Anti-Interferon-γ Autoantibodies Impair T-Lymphocyte Responses in Patients with Talaromyces marneffei Infections

Chen, Zhaoming; Yang, Xin‐She; Li, Zheng-Tu; Guan, Weijun; Qiu, Ye; Li, Shaoqiang; Zhan, Yangqing; Lei, Ziying; Liu, Jing; Zhang, Jianquan; Wang, Zhong-Fang; Ye, Feng

doi:10.2147/idr.s364388

Cited by 8 publications

(7 citation statements)

References 47 publications

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“…It remains to be proven whether the MCMV-BAC driven increase in DCs, and/or priming of them to respond/present antigen, leads directly to enhanced responsiveness of parasite specific T cells/expansion and clearance of parasite by Th1-promoted macrophage activation and Tfh-promoted antibody production. It is also possible that antigen presentation and Th1 response are reduced with the presence of detectable anti-IFN-γ auto-antibody [43]. Exploring this hypothesis to determine potential effects of anti-IFN-γ antibody, we found that administration of neutralizing antibody up to 2 days before infection with P. chabaudi does not have a significant effect on peak parasitemia, though there may be a trend towards increasing parasitemia.…”

Section: Discussionmentioning

confidence: 83%

Boosting Live Malaria Vaccine with Cytomegalovirus Vector Can Prolong Immunity through Innate and Adaptive Mechanisms

Gbédandé

Ibitokou

Ong

et al. 2023

Preprint

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Vaccines to persistent parasite infections have been challenging, and current iterations lack long-term protection. Cytomegalovirus (CMV) chronic vaccine vectors drive protection against SIV, tuberculosis and liver-stage malaria correlated with antigen-specific CD8 T cells with a Tem phenotype. This phenotype is likely driven by a combination of antigen-specific and innate adjuvanting effects of the vector, though these mechanisms are less well understood. Sterilizing immunity from live Plasmodium chabaudi vaccination lasts less than 200 days. While P. chabaudi-specific antibody levels remain stable after vaccination, the decay of parasite-specific T cells correlates with loss of challenge protection. Therefore, we enlisted murine CMV as a booster strategy to prolong T cell responses against malaria. To study induced T cell responses, we included P.chabaudi MSP-1 epitope B5 (MCMV-B5). We found that MCMV vector alone significantly protected against a challenge P. chabaudi infection 40-60 days later, and that MCMV-B5 was able to make B5-specific Teff, in addition to previously-reported Tem, that survive to the challenge timepoint. Used as a booster, MCMV-B5 prolonged protection from heterologous infection beyond day 200, and increased B5 TCR Tg T cell numbers, including both a highly-differentiated Tem phenotype and Teff, both previously reported to protect. B5 epitope expression was responsible for maintenance of Th1 and Tfh B5 T cells. In addition, the MCMV vector had adjuvant properties, contributing non-specifically through prolonged stimulation of IFN-γ. In vivo neutralization of IFN-γ, but not IL-12 and IL-18, late in the course of MCMV, led to loss of the adjuvant effect. Mechanistically, sustained IFN-γ from MCMV increased CD8α+ dendritic cell numbers, and led to increased IL-12 production upon Plasmodium challenge. In addition, neutralization of IFN-γ before challenge reduced the polyclonal Teff response to challenge. Our findings suggest that, as protective epitopes are defined, an MCMV vectored booster can prolong protection through the innate effects of IFN-γ.

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Section: Discussionmentioning

confidence: 83%

Boosting Live Malaria Vaccine with Cytomegalovirus Vector Can Prolong Immunity through Innate and Adaptive Mechanisms

Gbédandé

Ibitokou

Ong

et al. 2023

Preprint

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“…These observations indicate that anti-IFN-γ autoAbs may potentiate the severity of COVID-19 through functional neutralization of the IFN-γ-mediated signaling pathway. Although functional characterization of anti-IFN-γ autoantibodies is limited only to a standard assay of IFN-γ-induced STAT1 phosphorylation, Chen et al revealed that anti-IFN-γ autoantibodies could inhibit the phosphorylation of STAT1 and STAT3 in patients with Talaromyces marneffei infection [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

The detectable anti-interferon-γ autoantibodies in COVID-19 patients may be associated with disease severity

Chen

Yeo

Chang

et al. 2023

Virol J

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Background Neutralizing anti-interferon (IFN)-γ autoantibodies are linked to adult-onset immunodeficiency and opportunistic infections. Methods To explore whether anti-IFN-γ autoantibodies are associated with disease severity of coronavirus disease 2019 (COVID-19), we examined the titers and functional neutralization of anti-IFN-γ autoantibodies in COVID-19 patients. In 127 COVID-19 patients and 22 healthy controls, serum titers of anti-IFN-γ autoantibodies were quantified using enzyme-linked immunosorbent assay, and the presence of autoantibodies was verified with immunoblotting assay. The neutralizing capacity against IFN-γ was evaluated with flow cytometry analysis and immunoblotting, and serum cytokines levels were determined using the MULTIPLEX platform. Results A higher proportion of severe/critical COVID-19 patients had positivity for anti-IFN-γ autoantibodies (18.0%) compared with non-severe patients (3.4%, p < 0.01) or healthy control (HC) (0.0%, p < 0.05). Severe/critical COVID-19 patients also had higher median titers of anti-IFN-γ autoantibodies (5.01) compared with non-severe patients (1.33) or HC (0.44). The immunoblotting assay could verify the detectable anti-IFN-γ autoantibodies and revealed more effective inhibition of signal transducer and activator of transcription (STAT1) phosphorylation on THP-1 cells treated with serum samples from anti-IFN-γ autoantibodies-positive patients compared with those from HC (2.21 ± 0.33 versus 4.47 ± 1.64, p < 0.05). In flow-cytometry analysis, sera from autoantibodies-positive patients could also significantly more effectively suppress the STAT1 phosphorylation (median,67.28%, interquartile range [IQR] 55.2–78.0%) compared with serum from HC (median,106.7%, IQR 100.0–117.8%, p < 0.05) or autoantibodies-negative patients (median,105.9%, IQR 85.5–116.3%, p < 0.05). Multivariate analysis revealed that the positivity and titers of anti-IFN-γ autoantibodies were significant predictors of severe/critical COVID-19. Compared with non-severe COVID-19 patients, we reveal that a significantly higher proportion of severe/critical COVID-19 patients are positive for anti-IFN-γ autoantibodies with neutralizing capacity. Conclusion Our results would add COVID-19 to the list of diseases with the presence of neutralizing anti-IFN-γ autoAbs. Anti-IFN-γ autoantibodies positivity is a potential predictor of severe/critical COVID-19.

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“…Despite high levels of activated T cells being observed, their specific role remains unclear. A recent study suggested that the presence of anti-IFN-γ-auto-Abs in serum inhibited CD4+ Th1 and CD8+ T-cell immune responses [ 25 ]. It is possible that consistently high levels of activated T cells persisted in our patients due to the reduction in anti-IFN-γ-auto-Ab levels following BTZ treatment.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of Bortezomib for Treating Anti-Interferon-Gamma Autoantibody-Associated Adult-Onset Immunodeficiency Syndrome

Angkasekwinai,

Suputtamongkol,

Tantibhedhyangkul

et al. 2023

Clinical Infectious Diseases

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Background There is currently no effective treatment for adult-onset immunodeficiency (AOID) syndrome with anti-interferon-gamma autoantibodies (anti-IFN-γ-auto-Abs). The purpose of this study is to investigate the effectiveness of bortezomib (BTZ) for decreasing anti-IFN-γ-auto-Abs.‏ Methods A pre-and post-intervention study was conducted during February 2017-June 2019 at Siriraj Hospital (Bangkok, Thailand).‏ Five patients were invited to receive once weekly BTZ (1.‏3 mg/m2 body surface area) subcutaneously for 8 weeks followed by oral cyclophosphamide (1 mg/kg/day) for 4 months.‏ The primary outcomes were the difference in antibody level at 8 and 48 weeks compared to baseline, and the incidence of serious adverse events (AEs).‏ The secondary outcome was the occurrence of opportunistic infections (OIs) throughout 72 weeks after starting BTZ.‏ Results The median patient age was 46 years (range: 34-53).‏ All patients had 3-5 OIs prior to enrollment.‏ All patients were receiving antimycobacterial agents for treatment of nontuberculous mycobacterial infection at enrollment.‏ There was no significant difference in the mean optical density of auto-Abs at 8 weeks (3.‏73 ± 0.‏72) or 48 weeks (3.‏74 ± 0.‏53) compared to baseline (3.‏84 ± 0.‏49) (p = 0.‏336 and p = 0.‏555, respectively).‏ However, after serum dilution, the antibody titer non-significantly decreased during 8-16 weeks after BTZ initiation (p = 0.‏345).‏ Ten OIs were observed during 24-72 weeks after BTZ initiation, and Mycobacterium abscessus was the most prevalent pathogen.‏ Conclusions Treatment with BTZ followed by cyclophosphamide yielded no significant decrease in antibody titer levels, and ten OIs were observed during 24-72 weeks of BTZ.‏ No serious AEs were observed.‏ Combining rituximab with BTZ is likely necessary to prevent generation of new autoantibody-producing plasma cells.‏

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Anti-Interferon-γ Autoantibodies Impair T-Lymphocyte Responses in Patients with Talaromyces marneffei Infections

Cited by 8 publications

References 47 publications

Boosting Live Malaria Vaccine with Cytomegalovirus Vector Can Prolong Immunity through Innate and Adaptive Mechanisms

Boosting Live Malaria Vaccine with Cytomegalovirus Vector Can Prolong Immunity through Innate and Adaptive Mechanisms

The detectable anti-interferon-γ autoantibodies in COVID-19 patients may be associated with disease severity

Efficacy of Bortezomib for Treating Anti-Interferon-Gamma Autoantibody-Associated Adult-Onset Immunodeficiency Syndrome

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