Cryptococcus gattii Infection as the Major Clinical Manifestation in Patients with Autoantibodies Against Granulocyte-Macrophage Colony-Stimulating Factor

doi:10.1007/s10875-022-01341-2

. 2022 Nov;42(8):1730-1741.

doi: 10.1007/s10875-022-01341-2. Epub 2022 Aug 10.

Cryptococcus gattii Infection as the Major Clinical Manifestation in Patients with Autoantibodies Against Granulocyte-Macrophage Colony-Stimulating Factor

Shang-Yu Wang ^#^{1

2}, Yu-Fang Lo ^#¹, Han-Po Shih ¹, Mao-Wang Ho ³, Chun-Fu Yeh ^{1

4}, Jhan-Jie Peng ¹, He-Ting Ting ¹, Kuo-Hsi Lin ⁵, Wen-Chi Huang ⁶, Yi-Chun Chen ⁶, Yu-Hsin Chiu ⁷, Chien-Wei Hsu ^{8

9}, Yu-Ting Tseng ¹⁰, Lih-Shinn Wang ¹¹, Wei-Yi Lei ¹², Chen-Yuan Lin ^{13

14}, Yu Aoh ¹⁵, Chia-Huei Chou ³, Tsai-Yi Wu ¹, Jing-Ya Ding ¹, Chia-Chi Lo ¹, You-Ning Lin ¹, Kun-Hua Tu ^{1

16}, Wei-Te Lei ^{1

17}, Chen-Yen Kuo ^{1

18}, Chih-Yu Chi ^{1

3

19}, Cheng-Lung Ku ^{20

21

22}

Affiliations

¹ Laboratory of Human Immunology and Infectious Diseases, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.
² Division of General Surgery, Department of Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
³ Division of Infectious Diseases, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan.
⁴ Division of Infectious Diseases, Department of Internal Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
⁵ Division of Infectious Diseases, Department of Internal Medicine, Tungs' Taichung MetroHarbor Hospital, Taichung, Taiwan.
⁶ Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
⁷ Division of Infectious Diseases, Department of Internal Medicine, Chi Mei Medical Center, Liouying, Tainan, Taiwan.
⁸ Department of Chest Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
⁹ School of Medicine, National Yang-Ming University, Taipei, Taiwan.
¹⁰ Section of Infectious Diseases, Department of Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
¹¹ Division of Infectious Disease, Department of Internal Medicine, Buddhist Tzu Chi General Hospital and Tzu Chi University, Hualien, Taiwan.
¹² Department of Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and Tzu Chi University, Hualien, Taiwan.
¹³ Department of Hematology and Oncology, China Medical University Hospital, Taichung, Taiwan.
¹⁴ School of Pharmacy, China Medical University, Taichung, Taiwan.
¹⁵ Neuroscience Laboratory, Department of Neurology, China Medical University Hospital, Taichung, Taiwan.
¹⁶ Kidney Research Center, Department of Nephrology, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
¹⁷ Section of Immunology, Rheumatology, and Allergy Department of Pediatrics, Hsinchu Mackay Memorial Hospital, Hsinchu City, Taiwan.
¹⁸ Division of Infectious Diseases, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan city, Taiwan.
¹⁹ School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan.
²⁰ Laboratory of Human Immunology and Infectious Diseases, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan. clku@cgu.edu.tw.
²¹ Department of Nephrology, Chang Gung Memorial Hospital, Taoyuan, Taiwan. clku@cgu.edu.tw.
²² Center for Clinical and Medical Immunology, Chang Gung University, Taoyuan, Taiwan. clku@cgu.edu.tw.

^# Contributed equally.

PMID: 35947322
DOI: 10.1007/s10875-022-01341-2

Cryptococcus gattii Infection as the Major Clinical Manifestation in Patients with Autoantibodies Against Granulocyte-Macrophage Colony-Stimulating Factor

Shang-Yu Wang et al. J Clin Immunol. 2022 Nov.

. 2022 Nov;42(8):1730-1741.

doi: 10.1007/s10875-022-01341-2. Epub 2022 Aug 10.

Authors

Shang-Yu Wang ^#^{1

2}, Yu-Fang Lo ^#¹, Han-Po Shih ¹, Mao-Wang Ho ³, Chun-Fu Yeh ^{1

4}, Jhan-Jie Peng ¹, He-Ting Ting ¹, Kuo-Hsi Lin ⁵, Wen-Chi Huang ⁶, Yi-Chun Chen ⁶, Yu-Hsin Chiu ⁷, Chien-Wei Hsu ^{8

9}, Yu-Ting Tseng ¹⁰, Lih-Shinn Wang ¹¹, Wei-Yi Lei ¹², Chen-Yuan Lin ^{13

14}, Yu Aoh ¹⁵, Chia-Huei Chou ³, Tsai-Yi Wu ¹, Jing-Ya Ding ¹, Chia-Chi Lo ¹, You-Ning Lin ¹, Kun-Hua Tu ^{1

16}, Wei-Te Lei ^{1

17}, Chen-Yen Kuo ^{1

18}, Chih-Yu Chi ^{1

3

19}, Cheng-Lung Ku ^{20

21

22}

Affiliations

¹ Laboratory of Human Immunology and Infectious Diseases, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.
² Division of General Surgery, Department of Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
³ Division of Infectious Diseases, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan.
⁴ Division of Infectious Diseases, Department of Internal Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
⁵ Division of Infectious Diseases, Department of Internal Medicine, Tungs' Taichung MetroHarbor Hospital, Taichung, Taiwan.
⁶ Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
⁷ Division of Infectious Diseases, Department of Internal Medicine, Chi Mei Medical Center, Liouying, Tainan, Taiwan.
⁸ Department of Chest Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
⁹ School of Medicine, National Yang-Ming University, Taipei, Taiwan.
¹⁰ Section of Infectious Diseases, Department of Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
¹¹ Division of Infectious Disease, Department of Internal Medicine, Buddhist Tzu Chi General Hospital and Tzu Chi University, Hualien, Taiwan.
¹² Department of Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and Tzu Chi University, Hualien, Taiwan.
¹³ Department of Hematology and Oncology, China Medical University Hospital, Taichung, Taiwan.
¹⁴ School of Pharmacy, China Medical University, Taichung, Taiwan.
¹⁵ Neuroscience Laboratory, Department of Neurology, China Medical University Hospital, Taichung, Taiwan.
¹⁶ Kidney Research Center, Department of Nephrology, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
¹⁷ Section of Immunology, Rheumatology, and Allergy Department of Pediatrics, Hsinchu Mackay Memorial Hospital, Hsinchu City, Taiwan.
¹⁸ Division of Infectious Diseases, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan city, Taiwan.
¹⁹ School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan.
²⁰ Laboratory of Human Immunology and Infectious Diseases, Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan. clku@cgu.edu.tw.
²¹ Department of Nephrology, Chang Gung Memorial Hospital, Taoyuan, Taiwan. clku@cgu.edu.tw.
²² Center for Clinical and Medical Immunology, Chang Gung University, Taoyuan, Taiwan. clku@cgu.edu.tw.

^# Contributed equally.

PMID: 35947322
DOI: 10.1007/s10875-022-01341-2

Abstract

Purpose: Anti-granulocyte-macrophage colony-stimulating factor autoantibodies (anti-GM-CSF Abs) are a predisposing factor for pulmonary alveolar proteinosis (PAP) and Cryptococcus gattii cryptococcosis. This study aimed to investigate clinical manifestations in anti-GM-CSF Ab-positive patients with C. gattii cryptococcosis and analyze the properties of anti-GM-CSF Abs derived from these patients and patients with PAP.

Methods: Thirty-nine patients diagnosed with cryptococcosis (caused by C. neoformans or C. gattii) and 6 with PAP were enrolled in the present study. Clinical information was obtained from medical records. Blood samples were collected for analysis of autoantibody properties. We also explored the National Health Insurance Research Database (NHIRD) of Taiwan to investigate the epidemiology of cryptococcosis and PAP.

Results: High titers of neutralizing anti-GM-CSF Abs were identified in 15 patients with cryptococcosis (15/39, 38.5%). Most anti-GM-CSF Ab-positive cryptococcosis cases had central nervous system (CNS) involvement (14/15, 93.3%). Eleven out of 14 (78.6%) anti-GM-CSF Ab-positive CNS cryptococcosis patients were confirmed to be infected with C. gattii, and PAP did not occur synchronously or metachronously in a single patient from our cohort. Exploration of an association between HLA and anti-GM-CSF Ab positivity or differential properties of autoantibodies from cryptococcosis patients and PAP yielded no significant results.

Conclusion: Anti-GM-CSF Abs can cause two diseases, C. gattii cryptococcosis and PAP, which seldom occur in the same subject. Current biological evidence regarding the properties of anti-GM-CSF Abs cannot provide clues regarding decisive mechanisms. Further analysis, including more extensive cohort studies and investigations into detailed properties, is mandatory to better understand the pathogenesis of anti-GM-CSF Abs.

Keywords: Anti-GM-CSF; Anti-cytokine; Autoantibody; Cryptococcus gattii; Pulmonary alveolar proteinosis.

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References

1. Browne SK. Anticytokine autoantibody-associated immunodeficiency. Annu Rev Immunol. 2014;1(32):635–57. - DOI
1. Ku CL, Chi CY, von Bernuth H, Doffinger R. Autoantibodies against cytokines: phenocopies of primary immunodeficiencies? Hum Genet. 2020;139(6–7):783–94. - PubMed - PMC - DOI
1. Vincent T, Plawecki MM, Goulabchand R, Guilpain P, Eliaou JFF. Emerging clinical phenotypes associated with anti-cytokine autoantibodies. Autoimmun Rev. 2015;14(6):528–35. - PubMed - DOI
1. Shih HP, Ding JY, Yeh CF, Chi CY, Ku CL. Anti-interferon-γ autoantibody-associated immunodeficiency. Curr Opin Immunol. 2021;72:206–14. - PubMed - DOI
1. Ben-Dov I, Segel MJ. Autoimmune pulmonary alveolar proteinosis: clinical course and diagnostic criteria. Autoimmun Rev. 2014;13(4–5):513–7. - PubMed - DOI

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[1] Browne SK. Anticytokine autoantibody-associated immunodeficiency. Annu Rev Immunol. 2014;1(32):635–57. - DOI

[2] Browne SK. Anticytokine autoantibody-associated immunodeficiency. Annu Rev Immunol. 2014;1(32):635–57. - DOI

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

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

[5] Vincent T, Plawecki MM, Goulabchand R, Guilpain P, Eliaou JFF. Emerging clinical phenotypes associated with anti-cytokine autoantibodies. Autoimmun Rev. 2015;14(6):528–35. - PubMed - DOI

[6] Vincent T, Plawecki MM, Goulabchand R, Guilpain P, Eliaou JFF. Emerging clinical phenotypes associated with anti-cytokine autoantibodies. Autoimmun Rev. 2015;14(6):528–35. - PubMed - DOI

[7] Shih HP, Ding JY, Yeh CF, Chi CY, Ku CL. Anti-interferon-γ autoantibody-associated immunodeficiency. Curr Opin Immunol. 2021;72:206–14. - PubMed - DOI

[8] Shih HP, Ding JY, Yeh CF, Chi CY, Ku CL. Anti-interferon-γ autoantibody-associated immunodeficiency. Curr Opin Immunol. 2021;72:206–14. - PubMed - DOI

[9] Ben-Dov I, Segel MJ. Autoimmune pulmonary alveolar proteinosis: clinical course and diagnostic criteria. Autoimmun Rev. 2014;13(4–5):513–7. - PubMed - DOI

[10] Ben-Dov I, Segel MJ. Autoimmune pulmonary alveolar proteinosis: clinical course and diagnostic criteria. Autoimmun Rev. 2014;13(4–5):513–7. - PubMed - DOI

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Cryptococcus gattii Infection as the Major Clinical Manifestation in Patients with Autoantibodies Against Granulocyte-Macrophage Colony-Stimulating Factor

Affiliations

Cryptococcus gattii Infection as the Major Clinical Manifestation in Patients with Autoantibodies Against Granulocyte-Macrophage Colony-Stimulating Factor

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