, proceeded independently of ICs. Rather, disease in 3 different mouse models and patients with SLE was characterized by glomerular accumulation of patrolling monocytes (PMos), a cell type with an emerging key function in vascular inflammation. Consistent with such function in GN, monocyte-specific deletion of ABIN1 promoted kidney disease, whereas selective elimination of PMos provided protection. In contrast to GN, PMo elimination did not protect from reduced survival or disease symptoms such as IC generation and splenomegaly, suggesting that GN and other inflammatory processes are governed by distinct pathogenic mechanisms. These data identify TLR-activated PMos as the principal component of an intravascular process that contributes to glomerular inflammation and kidney injury.

Psoriasis is a chronic inflammatory skin disease with a clear genetic contribution, characterized by keratinocyte proliferation and immune cell infiltration. Various closely interacting cell types, including innate immune cells, T cells, and keratinocytes, are known to contribute to inflammation. Innate immune cells most likely initiate the inflammatory process by secretion of IL-23. IL-23 mediates expansion of T helper 17 (Th17) cells, whose effector functions, including IL-17A, activate keratinocytes. Keratinocyte activation in turn results in cell proliferation and chemokine expression, the latter of which fuels the inflammatory process through further immune cell recruitment. One question that remains largely unanswered is how genetic susceptibility contributes to this process and, specifically, which cell type causes disease due to psoriasis-specific genetic alterations. Here we describe a mouse model based on the human psoriasis susceptibility locus TNIP1, also referred to as ABIN1, whose gene product is a negative regulator of various inflammatory signaling pathways, including the Toll-like receptor pathway in innate immune cells. We find that Tnip1-deficient mice recapitulate major features of psoriasis on pathological, genomic, and therapeutic levels. Different genetic approaches, including tissue-specific gene deletion and the use of various inflammatory triggers, reveal that Tnip1 controls not only immune cells, but also keratinocyte biology. Loss of Tnip1 in keratinocytes leads to deregulation of IL-17-induced gene expression and exaggerated chemokine production in vitro and overt psoriasis-like inflammation in vivo. Together, the data establish Tnip1 as a critical regulator of IL-17 biology and reveal a causal role of keratinocytes in the pathogenesis of psoriasis.

Hepatitis E virus (HEV) infection is an important cause of acute viral hepatitis in several developing countries but has recently been shown to cause chronic hepatitis in immunosuppressed persons. Other hepatotropic viruses that cause chronic infection have been shown to infect peripheral blood mononuclear cells (PBMCs) and to persist in those cells. We therefore decided to look for evidence of replication of HEV in PBMCs obtained from patients with acute hepatitis E, using strand-specific assays for positive and negative HEV RNA. Of the 44 patients with acute hepatitis E during an outbreak in India, including 27 with detectable IgM anti-HEV and 19 with detectable serum HEV RNA, 11 had detectable HEV RNA in their PBMCs. However, of the six PBMC specimens with strong HEV RNA signal, none had detectable negative-strand HEV RNA, a marker of viral replication. These findings indicate the presence of HEV RNA but the absence of its replication in PBMCs from patients with acute hepatitis E.

Contains fulltext : 88045.pdf (Publisher’s version ) (Open Access) Rheumatoid arthritis is an autoimmune disease with 1% prevalence in the industrialized world. The contributions of the inflammasome components Nlrp3, ASC, and caspase-1 in the pathogenesis of collagen-induced arthritis have not been characterized. Here, we show that ASC(-/-) mice were protected from arthritis, whereas Nlrp3(-/-) and caspase-1(-/-) mice were susceptible to collagen-induced arthritis. Unlike Nlrp3(-/-) and caspase-1(-/-) mice, the production of collagen-specific antibodies was abolished in ASC(-/-) mice. This was due to a significantly reduced antigen-specific activation of lymphocytes by ASC(-/-) dendritic cells. Antigen-induced proliferation of purified ASC(-/-) T cells was restored upon incubation with wild type dendritic cells, but not when cultured with ASC(-/-) dendritic cells. Moreover, direct T cell receptor ligation with CD3 and CD28 antibodies induced a potent proliferation of ASC(-/-) T cells, indicating that ASC is specifically required in dendritic cells for antigen-induced T cell activation. Therefore, ASC fulfills a hitherto unrecognized inflammasome-independent role in dendritic cells that is crucial for T cell priming and the induction of antigen-specific cellular and humoral immunity and the onset of collagen-induced arthritis.

Persistent hepatitis E virus (HEV) infection has been reported among solid-organ transplant recipients in nonendemic areas. Such chronic infections have all been related to genotype 3 HEV, which is prevalent in these areas. Whether persistent infection occurs with genotype 1 HEV, prevalent in areas where the infection is hyperendemic, is unclear. We therefore tested sera from renal transplant recipients receiving immunosuppressive agents in India, where genotype 1 HEV infection is endemic, for alanine aminotransferase levels, and presence of IgM and IgG anti-HEV antibodies and HEV RNA. Of the 205 subjects studied [aged 16-65 (median, 38) years, 182 male], 46 (22.4%) had abnormal ALT levels (>40 IU/mL). IgG anti-HEV was detected in 52 (20.5%) and IgM anti-HEV was detected in 14 (6.8%) subjects, including four who had IgG anti-HEV; antibody positivity had no relation with serum ALT or serum creatinine. All the sera tested were negative for HEV RNA. These findings suggest that chronic infection with genotype 1 HEV is infrequent.

Outbreaks of acute hepatitis E, associated with consumption of contaminated drinking water, are frequent in India. Sewage is a major source for contamination of surface water. Data on the presence of hepatitis E virus (HEV) in sewage in India are limited. The aim of this study was to look for the presence of HEV RNA in concentrates of sewage specimens collected from a major open sewage drain in Lucknow, India during August 2004 to July 2006, by the polymerase chain reaction, using primers specific for human HEV (genotype 1) or Indian swine HEV (genotype 4). Of the 192 sewage specimens tested, 79 (41%) showed presence of human HEV RNA. The positivity rate was higher during the second year (52/103 [51%]) than during the first year (27/89 [30%]; P = 0.005). The seasonal pattern of HEV RNA positivity was as follows: winter months (November to February): 28 of 61 (46%); summer months (March to June): 36 of 66 (55%); and, monsoon months (July to October) 15 of 65 (23%). There was no reported outbreak of hepatitis E in the city during the study period. Swine HEV RNA was not detected in any of the 69 specimens tested. Repeat testing confirmed the reproducibility of the results. In addition, nucleic acid sequencing of six sewage isolates showed that these belonged to HEV genotype 1. The study suggests that HEV infection and fecal viral excretion may be common in HEV-endemic regions throughout the year even during non-epidemic periods.