B cell IgM isotype regulates airway smooth muscle contraction in allergic asthma
Authors and Affiliations:
Sabelo Hadebe*1, Jermaine Khumalo1,2, Katelyn Jones1, Anca Savulescu4, Sandisiwe Mangali1,2, Amkele Ngomti1,2,Martyna Scibiorek1,2, Frank Kirstein1, Frank Brombacher*1,2,3
1Division of Immunology, and South African Medical Research Council (SAMRC) Immunology of Infectious Diseases, Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
2International Centre for Genetic Engineering and Biotechnology (ICGEB) and Institute of Infectious Diseases and Molecular Medicine (IDM), Division of Immunology, Health Science Faculty, University of Cape Town, Cape Town, South Africa
3Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa), Institute of Infectious Diseases and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town, 7925, South Africa
4Division of Chemical, Systems & Synthetic Biology, Faculty of Health Sciences, Institute of Infectious Disease & Molecular Medicine, University of Cape Town, Cape Town, South Africa
Allergic asthma is a disease driven by T helper 2 (TH2)-type cells secreting interleukin (IL-) 4, 5 and 13. It is characterized by eosinophils, airway hyperresponsiveness (AHR) and IgE secreting B cells. B cells play a role in allergic asthma in an allergen load dependent manner. IgM isotype secreted by naïve B cells is important for class switching. It is currently unclear how IgM isotype contributes in the development of allergic asthma. We investigated the role of IgM isotype in a house dust mite (HDM)-induced TH2 allergic asthma model. We sensitised wild type (wt), IgM-deficient (IgM-/-) and B cell-deficient (uMT-/-) mice with high (>10 ug) and low (<3 ug) dose of HDM extracts. We found IgM to be essential in IgE production and in AHR, but not in TH2 airway inflammation or eosinophilia. Transfer of wild type serum, but not B cells into IgM-/-mice could restore class switching but not AHR. RNA seq suggested that IgM regulated AHR through modulating airway smooth muscle (ASM) genes, particularly those associated with acetylcholine and contraction. Using single cell force cytometry (FLECS) and CRISPR-Cas9 technology we validate the importance of some of these genes in human ASM contraction. These unprecedented findings suggest that IgM has a unique function in allergic asthma and regulates AHR by interacting with structural cells.