Neutralizing anti-IFN-γ IgG was increased in patients with systemic lupus erythematosus and associated with susceptibility to infection

Abstract

Objectives Systemic lupus erythematosus (SLE) is a complicated autoimmune disease, in which infection is a leading cause of death. Some SLE patients clinically presented with recurrent and refractory infections, which manifested as adult-onset immunodeficiency syndrome due to the production of anti-interferon-γ (anti-IFN-γ) autoantibodies. This study aimed to investigate the role of anti-IFN-γ autoantibodies concerning severe infections in SLE patients. Methods We detected serum levels of anti-IFN-γ IgG/IgM isotypes in SLE patients with severe infections (n = 55), SLE patients without severe infections (n = 120), rheumatoid arthritis (n = 24), ankylosing spondylitis (n = 24), and healthy controls (n = 60). The relationship between anti-IFN-γ autoantibodies and clinical characteristics and laboratory parameters were analyzed. We further evaluated the neutralizing ability of anti-IFN-γ IgG. Results The level of anti-IFN-γ IgG was significantly elevated in SLE patients with severe infections compared with the other groups (all p < 0.01), and the positive rates of anti-IFN-γ IgG in SLE patients with and without severe infections were 29.1% and 10.8%, respectively. Further analysis indicated that the levels of anti-IFN-γ IgG were positively associated with the SLEDAI score (r = 0.6420, p < 0.001), and it could predict the susceptibility to severe infections in SLE patients. Moreover, the inhibition and function assay showed that purified IgG from anti-IFN-γ IgG-positive SLE patients could neutralize IFN-γ, and further impair IFN-γ-induced STAT1 phosphorylation. Conclusions The neutralizing anti-IFN-γ IgG might increase the susceptibility to infection in SLE patients, which has important implications for the treatment. Key Points• The role of anti-IFN-γ autoantibodies concerning severe infections in SLE patients remains unknown.• The results of this study reveals that anti-IFN-γ IgG levels were significantly elevated in SLE patients with severe infections.• This study suggests that neutralizing anti-IFN-γ IgG might increase the susceptibility to infection in SLE patients.

Association of anti-interferon-γ autoantibodies with severe herpes zoster in rheumatoid arthritis patients treated with Janus kinase inhibitors

“…Given that MCP-1 could contribute to anti-microbial inflammatory response by attracting monocytes and T lymphocytes [25], the low level of MCP-1 may increase infection with intracellular pathogens such as varicella-zoster virus. Gathering the evidence from other studies [22][23][24][25][26] and ours, high-titer anti-IFN-γ IgG may reduce antimicrobial activity at least partly by counteracting the IFN-γ-mediated production of chemokines. Although anti-IFN-γ IgG could neutralize IFN-γ, the non-significant difference in plasma IFN-γ levels between RA patients with and without HZ was probably due to the small sample size in our study.…”

“…They also identified anti-IFN-γ IgG as a significant predictor for developing severe infections in SLE patients [23]. Anti-IFN-γ IgG-positive SLE patients were also more susceptible to mycobacterial and fungal infections compared to those without anti-IFN-γ IgG [23]. Although we demonstrated no significant difference in serum titers of anti-IFN-γ IgG between RA patients with and without new-onset HZ, significantly higher titers of anti-IFN-γ IgG were observed in RA patients with severe HZ than in those with non-severe HZ.…”

“…Recently, Chen et al revealed significantly higher titers of anti-IFN-γ IgG in SLE patients with severe infections compared to those without infections [23]. They also identified anti-IFN-γ IgG as a significant predictor for developing severe infections in SLE patients [23]. Anti-IFN-γ IgG-positive SLE patients were also more susceptible to mycobacterial and fungal infections compared to those without anti-IFN-γ IgG [23].…”

“…Increasing evidence suggests a close link between anti-IFN-γ autoAbs or chemokines and OIs [3][4][5][6][7]22,23], yet their relationship in RA patients with new-onset HZ has not been explored. Compared to RA patients without HZ development, our JAKi-treated patients with new-onset HZ have a longer disease duration, higher doses of corticosteroids, and a higher proportion of high-dose corticosteroids used.…”

“…Although anti-cytokine autoAbs have been observed in immune-mediated inflammatory diseases [8,22,23], whether anti-IFN-γ autoAbs in these diseases contribute to the susceptibility to infections remains unclear. Recently, Chen et al revealed significantly higher titers of anti-IFN-γ IgG in SLE patients with severe infections compared to those without infections [23]. They also identified anti-IFN-γ IgG as a significant predictor for developing severe infections in SLE patients [23].…”