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Systematic Lupus Erythematosus (SLE) is an autoimmune syndrome of unclear etiology. While T and B cell abnormalities contribute to disease pathogenesis, recent work suggests that inflammatory M1-like macrophages also play a role. Previous work showed that the TLR2/1 agonist PAM3CSK4 (PAM3) could stimulate normal human monocytes to preferentially differentiate into immunosuppressive M2-like rather than inflammatory M1like macrophages. This raised the possibility of PAM3 being used to normalize the M1:M2 ratio in SLE. Consistent with that possibility, monocytes from lupus patients differentiated into M2-like macrophages when treated with PAM3 in vitro. Furthermore, lupus-prone NZB x NZW F1 mice responded similarly to weekly PAM3 treatment. Normalization of the M2 macrophage frequency was associated with delayed disease progression, decreased autoantibody and inflammatory cytokine synthesis, reduced proteinuria and prolonged survival in NZB x NZW F1 mice. The ability of PAM3 to bias monocyte differentiation in favor of immunosuppressive macrophages may represent a novel approach to the therapy of SLE. not support inflammatory responses. 'Non-classical' monocytes express a CD14 low CD16 + phenotype and are inflammatory. An 'intermediate' or transitional monocyte population also exists that is CD14 + CD16 + and has both phagocytic and inflammatory properties [7]. In response to stimulation, monocytes differentiate into macrophages with diverse phenotypes and functions. These range from 'classical' pro-inflammatory M1-like macrophages that protect the host from infection to 'alternatively activated' M2like macrophages that are immunosuppressive, support tissue remodeling, and phagocytose apoptotic cells [8-10]. Recent studies suggest that monocytes and macrophages can contribute to the pathogenesis of SLE. Indeed, lupus flares are associated with a relative increase in the frequency of M1 vs M2 macrophages [11]. The frequency of inflammatory monocytes is also elevated in SLE patients and the concentration of serum cytokines that promote macrophage differentiation (such as CSF-1 and MCP-1) correlates with disease severity [12]. Normalizing the M1:M2 ratio by adoptive transfer of M2 macrophages is of benefit

Anti-synthetase syndrome (ASSD) is an autoimmune disease characterized by the presence of autoantibodies targeting one of several aminoacyl t-RNA synthetases (aaRSs) along with clinical features including interstitial lung disease, myositis, Raynaud’s phenomenon, arthritis, mechanic’s hands, and fever. The family of aaRSs consists of highly conserved cytoplasmic and mitochondrial enzymes, one for each amino acid, which are essential for the RNA translation machinery and protein synthesis. Along with their main functions, aaRSs are involved in the development of immune responses, regulation of transcription, and gene-specific silencing of translation. During the last decade, these proteins have been associated with cancer, neurological disorders, infectious responses, and autoimmune diseases including ASSD. To date, several aaRSs have been described to be possible autoantigens in different diseases. The most commonly described are histidyl (HisRS), threonyl (ThrRS), alanyl (AlaRS), glycyl (GlyRS), isoleucyl (IleRS), asparaginyl (AsnRS), phenylalanyl (PheRS), tyrosyl (TyrRS), lysyl (LysRS), glutaminyl (GlnRS), tryptophanyl (TrpRS), and seryl (SerRS) tRNA synthetases. Autoantibodies against the first eight autoantigens listed above have been associated with ASSD while the rest have been associated with other diseases. This review will address what is known about the function of the aaRSs with a focus on their autoantigenic properties. We will also describe the anti-aaRSs autoantibodies and their association to specific clinical manifestations, and discuss their potential contribution to the pathogenesis of ASSD.