Fc receptors (FcRs) belong to the ITAM-associated receptor family. FcRs control the humoral and innate immunity which are essential for appropriate responses to
infections and prevention of chronic
inflammation or auto-
immune diseases. Following their crosslinking by
immune complexes, FcRs play various roles such as modulation of the immune response by released
cytokines or of phagocytosis. Here, we review FcR involvement in pathologies leading notably to altered intracellular signaling with functionally relevant consequences to the host, and targeting of
Fc receptors as therapeutic approaches. Special emphasis will be given to some FcRs, such as the FcαRI, the FcγRIIA and the FcγRIIIA, which behave like the ancient god Janus depending on the ITAM motif to inhibit or activate immune responses depending on their targeting by monomeric/dimeric
immunoglobulins or by
immune complexes. This ITAM duality has been recently defined as inhibitory or activating ITAM (ITAMi or ITAMa) which are controlled by
Src family kinases. Involvement of various ITAM-bearing FcRs observed during infectious or
autoimmune diseases is associated with allelic variants, changes in
ligand binding ability responsible for host defense perturbation. During auto-
immune diseases such as
rheumatoid arthritis, lupus or
immune thrombocytopenia, the
autoantibodies and
immune complexes lead to
inflammation through FcR aggregation. We will discuss the role of FcRs in
autoimmune diseases, and focus on novel approaches to target FcRs for resolution of antibody-mediated autoimmunity. We will finally also discuss the down-regulation of FcR functionality as a therapeutic approach for
autoimmune diseases.