Junfeng Zheng

microRNA-122 stimulates translation of hepatitis C virus RNA

Hepatitis C virus (HCV) is a positive strand RNA virus that propagates primarily in the liver. We show here that the liver‐specific microRNA‐122 (miR‐122), a member of a class of small cellular RNAs that mediate post‐transcriptional gene regulation usually by repressing the translation of mRNAs through interaction with their 3′‐untranslated regions (UTRs), stimulates the translation of HCV. Sequestration of miR‐122 in liver cell lines strongly reduces HCV translation, whereas addition of miR‐122 stimulates HCV translation in liver cell lines as well as in the non‐liver HeLa cells and in rabbit reticulocyte lysate. The stimulation is conferred by direct interaction of miR‐122 with two target sites in the 5′‐UTR of the HCV genome. With a replication‐defective NS5B polymerase mutant genome, we show that the translation stimulation is independent of viral RNA synthesis. miR‐122 stimulates HCV translation by enhancing the association of ribosomes with the viral RNA at an early initiation stage. In conclusion, the liver‐specific miR‐122 may contribute to HCV liver tropism at the level of translation.

Meta-analysis reveals an association of PTPN22 C1858T with autoimmune diseases, which depends on the localization of the affected tissue

Protein tyrosine phosphatase non-receptor type 22 (PTPN22) is a strong susceptibility gene shared by many autoimmune diseases. The aim of this study was to explore the mechanisms underlying this relationship. We performed a comprehensive analysis of the association between PTPN22 polymorphism C1858T and autoimmune diseases. The results showed a remarkable pattern; PTPN22 C1858T was strongly associated with type I diabetes, rheumatoid arthritis, immune thrombocytopenia, generalized vitiligo with concomitant autoimmune diseases, idiopathic inflammatory myopathies, Graves’ disease, juvenile idiopathic arthritis, myasthenia gravis, systemic lupus erythematosus, anti-neutrophil cytoplasmic antibody-associated vasculitis and Addison’s disease. By contrast, PTPN22 C1858T showed a negligible association with systemic sclerosis, celiac disease, multiple sclerosis, psoriasis, ankylosing spondylitis, pemphigus vulgaris, ulcerative colitis, primary sclerosing cholangitis, primary biliary cirrhosis, Crohn’s disease and acute anterior uveitis. Further analysis revealed a clear distinction between the two groups of diseases with regard to their targeted tissues: most autoimmune diseases showing an insignificant association with PTPN22 C1858T manifest in skin, the gastrointestinal tract or in immune privileged sites. These results showed that the association of PTPN22 polymorphism with autoimmune diseases depends on the localization of the affected tissue, suggesting a role of targeted organ variation in the disease manifestations.

Meta-analysis reveals an association of STAT4 polymorphisms with systemic autoimmune disorders and anti-dsDNA antibody

Signal transducer and activator of transcription 4 (STAT4) has been recently identified as a susceptibility gene for multiple autoimmune diseases. Here we performed a comprehensive analysis of the association between STAT4 and several different autoimmune disorders to identify potential common inflammatory principles behind this association. Our meta-analysis revealed that the STAT4 rs7574865 polymorphism is associated with four autoimmune diseases with systemic pathology, including systemic lupus erythematosus (OR = 1.52; 95% CI = 1.48 - 1.56, P<1.0 × 10(-16)), rheumatoid arthritis (OR = 1.27; 95% CI = 1.21 - 1.33, P < 1.00 × 10(-16)), systemic sclerosis (OR = 1.38; 95% CI = 1.27 - 1.50, P < 1.44 × 10(-14)), and primary Sjogrens syndrome (OR = 1.32; 95% CI = 1.01 - 1.73, P = 4.40 × 10(-2)), while no association was found with type I diabetes, juvenile idiopathic arthritis, ulcerative colitis and Crohns disease. Furthermore, the stratified meta-analysis also demonstrate that the STAT4 rs7574865 polymorphism is associated with the presence of autoantibodies with systemic reactivity (anti-ds-DNA antibodies) in SLE patients (OR = 1.37; 95% CI = 1.21 - 1.56, P = 1.12 × 10(-6)). However, no such specific association was seen in RA with regard to the presence of non-systemically reacting antibodies, including rheumatoid factor and anti-cyclic citrullinated peptide antibodies. Taken together, these results suggest that STAT4 polymorphisms are associated with autoimmune diseases which are characterized by a systemic pathology and anti-dsDNA antibody.

The role of PTPN22 in autoimmunity: Learning from mice

Protein tyrosine phosphatase nonreceptor 22 (PTPN22) represents a strong susceptibility gene which is shared by many autoimmune diseases. Exploring the mechanism behind this association could help to understand their pathogenesis as well as to identify novel therapeutical targets. Recently, multiple mouse models including knock-out, knock-in, knock-down and transgenic mice were generated to delineate PTPN22s function in this context. Depending on the genetic background, mouse PTPN22_619W mutation results in spontaneous autoimmunity, essentially replicating the risk effect of the PTPN22_620W in human autoimmune diseases. Furthermore, findings from mouse models shed new light on both cellular as well as molecular mechanisms of the effect of PTPN22 on adaptive and innate immunity. Here we review recently emerged evidence of the interconnection between mouse PTPN22 and autoimmunity. We also discuss the consistence and discrepancy between findings derived from human and mouse studies.

The GTF2I rs117026326 polymorphism is associated with anti-SSA-positive primary Sjögren’s syndrome

Disclosure statement: S.G.M. has received honoraria for lecturing and travel expenses for attending meetings and has received financial research support from Bayer, Biogen Idec, Sanofi-Aventis, Bayer Schering, Merck Serono, Novo Nordisk, Genzyme, MSD and Teva. T.R. has received travel expenses and financial research support from Genzyme and has received honoraria for lecturing from Teva and Biogen Idec. H.W. has received compensation for serving on scientific advisory boards/steering committees for Bayer Healthcare, Biogen Idec, Genzyme, Merck Serono, Novartis and Sanofi Aventis; has received speaker’s honoraria and travel support from Bayer Vital, Bayer Schering, Biogen Idec, CSL Behring, Fresenius Medical Care, Genzyme, GlaxoSmithKline, GW Pharmaceuticals, Lundbeck, Merck Serono, Omniamed, Novartis and Sanofi Aventis; has received compensation as a consultant from Biogen Idec, Merck Serono, Novartis and Sanofi Aventis and has received research support from Bayer Vital, Biogen Idec, Genzyme Merck Serono, Novartis, Sanofi Aventis Germany and Sanofi US. S.B. has received financial research support from Novartis and has received honoraria for lecturing from Biogen Idec and Teva. The other author has declared no conflicts of interest.

EndoS reduces the pathogenicity of anti-mCOL7 IgG through reduced binding of immune complexes to neutrophils.

Endo-β-N-acetylglucosaminidase (EndoS) has been shown to act as a potent pathogen-derived immunomodulatory molecule in autoimmune diseases. Here we investigated how EndoS treatment reduces the pathogenicity of rabbit anti-mCOL7 IgG using different experimental models of epidermolysis bullosa acquisita (EBA). Our results show that the EndoS treatment does not interfere with the binding of the antibody to the antigen but reduces immune complex (IC)-mediated neutrophil activation by impairing the binding of the IC to FcγR on neutrophils. On the basis of this newly identified EndoS-mediated mechanism we hope to develop new strategies in the treatment of the disease.

CD11b-deficient mice exhibit an increased severity in the late phase of antibody transfer-induced experimental epidermolysis bullosa acquisita

CD11b, the α‐chain of β2 integrin Mac‐1, is involved in many activation processes of phagocytes. Depending on the respective autoimmune disorder, CD11b has been shown to exert pro‐inflammatory functions or be dispensable in their pathogenesis. Here, we investigated the role of CD11b in the pathogenesis of experimental epidermolysis bullosa acquisita (EBA), an autoimmune skin blistering disease mediated by autoantibodies to type VII collagen. Unexpectedly, in an antibody transfer‐induced model of EBA, CD11b‐deficient mice developed more severe disease symptoms than wild‐type mice in the late phase of the disease. Furthermore, as compared to wild‐type controls, CD11b‐deficient mice expressed increased levels of circulating IFN‐γ and IL‐4. Taken together, for the first time, our results suggest an anti‐inflammatory role for CD11b in experimental autoimmune diseases.

Association of BAFF and IL-17A with subphenotypes of primary Sjögren's syndrome.

Primary Sjögrens syndrome (pSS) is an autoimmune disease affecting exocrine glands. Both autoreactive T cells and B cells are involved in the development of pSS, but their exact contribution to the pathogenesis is not clear. Here, we aimed to investigate the association of B‐cell activating factor (BAFF) and interleukin (IL)‐17A with subphenotypes of pSS.

Autoantibodies against the Second Extracellular Loop of M3R Do neither Induce nor Indicate Primary Sjögren’s Syndrome

Objectives Anti-muscarinic acetylcholine type-3 receptor (anti-M3R) autoantibodies have been suggested to be pathogenic for primary Sjögren’s syndrome (pSS), and the second extracellular loop of M3R is suspected to carry a disease-promoting epitope. In this study, we aimed to evaluate the pathogenicity of autoantibodies against peptides derived from the second extracellular loop of M3R in mice and to determine whether those autoantibodies could be used as biomarker for pSS. Methods BALB/c mice were immunized with modified linear or cyclic peptides of the second extracellular loop of M3R. The function of exocrine glands was evaluated by measuring the secretion of saliva and tears. The histological evaluations were performed by using H&E staining or direct immunofluorescence staining. Autoantibodies against linear or cyclic peptides of the second extracellular loop of M3R in human and mice were determined using ELISA. Results Immunization induced mice to produce autoantibodies against the linear or cyclic peptides of the second extracellular loop of M3R, and those autoantibodies could bind onto salivary glands. However, those mice showed neither impairment in the secretion of tears or saliva nor histological abnormality in the exocrine glands. Furthermore, passive transfer of the IgG isolated from the immunized mice into healthy mice did not induced the dysfunction of the exocrine glands. The prevalence of autoantibodies against the peptides of the second extracellular loop of M3R was low in pSS patients, and it did not differ significantly from that in healthy controls. Conclusions Our results suggest that the autoantibodies against peptides of the second extracellular loop of M3R are not pathogenic in vivo and they are not suitable as biomarkers for pSS diagnosis.

B Cells Are Indispensable for a Novel Mouse Model of Primary Sjögren’s Syndrome

Primary Sjögren’s syndrome (pSS) is characterized by a panel of autoantibodies, while it is not clear whether B cells and autoantibodies play an essential role in pathogenesis of the disease. Here, we report a novel mouse model for pSS which is induced by immunization with the Ro60_316-335 peptide containing a predominant T cell epitope. After immunization, mice developed several symptoms mimicking pSS, including a decreased secretion of tears, lymphocytic infiltration into the lacrimal glands, autoantibodies, and increased levels of inflammatory cytokines. Disease susceptibility to this novel mouse model varies among strains, where C3H/HeJ (H2-k) and C3H/HeN (H2-k) are susceptible while DBA/1 (H2-q) and C57BL/6 (H2-b) are resistant. Depletion of B cells using anti-CD20 monoclonal antibodies prevented C3H/HeN mice from development of the pSS-like disease. In addition, HLA-DRB1*0803, a pSS risk allele, was predicted to bind to the hRo60_308-328 which contains a predominant T cell epitope of human Ro60. Therefore, this study provides a novel mouse model for pSS and reveals an indispensable role of B cells in this model. Moreover, it suggests that T cell epitope within Ro60 antigen is potentially pathogenic for pSS.