Prevalence of Anti-lymphocyte IgM Autoantibodies Driving Complement Activation in COVID-19 Patients

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2024 May 2

PMID 38694513

Authors

Ainhoa Perez-Diez

Xiangdong Liu

Stephanie Calderon

Ashlynn Bennett

Andrea Lisco

Anela Kellog

Frances Galindo

Matthew J Memoli

Joseph M Rocco

Brian P Epling

Elizabeth Laidlaw

Mike C Sneller

Maura Manion

Glenn W Wortmann

Rita Poon

Princy Kumar

Irini Sereti

Affiliations

Soon will be listed here.

Abstract

Introduction: COVID-19 patients can develop autoantibodies against a variety of secreted and membrane proteins, including some expressed on lymphocytes. However, it is unclear what proportion of patients might develop anti-lymphocyte antibodies (ALAb) and what functional relevance they might have.

Methods: We evaluated the presence and lytic function of ALAb in the sera of a cohort of 85 COVID-19 patients (68 unvaccinated and 17 vaccinated) assigned to mild (N=63), or moderate/severe disease (N=22) groups. Thirty-seven patients were followed-up after recovery. We also analyzed in vivo complement deposition on COVID-19 patients' lymphocytes and examined its correlation with lymphocyte numbers during acute disease.

Results: Compared with healthy donors (HD), patients had an increased prevalence of IgM ALAb, which was significantly higher in moderate/severe disease patients and persisted after recovery. Sera from IgM ALAb+ patients exhibited complement-dependent cytotoxicity (CDC) against HD lymphocytes. Complement protein C3b deposition on patients' CD4 T cells was inversely correlated with CD4 T cell numbers. This correlation was stronger in moderate/severe disease patients.

Discussion: IgM ALAb and complement activation against lymphocytes may contribute to the acute lymphopenia observed in COVID-19 patients.

References

Sneller M, Liang C, Marques A, Chung J, Shanbhag S, Fontana J . A Longitudinal Study of COVID-19 Sequelae and Immunity: Baseline Findings. Ann Intern Med. 2022; 175(7):969-979. PMC: 9128805. DOI: 10.7326/M21-4905. View

Wong A, Woodhouse I, Schneider F, Kulpa D, Silvestri G, Maier C . Broad auto-reactive IgM responses are common in critically ill patients, including those with COVID-19. Cell Rep Med. 2021; 2(6):100321. PMC: 8160082. DOI: 10.1016/j.xcrm.2021.100321. View

Memoli M, Czajkowski L, Reed S, Athota R, Bristol T, Proudfoot K . Validation of the wild-type influenza A human challenge model H1N1pdMIST: an A(H1N1)pdm09 dose-finding investigational new drug study. Clin Infect Dis. 2014; 60(5):693-702. PMC: 4342672. DOI: 10.1093/cid/ciu924. View

Ackermann M, Verleden S, Kuehnel M, Haverich A, Welte T, Laenger F . Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19. N Engl J Med. 2020; 383(2):120-128. PMC: 7412750. DOI: 10.1056/NEJMoa2015432. View

Rodrigues T, de Sa K, Ishimoto A, Becerra A, Oliveira S, Almeida L . Inflammasomes are activated in response to SARS-CoV-2 infection and are associated with COVID-19 severity in patients. J Exp Med. 2020; 218(3). PMC: 7684031. DOI: 10.1084/jem.20201707. View

Wan Y, Shang J, Graham R, Baric R, Li F . Receptor Recognition by the Novel Coronavirus from Wuhan: an Analysis Based on Decade-Long Structural Studies of SARS Coronavirus. J Virol. 2020; 94(7). PMC: 7081895. DOI: 10.1128/JVI.00127-20. View

Franke C, Ferse C, Kreye J, Reincke S, Sanchez-Sendin E, Rocco A . High frequency of cerebrospinal fluid autoantibodies in COVID-19 patients with neurological symptoms. Brain Behav Immun. 2020; 93:415-419. PMC: 7834471. DOI: 10.1016/j.bbi.2020.12.022. View

Carvelli J, Demaria O, Vely F, Batista L, Chouaki Benmansour N, Fares J . Association of COVID-19 inflammation with activation of the C5a-C5aR1 axis. Nature. 2020; 588(7836):146-150. PMC: 7116884. DOI: 10.1038/s41586-020-2600-6. View

Lobo P . Role of Natural Autoantibodies and Natural IgM Anti-Leucocyte Autoantibodies in Health and Disease. Front Immunol. 2016; 7:198. PMC: 4893492. DOI: 10.3389/fimmu.2016.00198. View

10.

Lage S, Rocco J, Laidlaw E, Rupert A, Galindo F, Kellogg A . Activation of Complement Components on Circulating Blood Monocytes From COVID-19 Patients. Front Immunol. 2022; 13:815833. PMC: 8892247. DOI: 10.3389/fimmu.2022.815833. View

11.

Blanco-Melo D, Nilsson-Payant B, Liu W, Uhl S, Hoagland D, Moller R . Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19. Cell. 2020; 181(5):1036-1045.e9. PMC: 7227586. DOI: 10.1016/j.cell.2020.04.026. View

12.

Zhang Y, Xiao M, Zhang S, Xia P, Cao W, Jiang W . Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19. N Engl J Med. 2020; 382(17):e38. PMC: 7161262. DOI: 10.1056/NEJMc2007575. View

13.

Gao T, Zhu L, Liu H, Zhang X, Wang T, Fu Y . Highly pathogenic coronavirus N protein aggravates inflammation by MASP-2-mediated lectin complement pathway overactivation. Signal Transduct Target Ther. 2022; 7(1):318. PMC: 9470675. DOI: 10.1038/s41392-022-01133-5. View

14.

Gagiannis D, Steinestel J, Hackenbroch C, Schreiner B, Hannemann M, Bloch W . Clinical, Serological, and Histopathological Similarities Between Severe COVID-19 and Acute Exacerbation of Connective Tissue Disease-Associated Interstitial Lung Disease (CTD-ILD). Front Immunol. 2020; 11:587517. PMC: 7566417. DOI: 10.3389/fimmu.2020.587517. View

15.

Wang Y, Wang Y, Luo W, Huang L, Xiao J, Li F . A comprehensive investigation of the mRNA and protein level of ACE2, the putative receptor of SARS-CoV-2, in human tissues and blood cells. Int J Med Sci. 2020; 17(11):1522-1531. PMC: 7359402. DOI: 10.7150/ijms.46695. View

16.

Horby P, Lim W, Emberson J, Mafham M, Bell J, Linsell L . Dexamethasone in Hospitalized Patients with Covid-19. N Engl J Med. 2020; 384(8):693-704. PMC: 7383595. DOI: 10.1056/NEJMoa2021436. View

17.

Wang E, Mao T, Klein J, Dai Y, Huck J, Jaycox J . Diverse functional autoantibodies in patients with COVID-19. Nature. 2021; 595(7866):283-288. DOI: 10.1038/s41586-021-03631-y. View

18.

Castleman M, Stumpf M, Therrien N, Smith M, Lesteberg K, Palmer B . SARS-CoV-2 infection relaxes peripheral B cell tolerance. J Exp Med. 2022; 219(6). PMC: 9014793. DOI: 10.1084/jem.20212553. View

19.

Liu Y, Ebinger J, Mostafa R, Budde P, Gajewski J, Walker B . Paradoxical sex-specific patterns of autoantibody response to SARS-CoV-2 infection. J Transl Med. 2021; 19(1):524. PMC: 8716184. DOI: 10.1186/s12967-021-03184-8. View

20.

. Increased complement activation is a distinctive feature of severe SARS-CoV-2 infection. Sci Immunol. 2021; 6(59). PMC: 8158979. DOI: 10.1126/sciimmunol.abh2259. View