Anticytokine Autoantibodies in Infectious Diseases: A Practical Overview

Abstract

Anticytokine autoantibodies (ACAAs) are a fascinating group of antibodies that have gained more and more attention in the field of autoimmunity and secondary immunodeficiencies over the years. Some of these antibodies are characterized by their ability to target and neutralize specific cytokines. ACAAs can play a role in the susceptibility to several infectious diseases, and their infectious manifestations depending on which specific immunological pathway is affected. In this review, we will give an outline per infection in which ACAAs might play a role and whether additional immunomodulatory treatment next to antimicrobial treatment can be considered. Finally, we describe the areas for future research on ACAAs.

Keywords: anti-GM-CSF; anti-interferon; anti-interleukin; cryptococcus; cytokine; non-tuberculous mycobacteria; secondary immunodeficiency.

Figure 1

Overview of most important ACAAs and their suggested mode of action. Central to the process of auto-antibody production are B lymphocytes and plasma cells, which can be targeted with host-directed therapies, such as rituximab (anti-CD20). (A) The cytokines IL-17 and IL-22 are essential in the interaction between epithelial barrier and Candida. IL-17 induces production of antimicrobial peptides and IL-22 enforces epithelial cell proliferation and repair, both through the IL-17-receptor and IL-22-receptor present in epithelial cells. This process is disrupted by anti-IL-17 and anti-IL-22 auto-antibodies. (B) IFNγ produced by Th1-cells is an essential activator of macrophages. It improves killing of intracellular pathogens, such as NTMs and several fungi, and induces IL-12 production, which in turn stimulates IFNγ production by Th1-cells. Anti-IFNγ auto-antibodies disrupt this proinflammatory loop. (C) GM-CSF is essential in the activation of, among others, alveolar macrophages, and the induction of production of reactive oxygen species. Anti-GM-CSF auto-antibodies therefore increase the risk for specific pulmonary infections with Nocardia and cryptococcal species and apart from local infection also increase the risk for disseminated disease such as Nocardia brain abscesses and cryptococcal meningitis. APECED, Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy; GM-CSF, Granulocyte-macrophage colony-stimulating factor; IFN, Interferon; IL, Interleukin; Mφ, macrophage; NTM, Non-tuberculous mycobacteria; Th, T-helper cell.