139During B cell development, the near random nature of the VDJ recombination process leads to the unavoidable production of self-reactive antibodies. In fact, studies in humans have demonstrated that many if not most newly generated B cells are autoreactive ( 1 ). Extensive studies of self-tolerant B cells in transgenic mouse models have revealed the complicated systems of B cell selection used to avoid autoimmunity. Current models suggest that B cells expressing a transgenic surface Ig that binds DNA or protein autoantigens fi rst attempt to alter the B cell receptor (BCR) by further variable gene rearrangement using " receptor editing " ( 2, 3 ). If receptor editing is unsuccessful, then the offending B cell may be eliminated by clonal deletion ( 4, 5 ) or it may enter maturity but with reduced or altered function so that it no longer reacts to the self-antigens, which is referred to as clonal anergy ( 6 -8 ). In this paper, we describe a human B cell population that is anergic. Clonal anergy was fi rst conceived by Nossal and Pike in 1980 ( 6 ) to explain why injection of neonatal mice with high dosages of an antigen induced deletion of the specifi c B cells, whereas lesser dosages allowed retention of the specifi c B cells, but the cells were incapable of becoming antibody-secreting cells. In 1988, Goodnow et al. ( 8 )

Autoimmune diseases are a family of chronic systemic inflammatory disorders, characterized by the dysregulation of the immune system which finally results in the break of tolerance to self-antigen.Several studies suggest that Toll-like receptors (TLRs) play an essential role in the pathogenesis of autoimmune diseases. TLRs belong to the family of pattern recognition receptors (PRRs) that recognize a wide range of pathogen-associated molecular patterns (PAMPs). TLRs are type I transmembrane proteins and located on various cellular membranes. Two main groups have been classified based on their location；the extracelluar group referred to the ones located on the plasma membrane while the intracellular group all located in endosomal compartments responsible for the recognition of nucleic acids. They are released by the host cells and trigger various intracellular pathways which results in the production of proinflammatory cytokines, chemokines, as well as the expression of co-stimulatory molecules to protect against invading microorganisms. Particular, TLR pathway-associated proteins, such as IRAK, TRAF, and SOCS are often dysregulated in this group of diseases. TLR-associated gene expression profile analysis together with single nucleotide polymorphism (SNP) assessment could be important to explain the pathomechanism driving autoimmune diseases. In this review, we summarize recent findings on TLR pathways regulation in various autoimmune diseases, including Sjögren's syndrome (SS), systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), systemic sclerosis (SSc), and psoriasis. KEYWORDS:Toll-like receptors (TLRs); autoimmune disease; IL-1 receptor associated kinase (IRAK); TNF receptor associated factor (TRAF); Suppressor of cytokine signaling (SOCS) 3 Autoimmune diseases are characterized by the dysregulation of the immune system which finally results in the break of tolerance to self-antigen. Even though the accurate etiology and pathogenesis of the majority of these diseases are still not clear, complex elements, including genetic, environmental, hormonal factors may provoke the autoimmune processes leading to the development of the disease.Concerning the role of derailed immune responses in the pathogenesis, aberrant processes both in the innate and adaptive immune system have been shown to participate in the disease initiation and perpetuation [1]. Within these processes, numerous studies have been demonstrated that Toll-like receptors (TLRs) have an essential role in various autoimmune diseases, including Sjögren's syndrome (SS), systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), systemic sclerosis (SSc), and psoriasis. [2,3]. Toll-like receptorsThe innate immune system is the first line of host defense mechanisms against invading microorganisms and forms the basis of the development of adaptive immunity. Host cells express diverse pattern recognition receptors (PRRs) include toll-like receptors (TLRs), C-type lectin-like receptors (CL...

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B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) are members of the tumour necrosis factor superfamily. We have examined circulating BAFF and APRIL in relation to serological deviations and lymphoid organization in the salivary glands of the chronic, autoimmune disorder Sjögren's syndrome. Lymphoid organization in the shape of ectopic germinal centers were detected in 33 of 130 consecutive minor salivary gland biopsies and coincided with increased focus score and elevated levels of serum IgG. Follicular dendritic cell networks, proliferation of mononuclear cells and altered B/T cell ratio also separated the two subgroups. Serum levels of sBAFF and sAPRIL were increased in Sjögren's syndrome compared to healthy blood donors, especially in anti-Ro/La+ patients. Though the differences could not be related to germinal center formation, positive correlations between serum levels of sBAFF and sAPRIL, focus score and IgG denotes their possible role in the disease progression of primary Sjögren's syndrome.

Vitamin D, besides having well‐known control functions of calcium and phosphorus metabolism, bone formation and mineralization, also has a role in the maintenance of immune‐homeostasis. The immune‐regulatory role of vitamin D affects both the innate and adaptive immune system contributing to the immune‐tolerance of self‐structures. Impaired vitamin D supply/regulation, amongst other factors, leads to the development of autoimmune processes in animal models of various autoimmune diseases. The administration of vitamin D in these animals leads to improvement of immune‐mediated symptoms. Moreover, in human autoimmune diseases, such as multiple sclerosis, or rheumatoid arthritis the pathogenic role of vitamin D has been described. The review aims at describing the complex immune‐regulatory role of vitamin D from the cellular level through autoimmune animal models and depicting the known contribution of vitamin D in the pathogenesis of human autoimmune diseases.

Plasma cytokines play an important role in the pathogenesis of Sjögren's syndrome (SS) by initiating and perpetuating various cellular and humoural autoimmune processes. The aim of the present study was to describe a broad spectrum of T-cell and B-cell cytokines, growth factors, chemokines and molecules that could contribute to cell death in SS. A novel protein array system was utilized to measure simultaneously the levels of 25 plasma cytokines of patients with primary SS and healthy individuals. Furthermore, we correlated these plasma cytokine levels with potential laboratory and clinical parameters related to disease activity in SS. A subset of plasma cytokines [e.g. interleukin-1b (IL-1b),

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