These different processes would probably not have the same impact on SLE, because this transient versus sustained stimulation might lead to the production of low antibody levels with low avidity, or high antibody levels with high avidity, respectively [15]. they have been associated with other organ-specific damage, such as anti-NMDAR antibodies in neuropsychiatric clinical manifestations or anti-2GP1 antibodies in vascular symptomatology. In this review, we describe the different auto-antibodies reported to be involved in SLE. How autoantibody isotypes and affinity-binding to their antigen might result in different pathogenic responses is also discussed. Keywords:autoantibodies, isotypes, lupus, SLE, Fc receptors == 1. Introduction == Systemic Lupus Erythematosus (SLE) is a chronic autoimmune and inflammatory syndrome whose broad etiology has been described as genetic, epigenetic, hormonal, environmental and immune-regulatory factors to be involved. It affects mostly women KPT-9274 at childbearing age and the clinically courses are unpredictable with periods of remission and flares. During the course of the disease many organs may be damaged (such as skin, joints, nervous and vascular systems, or kidneys) leading to a wide clinical heterogeneity. The presence of a large amount of autoantibodies specific to self-antigens mainly of nuclear origin (double-stranded DNA (dsDNA), Smith antigen and ribonucleoproteins (Sm/RNP), anti-Sjgrens-syndrome-related antigen A and B (SSA/Ro, and SSB/La, respectively) is the hallmark of the disease. The anti-nuclear antibodies (ANAs) are considered markers of diagnosis and prognosis of the disease [1] and significant associations between some autoantibody specificities and clinical features were described [2,3]. However, considering the important panel of new autoantibody specificities reported [4] as well as the diverse mechanisms studied in lupus pathology [5,6] the question whether SLE is a single disease with several phenotypes, or a similar and common phenotype present in a range of different diseases KPT-9274 [7], remains debated in the field. The pathogenesis of the autoantibodies has been the focus of many studies, and, in some cases, the tissue injury and ulterior phenotypic manifestations was shown to develop as a result of autoantibody-mediated mechanisms. This involves accumulation of Immune-Complexes (IC), cell surface binding and cytotoxicity, reactivity with autoantigens expressed on apoptotic or activated cell surfaces, penetration into living cells and binding to cross-reactive extracellular molecules [8,9]. However, the experimental evidence necessary (Witebsky criteria) [10] for some autoantibodies to be pathogenic is far from being elucidated. The ICs bind Fc receptors, thereby modulating innate and adaptive immune cells responses. The engagement induces the activation of intracellular signaling pathways through inhibitory and/or activating motives (ITIM or ITAM) to inhibit and/or elicit immune functions [11]. Genetic variants of Fc receptors have been associated with SLE susceptibility and SLE severity [12] and the reduced expression on the myeloid cell surface membranes led to the hypothesis of the contribution of a reduced FcR-mediated IC clearance in lupus nephritis [13]. Recently, it has been described that the differences in affinity of antibody and antigen interactions are discriminated by FcR and promote different molecular signals resulting in distinct immunological responses [14]. The presence of autoantibodies in other inflammatory processes (e.g., anti-dsDNA antibodies in bacterial infections [15]), the involvement of low-affinity autoantibodies in autoimmunty [16] as well as the number of self-antigens described in SLE [4], may suggest a different pathological role of autoantibodies in SLE Rabbit Polyclonal to PLA2G4C depending on their affinity and their specificity, and may explain the wide immune-mechanisms described, although further studies remain to be done. Deciphering the specificities and the pathogenic role(s) of autoantibodies in SLE may lead to the development of specific treatments for SLE patients. Recent advances on the use of medications targeting directly or indirectly the B cell compartment (anti-CD20 treatment, Rituximab; anti-BAFF treatment, Belimumab, respectively) or normal donors non-pathogenic IgG intravenous infusions (IVIg) correspond to therapeutic evidences demonstrating both the pathogenic role of autoantibodies and the promises raised by their targeting [17,18,19]. This review aims to compile the advances in understanding the functional relevance of the different autoantibody specificities, KPT-9274 isotypes and their binding receptors in the pathogenesis of SLE. == 2. Why Are the Autoantibodies Produced? == SLE is a prototypic autoimmune disease caused by the loss of B cell tolerance and subsequent recognition of self-antigens and becoming autoreactive. During B cell development pre-B cells mature into antibody-secreting plasma cells (PC) and receive multiple positive and negative signals to determine their activation, deletion or anergic status [20,21]. SLE patients and lupus-like disease mouse models reveal many examples of genetic abnormalities that impact different self-tolerance checkpoints leading to overproduction of autoantibodies [22]. Few examples of key findings in the loss of B cell tolerance during SLE KPT-9274 pathogenesis are presented below. However, the complex machinery registered in the production of autoantibodies has been extensively reviewed elsewhere [23]. Depending on the.