Redundant and Alternative Roles for Activating Fc Receptors and Complement in an Antibody-Dependent Model of Autoimmune Vitiligo

Abstract

Complement and Fc receptor (FcR)-positive cells mediate effector functions of antibodies. Antibody-dependent immunity against the melanosome membrane glycoprotein gp75/tyrosinase-related protein-1 (TYRP-1) of melanocytes leads to autoimmune hypopigmentation (vitiligo) in mice. Hypopigmentation occurred in mice deficient in activating FcR containing the common gamma subunit (Fc gamma R gamma(-/-)) and in mice deficient in the C3 complement component. Mice doubly deficient in both Fc gamma R gamma and C3 did not develop hypopigmentation, suggesting that complement and Fc gamma R formed redundant mechanisms. Following passive immunization with antibody, no further adaptive immune responses were required. Chimeric Fc gamma R gamma(-/-),C3(-/-) mice reconstituted with bone marrow from either Fc gamma R gamma(-/-) or C3(-/-) mice or adoptively transferred with Fc gamma R gamma(+/-) macrophages did develop antibody-mediated hypopigmentation. Thus, either complement or macrophages expressing activating Fc gamma R can independently and alternatively mediate disease in a model of autoimmune vitiligo.

The Alternative Pathway of Complement Activation Is Critical for Blister Induction in Experimental Epidermolysis Bullosa Acquisita

“…This scenario bears similarities to the effector phase of other autoantibody-induced inflammatory diseases, including arthritis (24), vitiligo (25), cryoglobulinemia (26,27), bullous pemphigoid (28), and antiphospholipid syndrome (29). In contrast, the pathogenic effects of autoantibodies in other autoimmune diseases such as pemphigus (30) are mediated strictly by binding to their target Ag and do not involve the complement network.…”

Immunity to melanoma: unraveling the relation of tumor immunity and autoimmunity

“…Surprisingly, the effector cells responsible for depigmentation included a Thy1+population (Hara et al, 1995). Recently, the pathogenesis of antibody-mediated vitiligo has been characterized (Trcka et al, 2002). Two redundant and alternative pathways can mediate vitiligo in this model, involving either FcgR or complement systems.…”

Targeting death-inducing receptors in cancer therapy

“…It has been reported that tumor-specific T-cell responses critically contributed to successful antibody-based tumortargeting therapy that causes cell death through inhibition of growth signals and Fc receptor-mediated ADCC and/or CDC (Cragg et al, 1999;Clynes et al, 2000;Selenko et al, 2001;Trcka et al, 2002;zum Buschenfelde et al, 2002;Smith, 2003;Gelderman et al, 2004). Agonistic anti-DR5 mAb triggered tumor cell death directly via caspase activation, but also secondarily evoked tumor-specific CTL that could also eliminate anti-DR5-resistant variants .…”