Autoantibodies in immunodeficiency syndromes: The Janus faces of immune dysregulation

Abstract

Immunodeficiency syndromes represent a diverse group of inherited and acquired disorders, characterized by a spectrum of clinical manifestations, including recurrent infections, autoimmunity, lymphoproliferation and malignancy. Autoantibodies against various self-antigens reflect the immune dysregulation underlying these disorders, and could contribute to certain clinical findings, such as susceptibility to opportunistic infections, cytopenia of different hematopoietic lineages, and organ-specific autoimmune diseases. The mechanism of autoantibody production in the context of immunodeficiency remains largely unknown but is likely shaped by both intrinsic genetic aberrations and extrinsic exposures to possible infectious agents. These autoantibodies if harbor neutralizing activities and reach certain levels in the circulation, could disrupt the biological functions of their targets, resulting in specific clinical manifestations. Herein, we reviewed the prevalence of autoantibodies against cytokines, hematopoietic cells and organ-specific antigens in immunodeficiency syndromes and examined their associations with certain clinical findings. Moreover, the potential mechanism of autoantibody production was also discussed. These may shed light on the development of mechanism-based therapies to reset the dysregulated immune system in immunodeficient patients.

Keywords: Autoantibodies; Autoimmunity; Cytokines; Cytopenia; Immunodeficiency; Infections.

Fig. 1.

Association of autoantibodies to immunodeficiency and/or autoimmunity. Th17, T-helper 17 cells; IFN, interferon; IL, interleukin; GM-CSF, granulocyte-macrophage colony-stimulating factor; G-CSF, granulocyte colony-stimulating factor; RBC, red blood cell; Abs, antibodies.

Fig. 2.

Molecular defects of adult-onset immunodeficiency related to autoantibodies against IFN-γ/IL-12 axis. Macrophages infected by mycobacteria could produce IL-12 and IL-23, and the former in turn stimulates T cells to produce IFN-γ, which is neutralized by pathogenic autoantibodies. Therapeutic options include anti-mycobacterial antibiotics, antibody depletion therapy and potentially modified IFN-γ that could escape autoantibody neutralization.