Comparing the immune abnormalities in MIS-C to healthy children and those with inflammatory disease reveals distinct inflammatory cytokine production and a monofunctional T cell response

Claire Butters; Ntombi Benede; Thandeka Moyo-Gwete; Simone I Richardson; Ursula Rohlwink; Muki Shey; Frances Ayres; Nelia P Manamela; Zanele Makhado; Sashkia R Balla; Mashudu Madzivhandila; Amkele Ngomti; Richard Baguma; Heidi Facey-Thomas; Timothy F Spracklen; Jonathan Day; Hamza van der Ross; Catherine Riou; Wendy A Burgers; Christiaan Scott; Liesl Zühlke; Penny L Moore; Roanne S Keeton; Kate Webb

doi:10.1016/j.clim.2023.109877

Comparing the immune abnormalities in MIS-C to healthy children and those with inflammatory disease reveals distinct inflammatory cytokine production and a monofunctional T cell response

Clin Immunol. 2024 Feb:259:109877. doi: 10.1016/j.clim.2023.109877. Epub 2023 Dec 22.

Authors

Claire Butters¹, Ntombi Benede², Thandeka Moyo-Gwete³, Simone I Richardson⁴, Ursula Rohlwink⁵, Muki Shey⁶, Frances Ayres⁷, Nelia P Manamela⁸, Zanele Makhado⁹, Sashkia R Balla¹⁰, Mashudu Madzivhandila⁹, Amkele Ngomti¹¹, Richard Baguma¹², Heidi Facey-Thomas¹³, Timothy F Spracklen¹⁴, Jonathan Day¹⁵, Hamza van der Ross¹⁶, Catherine Riou¹⁷, Wendy A Burgers¹⁸, Christiaan Scott¹⁹, Liesl Zühlke²⁰, Penny L Moore²¹, Roanne S Keeton²², Kate Webb²³

Affiliations

¹ Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital, University of Cape Town, Klipfontein Road, Rondebosch, 7700 Cape Town, South Africa; Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Anzio Road, Observatory, 7935 Cape Town, South Africa. Electronic address: [email protected].
² Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Anzio Road, Observatory, 7935 Cape Town, South Africa; Division of Medical Virology, Department of Pathology, University of Cape Town, Anzio Road, Observatory, 7935 Cape Town, South Africa. Electronic address: [email protected].
³ SA MRC Antibody Immunity Research Unit, School of Pathology, University of the Witwatersrand, Modderfontein Road, Sandringham, 2192 Johannesburg, South Africa; National Institute for Communicable Diseases of the National Health Laboratory Services, Modderfontein Road, Sandringham, 2192 Johannesburg, South Africa. Electronic address: [email protected].
⁴ SA MRC Antibody Immunity Research Unit, School of Pathology, University of the Witwatersrand, Modderfontein Road, Sandringham, 2192 Johannesburg, South Africa; National Institute for Communicable Diseases of the National Health Laboratory Services, Modderfontein Road, Sandringham, 2192 Johannesburg, South Africa. Electronic address: [email protected].
⁵ Division of Neurosurgery, Department of Surgery, Red Cross War Memorial Children's Hospital, University of Cape Town, Klipfontein Road, Rondebosch, 7700 Cape Town, South Africa; Neuroscience Institute, University of Cape Town, Anzio Road, Observatory, 7935 Cape Town, South Africa; Crick African Network, The Francis Crick Institute, Midland Road, London NW1 1AT, United Kingdom. Electronic address: [email protected].
⁶ Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Anzio Road, Observatory, 7935 Cape Town, South Africa; Department of Medicine, University of Cape Town, Anzio Road, Observatory, 7935 Cape Town, South Africa; Wellcome Centre for Infectious Diseases Research in Africa, University of Cape Town, Anzio Road, Observatory, 7935 Cape Town, South Africa. Electronic address: [email protected].
⁷ SA MRC Antibody Immunity Research Unit, School of Pathology, University of the Witwatersrand, Modderfontein Road, Sandringham, 2192 Johannesburg, South Africa; National Institute for Communicable Diseases of the National Health Laboratory Services, Modderfontein Road, Sandringham, 2192 Johannesburg, South Africa. Electronic address: [email protected].
⁸ SA MRC Antibody Immunity Research Unit, School of Pathology, University of the Witwatersrand, Modderfontein Road, Sandringham, 2192 Johannesburg, South Africa; National Institute for Communicable Diseases of the National Health Laboratory Services, Modderfontein Road, Sandringham, 2192 Johannesburg, South Africa. Electronic address: [email protected].
⁹ SA MRC Antibody Immunity Research Unit, School of Pathology, University of the Witwatersrand, Modderfontein Road, Sandringham, 2192 Johannesburg, South Africa; National Institute for Communicable Diseases of the National Health Laboratory Services, Modderfontein Road, Sandringham, 2192 Johannesburg, South Africa.
¹⁰ SA MRC Antibody Immunity Research Unit, School of Pathology, University of the Witwatersrand, Modderfontein Road, Sandringham, 2192 Johannesburg, South Africa; National Institute for Communicable Diseases of the National Health Laboratory Services, Modderfontein Road, Sandringham, 2192 Johannesburg, South Africa. Electronic address: [email protected].
¹¹ Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Anzio Road, Observatory, 7935 Cape Town, South Africa; Division of Medical Virology, Department of Pathology, University of Cape Town, Anzio Road, Observatory, 7935 Cape Town, South Africa. Electronic address: [email protected].
¹² Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Anzio Road, Observatory, 7935 Cape Town, South Africa; Division of Medical Virology, Department of Pathology, University of Cape Town, Anzio Road, Observatory, 7935 Cape Town, South Africa.
¹³ Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital, University of Cape Town, Klipfontein Road, Rondebosch, 7700 Cape Town, South Africa. Electronic address: [email protected].
¹⁴ Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital, University of Cape Town, Klipfontein Road, Rondebosch, 7700 Cape Town, South Africa; Cape Heart Institute, University of Cape Town, Anzio Road, Observatory, 7935 Cape Town, South Africa. Electronic address: [email protected].
¹⁵ Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital, University of Cape Town, Klipfontein Road, Rondebosch, 7700 Cape Town, South Africa.
¹⁶ Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital, University of Cape Town, Klipfontein Road, Rondebosch, 7700 Cape Town, South Africa. Electronic address: [email protected].
¹⁷ Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Anzio Road, Observatory, 7935 Cape Town, South Africa; Division of Medical Virology, Department of Pathology, University of Cape Town, Anzio Road, Observatory, 7935 Cape Town, South Africa; Wellcome Centre for Infectious Diseases Research in Africa, University of Cape Town, Anzio Road, Observatory, 7935 Cape Town, South Africa. Electronic address: [email protected].
¹⁸ Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Anzio Road, Observatory, 7935 Cape Town, South Africa; Division of Medical Virology, Department of Pathology, University of Cape Town, Anzio Road, Observatory, 7935 Cape Town, South Africa; Wellcome Centre for Infectious Diseases Research in Africa, University of Cape Town, Anzio Road, Observatory, 7935 Cape Town, South Africa. Electronic address: [email protected].
¹⁹ Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital, University of Cape Town, Klipfontein Road, Rondebosch, 7700 Cape Town, South Africa; Clinical Research Centre, University of Cape Town, Groote Schuur Hospital, Observatory, 7935 Cape Town, South Africa. Electronic address: [email protected].
²⁰ Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital, University of Cape Town, Klipfontein Road, Rondebosch, 7700 Cape Town, South Africa; Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Anzio Road, Observatory, 7935 Cape Town, South Africa; Cape Heart Institute, University of Cape Town, Anzio Road, Observatory, 7935 Cape Town, South Africa; South African Medical Research Council, Francie Van Zijl Drive, Parow Valley, 7501 Cape Town, South Africa. Electronic address: [email protected].
²¹ SA MRC Antibody Immunity Research Unit, School of Pathology, University of the Witwatersrand, Modderfontein Road, Sandringham, 2192 Johannesburg, South Africa; National Institute for Communicable Diseases of the National Health Laboratory Services, Modderfontein Road, Sandringham, 2192 Johannesburg, South Africa; Centre for the AIDS Programme of Research in South Africa, Umbilo Road, 4001 Durban, South Africa. Electronic address: [email protected].
²² Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Anzio Road, Observatory, 7935 Cape Town, South Africa; Division of Medical Virology, Department of Pathology, University of Cape Town, Anzio Road, Observatory, 7935 Cape Town, South Africa. Electronic address: [email protected].
²³ Department of Paediatrics and Child Health, Red Cross War Memorial Children's Hospital, University of Cape Town, Klipfontein Road, Rondebosch, 7700 Cape Town, South Africa; Crick African Network, The Francis Crick Institute, Midland Road, London NW1 1AT, United Kingdom. Electronic address: [email protected].

PMID: 38141746
DOI: 10.1016/j.clim.2023.109877

Abstract

Multisystem inflammatory syndrome in children (MIS-C) is a severe, hyperinflammatory disease that occurs after exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The underlying immune pathology of MIS-C is incompletely understood, with limited data comparing MIS-C to clinically similar paediatric febrile diseases at presentation. SARS-CoV-2-specific T cell responses have not been compared in these groups to assess whether there is a T cell profile unique to MIS-C. In this study, we measured inflammatory cytokine concentration and SARS-CoV-2-specific humoral immunity and T cell responses in children with fever and suspected MIS-C at presentation (n = 83) where MIS-C was ultimately confirmed (n = 58) or another diagnosis was made (n = 25) and healthy children (n = 91). Children with confirmed MIS-C exhibited distinctly elevated serum IL-10, IL-6, and CRP at presentation. No differences were detected in SARS-CoV-2 spike IgG serum concentration, neutralisation capacity, antibody dependant cellular phagocytosis, antibody dependant cellular cytotoxicity or SARS-CoV-2-specific T cell frequency between the groups. Healthy SARS-CoV-2 seropositive children had a higher proportion of polyfunctional SARS-CoV-2-specific CD4+ T cells compared to children with MIS-C and those with other inflammatory or infectious diagnoses, who both presented a largely monofunctional SARS-CoV-2-specific CD4+ T cell profile. Treatment with steroids and/or intravenous immunoglobulins resulted in rapid reduction of inflammatory cytokines but did not affect the SARS-CoV-2-specific IgG or CD4+ T cell responses in MIS-C. In these data, MIS-C had a unique cytokine profile but not a unique SARS-CoV-2 specific humoral or T cell cytokine response.

Keywords: Antibody effector function; Inflammatory cytokine profile; MIS-C; SARS-CoV-2-specific T cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antibodies, Viral
COVID-19* / complications
Child
Connective Tissue Diseases*
Cytokines
Fever
Humans
Immunoglobulin G
SARS-CoV-2
Systemic Inflammatory Response Syndrome*

Substances

Cytokines
Immunoglobulin G
Antibodies, Viral

Supplementary concepts

pediatric multisystem inflammatory disease, COVID-19 related

Grants and funding

MR/P028071/1/MRC_/Medical Research Council/United Kingdom