The Role of Human Fc Gamma Receptors in the Pathophysiology of Lupus Syndrome

Abstract

Systemic Lupus Erythematosus (SLE) is a chronic autoimmune syndrome, which currently has no curative treatment. The main drivers of this inflammatory disease are the IgG family autoantibodies that are produced against self‐antigens resulting from dysregulated apoptosis. These pathogenic autoantibodies form immune complexes (ICs), which become deposited in various tissues and cause organ damage. IgG ICs mainly interact with target cells by engaging with a family of receptors known as Fc gamma receptors (FcγRs). FcγRs are thought to be important contributors to inflammation in autoimmune diseases such as SLE. These receptors cooperate in modulating antigen processing and presentation, autoantibody production, and the promotion of inflammatory processes. Current mouse models do not adequately produce translatable data regarding the crucial role of FcγRs in SLE pathogenesis because the repertoire of FcγRs in mice is significantly different to that of humans. The human FcγR family consists of FcγRI, FcγRIIa, FcγRIIb, FcγRIIIa, and FcγRIIIb whereas mice express FcγRI, FcγRIIb, FcγRIII and FcγRIV. Furthermore, FcγRIIa, which is absent in wild type (WT) mice, is the only IgG receptor present on human platelets. The present study used the pristane method of lupus induction in WT mice and in mice in which all murine FcγRs have been replaced by human FcγRs (hu‐FcγR mice) to study the role of individual human FcγRs in the initiation and progression of lupus‐like autoimmune syndrome. After chemically inducing SLE in hu‐FcγR mice, we have found that both the initiation and progression of SLE is significantly accelerated compared to WT mice, suggesting that the combination of human FcγRs play a dominant role in the pathogenesis of lupus. Symptoms such as hypothermia, chopped breathing and weight loss was present in 61% of hu‐FcγR mice after 15 days or less after injection compared to only 33% in WT mice (p<0.05). hu‐FcγR mice presented splenomegaly, glomerulonephritis, and lung vasculitis as early as 10 days after injection. Antinuclear antibodies were found in 47% of injected hu‐FcγR mice compared to 28% in WT mice (p<0.05). These results suggest that FcγRs can significantly affect the development of a lupus‐like syndrome in mice. Furthermore, mice with human FcγRs should be considered as a more suitable model to study autoimmune disorders such as SLE. The present study and other necessary investigations in this topic may not only profoundly impact our knowledge of inflammation in SLE, but also identify specific FcγRs as novel therapeutic targets. Ultimately, because of the involvement of FcγRs in modulation of the inflammatory response, our findings have the potential to impact therapeutic approaches for other inflammatory autoimmune disorders, such as rheumatoid arthritis and antiphospholipid syndrome.Support or Funding InformationThis study was supported by Florida Hospital and the Adventist University of Health Sciences.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.