Systemic Lupus Erythematosus Patients Exhibit Reduced Expression of CLEC16A Isoforms in Peripheral Leukocytes

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease with multiple etiological factors. The SLE susceptibility locus on chromosome 16p13 encodes a novel gene CLEC16A and its functional relationship with SLE is unclear. This study aimed to investigate the expression correlation of the two major CLEC16A spliced transcripts with SLE development. Expressions of the long (V1) and short (V2) CLEC16A isoforms in the peripheral blood mononuclear cells (PBMCs) were assayed by quantitative real time PCR and compared between healthy individuals and SLE patients. Correlation of CLEC16A isoform expression levels with SLE susceptibility, disease severity and twelve clinical parameters were also evaluated. Full length transcripts of CLEC16A V1 and V2 isoforms were readily amplified from PBMCs of healthy controls and patients at varying abundance. Compared with healthy controls (n = 86), expression levels of V1 and V2 were significantly reduced by ~two- and four-fold respectively in SLE patients (n = 181). The relative V2/V1 ratio was also significantly reduced by approximately two-fold. With regard to SLE disease parameters, only a weak positive correlation was found between CLEC16A V1 expression levels and SLE disease activity index (SLEDAI) score. Taken together, CLEC16A was found to be a susceptibility factor for SLE, with possible contribution to the development of the disease.published_or_final_versio

Increased Set1 binding at the promoter induces aberrant epigenetic alterations and up-regulates cyclic adenosine 5'-monophosphate response element modulator alpha in systemic lupus erythematosus.

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Anti-CD47 antibody suppresses tumor growth and augments the effect of chemotherapy treatment in hepatocellular carcinoma

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is often associated with metastasis and recurrence leading to a poor prognosis. Therefore, development of novel treatment regimens is urgently needed to improve the survival of HCC patients. In this study, we aimed to investigate the in vitro and in vivo effects of anti-CD47 antibody alone and in combination with chemotherapy in HCC. METHODS: In this study, we examined the functional effects of anti-CD47 antibody (B6H12) on cell proliferation, sphere formation, migration and invasion, chemosensitivity, macrophage-mediated phagocytosis, and tumorigenicity both in vitro and in vivo. The therapeutic efficacy of anti-CD47 antibody alone or in combination with doxorubicin was examined in patient-derived HCC xenograft. RESULTS: Blocking CD47 with anti-CD47 monoclonal antibody (B6H12) at 10mug/mL could suppress self-renewal, tumorigenicity and migration and invasion abilities of MHCC-97L and Huh-7 cells. Interestingly, anti-CD47 antibody synergized the effect of HCC cells to chemotherapeutic drugs including doxorubicin and cisplatin. Blockade of CD47 by anti-CD47 antibody induced macrophage-mediated phagocytosis. Using a patient-derived HCC xenograft mouse model, we found that anti-CD47 antibody (400mug/mouse) in combination with doxorubicin (2mg/kg) exerted maximal effects on tumor suppression, as compared with doxorubicin and anti-CD47 antibody alone. CONCLUSIONS: Anti-CD47 antibody treatment could complement chemotherapy which may be a promising therapeutic strategy for the treatment of HCC patients. This article is protected by copyright. All rights reserved.postprin

Th17 cells play a critical role in the development of experimental Sjogren's syndrome

Objective Although Th17 cells have been increasingly recognised as an important effector in various autoimmune diseases, their function in the pathogenesis of Sjögren's syndrome (SS) remains largely uncharacterised. This study aims to determine the role of Th17 cells in the development of experimental SS (ESS). Methods The ESS was induced in wildtype and IL-17A knockout (IL-17 KO) C57BL/6 mice immunised with salivary glands (SG) proteins. Phenotypic analysis of immune cells in the draining cervical lymph nodes (CLN) and SG was performed by flow cytometry and immunofluorescence microscopy. To determine the role of Th17 cells in ESS, immunised IL-17 KO mice were adoptively transferred with in vitro-generated Th17 cells and monitored for SS development. The salivary flow rate was measured, whereas inflammatory infiltration and tissue destruction in SG were assessed by histopathology. Results SG protein-immunised mice developed overt SS symptoms with increased Th17 cells detected in CLN and within lymphocytic foci in inflamed SG. Notably, immunised IL-17 KO mice were completely resistant for SS induction, showing no evidence of disease symptoms and histopathological changes in SG. Adoptive transfer of Th17 cells rapidly induced the onset of ESS in immunised IL-17 KO mice with markedly reduced saliva secretion, elevated autoantibody production and pronounced inflammation and tissue damage in SG. Conclusions Our findings have defined a critical role of Th17 cells in the pathogenesis of ESS. Further studies may validate Th17 cell as a potential target for treating SS.postprin

Association of ICAM3 genetic variant with severe acute respiratory syndrome

Genetic polymorphisms have been demonstrated to be associated with vulnerability to human infection. ICAM3, an intercellular adhesion molecule important for T cell activation, and FCER2 (CD23), an immune response gene, both located on chromosome 19p13.3, were investigated for host genetic susceptibility and association with clinical outcome. A case-control study based on 817 patients with confirmed severe acute respiratory syndrome (SARS), 307 health care worker control subjects, 290 outpatient control subjects, and 309 household control subjects unaffected by SARS from Hong Kong was conducted to test for genetic association. No significant association to susceptibility to SARS infection caused by the novel coronavirus (SARS-CoV) was found for the FCER2 and the ICAM3 single nucleotide polymorphisms. However, patients with SARS homozygous for ICAM3 Gly143 showed significant association with higher lactate dehydrogenase levels (P = .0067; odds ratio [OR], 4.31 [95% confidence interval {CI}, 1.37-13.56]) and lower total white blood cell counts (P = .022; OR, 0.30 [95% CI, 0.10-0.89]) on admission. These findings support the role of ICAM3 in the immunopathogenesis of SARS. © 2007 by the Infectious Diseases Society of America. All rights reserved.published_or_final_versio

The role of host genetic factors in respiratory tract infectious diseases:systematic review, meta-analyses and field synopsis

Host genetic factors have frequently been implicated in respiratory infectious diseases, often with inconsistent results in replication studies. We identified 386 studies from the total of 24,823 studies identified in a systematic search of four bibliographic databases. We performed meta-analyses of studies on tuberculosis, influenza, respiratory syncytial virus, SARS-Coronavirus and pneumonia. One single-nucleotide polymorphism from IL4 gene was significant for pooled respiratory infections (rs2070874; 1.66 [1.29-2.14]). We also detected an association of TLR2 gene with tuberculosis (rs5743708; 3.19 [2.03-5.02]). Subset analyses identified CCL2 as an additional risk factor for tuberculosis (rs1024611; OR = 0.79 [0.72-0.88]). The IL4-TLR2-CCL2 axis could be a highly interesting target for translation towards clinical use. However, this conclusion is based on low credibility of evidence - almost 95% of all identified studies had strong risk of bias or confounding. Future studies must build upon larger-scale collaborations, but also strictly adhere to the highest evidence-based principles in study design, in order to reduce research waste and provide clinically translatable evidenc

C-Type Lectin Receptors in Antimicrobial Immunity

Organized by Department of Medicine, the University of Hong Kong ; Sponsored by the Croucher Foundatio

Autoimmune-associated CLEC16A modulates inflammasome activity in human macrophages

Innate immunity: no. T.60C-type lectin domain family 16 member A (CLEC16A) is genetically-associated with a spectrum of autoimmune diseases including type I diabetes, multiple sclerosis and systemic lupus erythematosus (SLE). Functional characterization studies of Drosophila and mammalian CLEC16A homologues revealed their regulatory roles in different aspects of autophagy. Recent research advances in autophagy reveal its cross-regulatory relationship with inflammasome and have prompted us to evaluate the role of CLEC16A in inflammasome induction. The functional role of CLEC16A in inflammasome pathway was investigated using human monocyte-derived macrophages. Specific siRNAs targeting CLEC16A in macrophages resulted in a reduction in IL-1β secretion upon lipopolysaccharides stimulation with nigericin or poly(dA-dT), indicating that CLEC16 could modulate NLRP3 and AIM2 inflammasomes activity. Expression analyses showed that the inhibition of CLEC16A had minimal impact on mRNA levels of NLRP3, adaptor protein apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC), interleukin-1 converting enzyme caspase-1 and the precursor pro-IL-1β, suggesting CLEC16A may act indirectly on the NLRP3 inflammasome pathway. Macrophages derived from SLE patients exhibited higher CLELC16A mRNA expression when compared with healthy controls. Interestingly, SLE macrophages produced more IL-1β upon NLRP3 as well as AIM2 inflammasomes activation. Taken together, CLEC16A may indirectly modulate inflammasome activity and affect IL-1β production in SLE macrophages. The mechanism involved is currently under further investigation

DC-SIGN and L-SIGN: The SIGNs for infection

Two closely related trans-membrane C-type lectins dendritic cell-specific intracellular adhesion molecules (ICAM)-3 grabbing non-integrin (DC-SIGN or CD209) and liver/lymph node-specific ICAM-3 grabbing non-integrin (L-SIGN also known as DC-SIGNR, CD209L or CLEC4M) directly recognize a wide range of micro-organisms of major impact on public health. Both genes have long been considered to share similar overall structure and ligand-binding characteristics. This review presents more recent biochemical and structural studies, which show that they have distinct ligand-binding properties and different physiological functions. Of importance in both these genes is the presence of an extra-cellular domain consisting of an extended neck region encoded by tandem repeats that support the carbohydrate-recognition domain, which plays a crucial role in influencing the pathogen-binding properties of these receptors. The notable difference between these two genes is in this extra-cellular domain. Whilst the tandem-neck-repeat region remains relatively constant size for DC-SIGN, there is considerable polymorphism for L-SIGN. Homo-oligomerization of the neck region of L-SIGN has been shown to be important for high-affinity ligand binding, and heterozygous expression of the polymorphic variants of L-SIGN in which neck lengths differ could thus affect ligand-binding affinity. Functional studies on the effect of this tandem-neck-repeat region on pathogen-binding, as well as genetic association studies for various infectious diseases and among different populations, are discussed. Worldwide demographic data of the tandem-neck-repeat region showing distinct differences in the neck-region allele and genotype distribution among different ethnic groups are presented. These findings support the neck region as an excellent candidate acting as a functional target for selective pressures exerted by pathogens. © 2008 Springer-Verlag.link_to_subscribed_fulltex

Toll prevents a move

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