Characterization of anti-interferon-γ antibodies in HIV-negative immunodeficient patients infected with unusual intracellular microorganisms

Abstract

A major characteristic of immunodeficiency associated with life-threatening intracellular infection in adults is the presence of anti-interferon-γ antibodies. Although little is known about the mechanism underlying this syndrome, it is believed that the antibodies inhibit the activity of downstream signaling pathway of interferon-γ. In this study, the characteristics of these antibodies in patients who presented, or have a history of, intracellular infection and were positive to anti-interferon-γ antibodies were investigated. The antibodies exhibited mainly the IgG1 and the IgG4 subtypes and recognized the C-terminal of the interferon-γ linear epitope containing the KRKR motif, which is required for the biological activity of interferon-γ. The antibodies bound to recombinant interferon-γ with significantly lower avidity than antibodies to a recall antigen, tetanus toxoid, suggesting that the antibodies might have not undergone affinity maturation. The data from this study may provide fundamental information to better understand the properties of anti-interferon-γ antibodies, which can be useful for future studies. Impact statement An increase in the number of immunodeficient patients related to autoantibodies to interferon (IFN)-γ has been observed particularly in East Asian adults. These patients are often presented with opportunistic infections caused by intracellular pathogens, including non-tuberculous mycobacteria (NTM), Cryptococcus neoformans, Penicillium marneffei (now called Talaromyces marneffei), and non-typhoidal Salmonella spp. The mortality rate for this syndrome is relatively high with 32% patients dying at the median time of 25 months after diagnosis. Characterization of these autoantibodies may promote better understanding of the syndrome, an emerging health problem affecting East Asia populations and impeding their welfare and economic development.

Blockade Effects of Anti-Interferon- (IFN-) γ Autoantibodies on IFN-γ-Regulated Antimicrobial Immunity

“…Although the generation of anti-IFN- γ autoAbs is highly associated with the development of disseminated NTM infection in patients without HIV-induced immunodeficiency [4], the levels and pathogenic roles of anti-IFN- γ autoAbs in the progression of adult-onset immunodeficiency are still unclear. Based on the current tests for measuring anti-IFN- γ autoAb expression, possible epitopes related to IFN- γ bioactivity have been selected for validation [13, 27]. The possible targeting effects retarding IFN- γ bioactivity need further investigation.…”

Neutralizing Activity of Anti-interferon-γ Autoantibodies in Adult-Onset Immunodeficiency Is Associated With Their Binding Domains

“…However, the binding of this region to the receptor has not been confirmed by X-ray crystallography (15). Surprisingly, in some patients, their autoAbs did not bind to this region (8, 9). This observation was confirmed by our study, and the epitope mapping of the human anti-IFN-γ autoAbs in the serum of an AOID patient (A3) that used synthetic peptides showed that the autoAbs could recognize both peptide 14 and peptide 15 which share the KRKR motif.…”

“…Therefore, the identification of the neutralizing anti-IFN-γ autoAbs in individuals with disseminated tuberculous or late-onset NTM infection is crucial for identifying pathogenic autoAbs. Recently, the characteristics of anti-IFN-γ autoAbs were investigated and it was demonstrated that the anti-IFN-γ autoAbs in patients with unusual intracellular pathogens recognized the C-terminus of the IFN-γ linear epitope containing the KRKR motif and were mainly of the IgG1 and IgG4 subclasses (9). Even though those autoAbs had neutralizing activity, in some AOID patients, the autoAbs are unable to bind to this peptide.…”

“…Previously, the IFN-γ C-terminal region, which contains the KRKR motif, has been reported as the epitope that is recognized by the anti-IFN-γ autoAbs in patients with opportunistic infections (7, 9). This region has been reported to be involved in IFN-γ receptor activation.…”

“…It has been reported that the anti-IFN-γ autoAbs in these patients were of the IgG1 and IgG4 subclasses. In ~40% of patients, these autoAbs recognize the linear epitope containing the KRKR motif, which is located at the C-terminus of IFN-γ (9). In some patients, neutralizing anti-IFN-γ autoAbs did not recognize the C-terminal epitope, suggesting that those autoAbs recognize other epitopes that are essential for IFN-γ-mediated signaling (8, 9).…”