2016;76:13C21. responses to a variety of challenges, including bacterial infection and IgG-immune complexes, were not. Like FcRIIb-deficient mice, FcRI/II/III/IV-/- mice developed higher Ab titres, but no autoantibodies. Amlexanox These observations show a redundant role for activating FcRs in the modulation of the adaptive immune response role of the receptors for IgG, FcR, is usually severely hampered not only by Rabbit polyclonal to ZCCHC13 the complexity of the FcR gene family itself but also because of their functional redundancy with the match system. FcR and match link innate and adaptive immunity on two levels. First of all, they mediate the activation of downstream effector pathways of innate immune cells by antigen (Ag) specific IgG. Second of all, they are involved in the IgG immune complex (IC) mediated regulation of adaptive immunity. Four different FcR, have been recognized in the mouse. The IgG binding -chains of the activating FcRI, FcRIII and FcRIV, are associated with the FcR chain, a signal transduction subunit which is also required for cell surface expression (1). The activating FcR are counterbalanced by the inhibiting receptor FcRIIb. The four FcR, are expressed in different combinations on a variety of immune cells, mainly myeloid effector cells. The role of FcR has been extensively analyzed by analyzing the phenotype of mice deficient either for one or combinations of two or three FcR or the FcR chain. By establishing a variety of disease models such as arthritis, hemolytic anemia, anaphylaxis and lupus like disease in these KO mice, we as well as others have shown that FcR play an important role in the downstream antibody (Ab) effector pathways which drive the pathogenesis in these diseases (2). However, by using antibodies with a mutation in their Fc domain name, destroying FcR binding without affecting interactions with match, it has recently been shown that several IgG downstream effector functions can be mediated also by match (3). Mice deficient in the early pathway components C1q, C3 and C4 and the match receptors Cr1/Cr2 have impaired humoral responses to T cell dependent and T cell impartial Ag (4C6) indicating that the match system plays an important role in priming and regulation of the adaptive immune response (7). Moreover, C1q deficient mice develop spontaneously lupus like disease. Amlexanox A series of observations suggest that FcR also play a role in priming and regulation of adaptive immunity and the maintenance of immune tolerance. Ag-specific IgG1, IgG2a, and IgG2b enhance Ab and CD4+ T cell responses to soluble protein Ag via activating FcRs, probably by increasing Ag presentation by dendritic cells to Th cells (8). With Ag-specific IgG3, an IgG subclass not interacting with FcR, this process is usually match dependent (9). In FcR chain KO mice, immunized with the model Ag KLH, the delayed-type hypersensitivity (DTH) response after challenge is usually significantly decreased compared to the DTH in WT mice. Moreover, the secondary responses of CD4+ T cells to Ag and Ab formation were also reduced in these mice (10). Amlexanox These data suggest that activating FcRs on antigen presenting cells (APCs) facilitate Ag presentation resulting in efficient priming of Th cell responses in an IC-dependent manner which is required for a full-blown Ab response. We and others have shown that soluble IgG-IC enhance cross presentation by DCs resulting in a strong induction of the proliferation of antigen specific CTLs (11C14). It is generally believed that FcR play an important role in this process (15). Combined, these observations suggest an important role of activating FcRs in modulating the adaptive immune response. In addition, cross-linking the B cell receptor with FcRIIb by IgG-IC results in down regulations of Ab production. FcRIIb deficient mice develop higher Ab titers compared to WT mice (16). Moreover it has been shown that FcRIIb deficient mice when backcrossed into C57BL/6 background develop spontaneously lupus like disease (17). In conclusion, many observations in WT and FcR KO mice suggest a pleiotropic role of FcR in the immune system. However, many of these studies have some flaws. Several studies were performed in FcR chain deficient mice. The FcR chain is a promiscuous signal transduction Amlexanox subunit, associated with at least nine other receptor complexes (18). Most FcR KO mice have been generated by gene targeting in 129-derived ES cells, and subsequently backcrossed into C57BL/6 background. We Amlexanox have shown that after backcrossing the remaining 129-derived sequences flanking the FcRIIb KO allele, including the hypomorphic autoimmune susceptibility SLAM locus (19) cause the autoimmune phenotype of the FcRIIb KO mouse on mixed 129/C57BL/6 background whereas the FcRIIb deficiency only enhances the lupus like disease (20). In many in vivo cross-presentation studies bone marrow derived DCs.