Human autoantibodies underlying infectious diseases

Abstract

The vast interindividual clinical variability observed in any microbial infection—ranging from silent infection to lethal disease—is increasingly being explained by human genetic and immunological determinants. Autoantibodies neutralizing specific cytokines underlie the same infectious diseases as inborn errors of the corresponding cytokine or response pathway. Autoantibodies against type I IFNs underlie COVID-19 pneumonia and adverse reactions to the live attenuated yellow fever virus vaccine. Autoantibodies against type II IFN underlie severe disease caused by environmental or tuberculous mycobacteria, and other intra-macrophagic microbes. Autoantibodies against IL-17A/F and IL-6 are less common and underlie mucocutaneous candidiasis and staphylococcal diseases, respectively. Inborn errors of and autoantibodies against GM-CSF underlie pulmonary alveolar proteinosis; associated infections are less well characterized. In individual patients, autoantibodies against cytokines preexist infection with the pathogen concerned and underlie the infectious disease. Human antibody-driven autoimmunity can interfere with cytokines that are essential for protective immunity to specific infectious agents but that are otherwise redundant, thereby underlying specific infectious diseases.

From rare disorders of immunity to common determinants of infection: Following the mechanistic thread

“… (5) Patient- and population-based immunological studies (magenta). Auto-Abs against four cytokines (type I and II IFNs, IL-6, and IL-17A/F) have been shown to underlie infectious phenocopies of the corresponding inborn errors of cytokines or their response pathways ( Ku et al., 2020 ; Puel et al., 2022 ). The best characterized are probably auto-Abs neutralizing type II IFN, which underlie a phenocopy of MSMD and, more rarely, TB ( Puel et al., 2022 ; Shih et al., 2021 ).…”

“…Auto-Abs against four cytokines (type I and II IFNs, IL-6, and IL-17A/F) have been shown to underlie infectious phenocopies of the corresponding inborn errors of cytokines or their response pathways ( Ku et al., 2020 ; Puel et al., 2022 ). The best characterized are probably auto-Abs neutralizing type II IFN, which underlie a phenocopy of MSMD and, more rarely, TB ( Puel et al., 2022 ; Shih et al., 2021 ). Auto-Abs neutralizing type I IFNs, first described in the early 1980s, were long thought to be clinically silent, except for a 77-year-old woman with disseminated zoster studied by Ion Gresser ( Pozzetto et al., 1984 ).…”

Virus Infection and Systemic Inflammation: Lessons Learnt from COVID-19 and Beyond

“…Autoimmune B-cell phenotypes in humans exhibiting inborn errors of cytokine immunity can produce neutralizing autoantibodies (Auto-Abs) against IFNs such as IFN-α,β,ω (favoring viral diseases), IFN-γ (favoring mycobacterial diseases), or against cytokines such as IL-6 (favoring staphylococcal diseases) and IL-17A, IL-17F (favoring mucocutaneous candidiasis), that resemble the clinical phenotypes of mutations encoding these defective cytokines and/or their receptor subunits (reviewed by [ 130 ]). Type I IFN Auto-Abs were initially reported in patients that were diagnosed with systemic lupus erythematosus, myasthenia gravis, thymic abnormalities, as well as in IFN recipients (reviewed in [ 108 ]).…”

“…Type I IFN Auto-Abs were initially reported in patients that were diagnosed with systemic lupus erythematosus, myasthenia gravis, thymic abnormalities, as well as in IFN recipients (reviewed in [ 108 ]). While these type I IFN Auto-Abs received little attention due to the absence of negative clinical reports [ 125 , 130 ] the COVID-19 pandemic has put a new spotlight on the immunopathological implications of type I IFN Auto-Abs for human susceptibility to viral infections and disease progression. More than 10% of patients with severe COVID-19-associated pneumonia tested positive for neutralizing Auto-Abs against IFN-α2 and/or IFN-ω [ 131 ].…”

IL-6 Autoantibodies Predict Lower Platelet Counts and Altered Plasma Cytokine Profiles in Healthy Blood Donors: Results From the Danish Blood Donor Study

“…There is emerging evidence that naturally occurring cytokine-specific autoantibodies (c-aAb) represent a novel immunosuppressing phenomenon which is observed for a wide range of target cytokines in both healthy and diseased individuals (13)(14)(15)(16)(17), and may predict infection (18). Our group has developed and validated an in-house assay for the detection of c-aAb and reported high titers of c-aAb to be relatively common in Danish blood donors, including a 0.1-1% prevalence of high titers of IL-6 specific c-aAb (19)(20)(21).…”