Skip to main content

Advertisement

SpringerLink
Log in

Clinicopathological Manifestations and Immune Phenotypes in Adult-Onset Immunodeficiency with Anti-interferon-γ Autoantibodies

  • Original Article
  • Published:
Journal of Clinical Immunology Aims and scope Submit manuscript

Abstract

Purpose

Anti-interferon (IFN)-γ autoantibodies (anti-IFN-γ Abs) is an emerging adult-onset immunodeficiency syndrome. Immune dysfunction in this distinct disorder remains to be clarified.

Methods

We prospectively collected blood samples of 20 patients with anti-IFN-γ Abs and 40 healthy normal subjects. The percentages of lymphocyte subpopulations, most relevant to T, B, and NK cells, and the percentages of stimulated lymphocytes with cytokine production were assessed using eight-color flow cytometry. The results were adjusted to age and absolute lymphocyte counts.

Results

Most (85%) patients presented nontuberculous mycobacterial infection. Skin lesions were predominantly manifested by neutrophilic dermatoses. The involved lymph nodes had granulomatous inflammation, except 22.2% showing atypical lymphoid hyperplasia without granuloma formation. The percentages of CD4 + T cells and nonactivated subpopulations (recent thymic emigrants and naïve subtypes) decreased significantly with increased expression of activation markers and polarization to differentiated cells. The percentage of NK cells increased, but that of two major NK subpopulations, CD161 + CD56bright and CD161 + CD56 + CD16 + subsets, decreased. Increased CD161dim, CD161 + CD56 − CD16 + , and CD57 + NK cell subsets coupled with the decreased expression of NKp30 and NKp46 indicate reconfiguration of the NK cell population and acquisition of adaptive features. Intracellular cytokine production of the lymphocyte subpopulations was significantly low in the patients compared with the control group.

Conclusion

We conclude that the immune system in patients with anti-IFN-γ Abs could be exhausted in T cells and be adaptive in NK cells, contributing to the distinct clinicopathologic features.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data Availability

Upon request.

Code Availability

Upon request.

References

  1. Batoni G, Esin S, Favilli F, Pardini M, Bottai D, Maisetta G, et al. Human CD56bright and CD56dim natural killer cell subsets respond differentially to direct stimulation with Mycobacterium bovis bacillus Calmette-Guerin. Scand J Immunol. 2005;62(6):498–506.

    Article  CAS  PubMed  Google Scholar 

  2. Boldt A, Borte S, Fricke S, Kentouche K, Emmrich F, Borte M, et al. Eight-color immunophenotyping of T-, B-, and NK-cell subpopulations for characterization of chronic immunodeficiencies. Cytometry B Clin Cytom. 2014;86(3):191–206.

    Article  PubMed  Google Scholar 

  3. Browne SK, Burbelo PD, Chetchotisakd P, Suputtamongkol Y, Kiertiburanakul S, Shaw PA, et al. Adult-onset immunodeficiency in Thailand and Taiwan. N Engl J Med. 2012;367(8):725–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Chawansuntati K, Rattanathammethee K, Wipasa J. Minireview: Insights into anti-interferon-gamma autoantibodies. Exp Biol Med (Maywood). 2021;246(7):790–5.

    Article  Google Scholar 

  5. Chi CY, Chu CC, Liu JP, Lin CH, Ho MW, Lo WJ, Lin PC, Chen HJ, Chou CH, Feng JY, et al. Anti-IFN-gamma autoantibodies in adults with disseminated nontuberculous mycobacterial infections are associated with HLA-DRB1*16:02 and HLA-DQB1*05:02 and the reactivation of latent varicella-zoster virus infection. Blood. 2013;121(8):1357–66.

    Article  CAS  PubMed  Google Scholar 

  6. Chi CY, Lin CH, Ho MW, Ding JY, Huang WC, Shih HP, et al. Clinical manifestations, course, and outcome of patients with neutralizing anti-interferon-gamma autoantibodies and disseminated nontuberculous mycobacterial infections. Med (Baltim). 2016;95(25):e3927

  7. Chruewkamlow N, Mahasongkram K, Pata S, Chaiwarith R, Salee P, Supparatpinyo K, et al. Immune alterations in patients with anti-interferon-gamma autoantibodies. PLOS ONE. 2016;11(1):e0145983

  8. Duah M, Li L, Shen J, Lan Q, Pan B, Xu K. Thymus degeneration and regeneration. Front Immunol. 2021;12:706244

  9. Fink PJ. The biology of recent thymic emigrants. Annu Rev Immunol. 2013;31:31–50.

    Article  CAS  PubMed  Google Scholar 

  10. Forconi CS, Oduor CI, Oluoch PO, Ong’echa JM, Munz C, Bailey JA, et al. A new hope for CD56(neg)CD16(pos) NK cells as unconventional cytotoxic mediators: an adaptation to chronic diseases. Front Cell Infect Microbiol. 2020;10:162.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Gonzalez SM, Taborda NA, Rugeles MT. Role of different subpopulations of CD8+ T cells during HIV exposure and infection. Front Immunol. 2017;8:936.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Guo J, Ning XQ, Ding JY, Zheng YQ, Shi NN, Wu FY, Lin YK, Shih HP, Ting HT, Liang G et al. Anti-IFN-gamma autoantibodies underlie disseminated Talaromyces marneffei infections. J Exp Med. 2020; 217(12)

  13. Hong GH, Ortega-Villa AM, Hunsberger S, Chetchotisakd P, Anunnatsiri S, Mootsikapun P, et al. Natural history and evolution of anti-interferon-gamma autoantibody-associated immunodeficiency syndrome in Thailand and the United States. Clin Infect Dis. 2020;71(1):53–62.

    Article  CAS  PubMed  Google Scholar 

  14. Jutivorakool K, Sittiwattanawong P, Kantikosum K, Hurst CP, Kumtornrut C, Asawanonda P, et al. Skin manifestations in patients with adult-onset immunodeficiency due to anti-interferon-gamma autoantibody: a relationship with systemic infections. Acta Derm Venereol. 2018;98(8):742–7.

    Article  CAS  PubMed  Google Scholar 

  15. Kared H, Martelli S, Ng TP, Pender SL, Larbi A. CD57 in human natural killer cells and T-lymphocytes. Cancer Immunol Immunother. 2016;65(4):441–52.

    Article  CAS  PubMed  Google Scholar 

  16. Koizumi Y, Mikamo H. Anti-Interferon-gamma autoantibody and disseminated nontuberculous mycobacteria infection. What should be done to improve its clinical outcome? Clin Infect Dis. 2021;72(12):2209–11

  17. Krisnawati DI, Liu YC, Lee YJ, Wang YT, Chen CL, Tseng PC, et al. Functional neutralization of anti-IFN-gamma autoantibody in patients with nontuberculous mycobacteria infection. Sci Rep. 2019;9(1):5682.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Ku CL, Chi CY, von Bernuth H, Doffinger R. Autoantibodies against cytokines: phenocopies of primary immunodeficiencies? Hum Genet. 2020;139(6–7):783–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kurioka A, Cosgrove C, Simoni Y, van Wilgenburg B, Geremia A, Bjorkander S, et al. CD161 defines a functionally distinct subset of pro-inflammatory natural killer cells. Front Immunol. 2018;9:486.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Lim A, Allison C, Tan DB, Oliver B, Price P, Waterer G. Immunological markers of lung disease due to non-tuberculous mycobacteria. Dis Markers. 2010;29(2):103–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Li WS, Huang WC, Ku CL, Lee CH. Osteolytic lesions resulting from opportunistic infections. Kaohsiung J Med Sci. 2017;33(7):365–6.

    Article  PubMed  Google Scholar 

  22. Liu TT, Weng SW, Wang MC, Huang WT. Nontuberculous mycobacterial infection with concurrent IgG4-related lymphadenopathy. APMIS. 2016;124(3):216–20.

    Article  CAS  PubMed  Google Scholar 

  23. Long EO, Kim HS, Liu D, Peterson ME, Rajagopalan S. Controlling natural killer cell responses: integration of signals for activation and inhibition. Annu Rev Immunol. 2013;31:227–58.

    Article  CAS  PubMed  Google Scholar 

  24. Lopez-Vergès S, Milush JM, Pandey S, York VA, Arakawa-Hoyt J, Pircher H, et al. CD57 defines a functionally distinct population of mature NK cells in the human CD56dimCD16+ NK-cell subset. Blood. 2010;116(19):3865–74.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Mavilio D, Lombardo G, Benjamin J, Kim D, Follman D, Marcenaro E, et al. Characterization of CD56−/CD16+ natural killer (NK) cells: a highly dysfunctional NK subset expanded in HIV-infected viremic individuals. Proc Natl Acad Sci U S A. 2005;102(8):2886–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Michel T, Poli A, Cuapio A, Briquemont B, Iserentant G, Ollert M, et al. Human CD56bright NK cells: an update. J Immunol. 2016;196(7):2923–31.

    Article  CAS  PubMed  Google Scholar 

  27. Moore JW, Beattie L, Osman M, Owens BM, Brown N, Dalton JE, et al. CD4+ recent thymic emigrants are recruited into granulomas during Leishmania donovani infection but have limited capacity for cytokine production. PLOS ONE. 2016;11(9):e0163604

  28. Nielsen CM, White MJ, Goodier MR, Riley EM. Functional significance of CD57 expression on human NK cells and relevance to disease. Front Immunol. 2013;4:422.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Pithukpakorn M, Roothumnong E, Angkasekwinai N, Suktitipat B, Assawamakin A, Luangwedchakarn V, Umrod P, Thongnoppakhun W, Foongladda S, Suputtamongkol Y. HLA-DRB1 and HLA-DQB1 are associated with adult-onset immunodeficiency with acquired anti-interferon-gamma autoantibodies. PLOS ONE. 2015; 10(5):e0128481

  30. Shih HP, Ding JY, Yeh CF, Chi CY, Ku CL. Anti-interferon-gamma autoantibody-associated immunodeficiency. Curr Opin Immunol. 2021;72:206–14.

    Article  CAS  PubMed  Google Scholar 

  31. Wang Z, Zhu L, Nguyen THO, Wan Y, Sant S, Quiñones-Parra SM, et al. Clonally diverse CD38+HLA-DR+CD8+ T cells persist during fatal H7N9 disease. Nat Commun. 2018;9(1):824.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Wipasa J, Wongkulab P, Chawansuntati K, Chaiwarit R, Supparatpinyo K. Cellular immune responses in HIV-negative immunodeficiency with anti-interferon-gamma antibodies and opportunistic intracellular microorganisms. PLOS ONE. 2014;9(10):e110276

  33. Wu UI, Holland SM. Host susceptibility to non-tuberculous mycobacterial infections. Lancet Infect Dis. 2015;15(8):968–80.

    Article  CAS  PubMed  Google Scholar 

  34. Wu UI, Wang JT, Sheng WH, Sun HY, Cheng A, Hsu LY, et al. Incorrect diagnoses in patients with neutralizing anti-interferon-gamma-autoantibodies. Clin Microbiol Infect. 2020;26(12):1684.e1-6.

    Article  Google Scholar 

Download references

Acknowledgements

We acknowledge Mr. Yu-Shiang Hu (senior product specialist, BD Biosciences, Taiwan) for his help with the experimental setting and Biostatistics Center, Kaohsiung Chang Gung Memorial Hospital for statistics work.

Funding

This study was supported by the Chang Gung Memorial Hospital (grant number CMRPG8K0341).

Author information

Authors and Affiliations

  1. Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, 83301, Taiwan

    Yi-Chun Chen, Chen-Hsiang Lee & Wen-Chi Huang

  2. Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, 83301, Taiwan

    Shao-Wen Weng

  3. School of Medicine, College of Medicine, Chang Gung University, Taoyuan, 33382, Taiwan

    Shao-Wen Weng, Chen-Hsiang Lee & Wan-Ting Huang

  4. Laboratory of Human Immunology and Infectious Diseases, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, 33382, Taiwan

    Jing-Ya Ding & Cheng-Lung Ku

  5. Department of Nephrology, Linkou Chang Gung Memorial Hospital, Taoyuan, 33382, Taiwan

    Cheng-Lung Ku

  6. Center for Molecular and Clinical Immunology, Chang Gung University, Taoyuan, 33382, Taiwan

    Cheng-Lung Ku

  7. Department of Laboratory Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, 83301, Taiwan

    Huey-Ling You & Wan-Ting Huang

  8. Department of Medical Laboratory Sciences and Biotechnology, Fooyin University, Kaohsiung, 83102, Taiwan

    Huey-Ling You & Wan-Ting Huang

  9. Department of Pathology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, 83301, Taiwan

    Wan-Ting Huang

Authors
  1. Yi-Chun Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shao-Wen Weng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jing-Ya Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chen-Hsiang Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Cheng-Lung Ku
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wen-Chi Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Huey-Ling You
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Wan-Ting Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

WTH conceptualized and designed the study. CLK and JYD designed and performed the experiments to detect neutralizing anti-IFN-γ antibodies. WCH and HLY acquired the data. YCC, CHL, and WTH interpreted the data. YCC and WTH conducted the literature review and wrote the draft manuscript. SWW performed the statistical analysis. All authors critically reviewed and approved the final manuscript.

Corresponding author

Correspondence to Wan-Ting Huang.

Ethics declarations

Ethics Approval

This study was approved by the Ethics Committee of the Chang Gung Memorial Hospital, Kaohsiung, Taiwan, in accordance with the Declaration of Helsinki (IRB201901509B0C501).

Consent to Participate

All participants provided written informed consent.

Consent for Publication

Obtained.

Conflict of Interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, YC., Weng, SW., Ding, JY. et al. Clinicopathological Manifestations and Immune Phenotypes in Adult-Onset Immunodeficiency with Anti-interferon-γ Autoantibodies. J Clin Immunol 42, 672–683 (2022). https://doi.org/10.1007/s10875-022-01210-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10875-022-01210-y

Keywords

Search

Navigation