Autoimmune diseases are immune disorders characterized by T cell hyperactivity and B cell overstimulation leading to overproduction of autoantibodies. Although the pathogenesis of various autoimmune diseases remains to be elucidated, environmental factors have been thought to contribute to the initiation and maintenance of auto-respond inflammation. Toll-like receptors (TLRs) are pattern recognition receptors belonging to innate immunity that recognize and defend invading microorganisms. Besides these exogenous pathogen-associated molecular patterns, TLRs can also bind with damage-associated molecular patterns produced under strike or by tissue damage or cells apoptosis. It is believed that TLRs build a bridge between innate immunity and autoimmunity. There are five adaptors to TLRs including MyD88, TRIF, TIRAP/MAL, TRAM, and SARM. Upon activation, TLRs recruit specific adaptors to initiate the downstream signaling pathways leading to the production of inflammatory cytokines and chemokines. Under certain circumstances, ligation of TLRs drives to aberrant activation and unrestricted inflammatory responses, thereby contributing to the perpetuation of inflammation in autoimmune diseases. In the past, most studies focused on the intracellular TLRs, such as TLR3, TLR7, and TLR9, but recent studies reveal that cell surface TLRs, especially TLR2 and TLR4, also play an essential role in the development of autoimmune diseases and afford multiple therapeutic targets. In this review, we summarized the biological characteristics, signaling mechanisms of TLR2/4, the negative regulators of TLR2/4 pathway, and the pivotal function of TLR2/4 in the pathogenesis of autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, Sjogren's syndrome, psoriasis, multiple sclerosis, and autoimmune diabetes.

BackgroundThe pathogenesis of systemic lupus erythematosus (SLE) has not yet been completely elucidated. One of the hallmarks of SLE is the production of autoantibodies by uncontrolled over-activated B cells. Early B cell factor 1 (EBF1) contributes to the development, activation, and proliferation of B cells through activation of the AKT signaling pathway. Accumulating evidence has demonstrated that several microRNAs (miRNAs) contribute to the pathogenesis of autoimmune diseases through the regulation of B cells in SLE. We aim to investigate the expression patterns of miR-1246 in B cells and its contribution to pathogenesis of SLE.ResultsOur results showed that the expression of miR-1246 was significantly decreased in B cells from SLE patients. We verified that miR-1246 specifically targeted the EBF1 messenger RNA (mRNA) by interacting with its 3′-untranslated region (3′-UTR) and regulated the expression of EBF1. Transfection of miR-1246 inhibitors into healthy B cells upregulated the expression of EBF1, enhanced B cell function, and increased the production of B cell surface co-stimulatory molecules CD40, CD80, and CD86. We also observed that abnormal activation of the AKT signaling pathway was associated with decreased P53 expression, leading to the downregulation of the miR-1246 expression; and upregulation of the miR-1246 expression reversed the responsiveness of B cells by inhibiting EBF1 expression.ConclusionsActivated B cells in lupus could decrease the expression of miR-1246 through the AKT-P53 signaling pathway, which in turn enhances the expression of EBF1, thereby promoting further activation of B cells. Conversely, upregulation of miR-1246 could interrupt this amplification pathway. Our findings thus provide a theoretical framework towards the research of novel biological targets in SLE treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-015-0063-7) contains supplementary material, which is available to authorized users.

The innate immune system has been shown to play an important pathologic role in systemic lupus erythematosus (SLE). TLR2, a PRR, recognizes exogenous PAMPs, and endogenous damage-associated molecular patterns and has been implicated in the initiation and maintenance of the perpetuated inflammatory reactions in autoimmune diseases. Here, we report increased expression of TLR2 in CD4+ and CD8 + T cells, CD19 + B cells, and CD14 + monocytes from SLE patients. Conventional treatment, such as hydroxychloroquine and corticosteroids, showed no effect on TLR2 expression in CD4 + T cells from SLE patients. In vitro stimulation of TLR2 in CD4 + T cells from SLE patients increased CD40L and CD70 expression, as well as secretion of IL-6, IL-17A, IL-17F, and TNF-α, while Foxp3 transcription decreased. This effect was reversed by TLR2 siRNA. Moreover, TLR2 activation upregulated H3K4 tri-methylation and H4 acetylation levels while downregulated H3K9 tri-methylation level in the IL-17A promoter region. In addition, it also increased H4 acetylation levels and decreased H3K9 tri-methylation levels in the IL-17F promoter region. In summary, our findings demonstrate that increased expression of TLR2 contributes to immune reactivity and promotes IL-17A and IL-17F expression through histone modifications in SLE.Keywords: Histone modification r IL-17 r Systemic lupus erythematosus r T cells r TLR2 IntroductionSystemic lupus erythematosus (SLE) is a prototypical systemic autoimmune disease that results in multiple organ damage and diverse clinical manifestations [1]. SLE is characterized by T-cell hyperactivity and B-cell overstimulation. Uncontrolled T-cell activation results in increased secretion of inflammatory cytokines, production of autoantibodies, and aberrant inflamCorrespondence: Prof. Qianjin Lu e-mail: qianlu5860@gmail.com matory response, which contribute to the development of SLE [2]. How T cells become hyperactive during SLE remains to be determined. However, both genetic background and environmental factors are believed to contribute to the development of SLE [3]. A number of epidemiological studies have suggested that onset and flares of SLE are associated with infection [4]. One of the mechanisms whereby invasive microorganisms disrupt host immune system is through the interaction with TLRs, as demonstrated in experimental lupus [5,6]. * These authors contributed equally to this work. Eur. J. Immunol. 2015. 45: 2683-2693 TLRs are membrane-bound proteins referred to as pathogenassociated molecular patterns that belong to innate immune system. Each TLR can recognize a specific set of microbes bearing PAMPs and endogenous damage-associated molecular patterns (DAMPs) [7]. Activation of TLRs can trigger intracellularsignaling cascades and upregulate the expression of inflammatory cytokines [8]. TLR2 is a cell-surface TLR with extracellular recognition domain that can bind with exogenous ligands including lipoproteins, peptidoglycan, lipoteichoic acid, and endogenous DAMPs, such as HSP70 and high mobility group box protei...