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Nature ; 611(7935): 352-357, 2022 11.
Article in English | MEDLINE | ID: covidwho-2264293


The vertebrate adaptive immune system modifies the genome of individual B cells to encode antibodies that bind particular antigens1. In most mammals, antibodies are composed of heavy and light chains that are generated sequentially by recombination of V, D (for heavy chains), J and C gene segments. Each chain contains three complementarity-determining regions (CDR1-CDR3), which contribute to antigen specificity. Certain heavy and light chains are preferred for particular antigens2-22. Here we consider pairs of B cells that share the same heavy chain V gene and CDRH3 amino acid sequence and were isolated from different donors, also known as public clonotypes23,24. We show that for naive antibodies (those not yet adapted to antigens), the probability that they use the same light chain V gene is around 10%, whereas for memory (functional) antibodies, it is around 80%, even if only one cell per clonotype is used. This property of functional antibodies is a phenomenon that we call light chain coherence. We also observe this phenomenon when similar heavy chains recur within a donor. Thus, although naive antibodies seem to recur by chance, the recurrence of functional antibodies reveals surprising constraint and determinism in the processes of V(D)J recombination and immune selection. For most functional antibodies, the heavy chain determines the light chain.

Antibodies , Clonal Selection, Antigen-Mediated , Immunoglobulin Heavy Chains , Immunoglobulin Light Chains , Animals , Amino Acid Sequence , Antibodies/chemistry , Antibodies/genetics , Antibodies/immunology , Antigens/chemistry , Antigens/immunology , B-Lymphocytes/cytology , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , Complementarity Determining Regions/chemistry , Complementarity Determining Regions/immunology , Immunoglobulin Heavy Chains/chemistry , Immunoglobulin Heavy Chains/genetics , Immunoglobulin Heavy Chains/immunology , Mammals , Immunoglobulin Light Chains/chemistry , Immunoglobulin Light Chains/genetics , Immunoglobulin Light Chains/immunology , Immunologic Memory , V(D)J Recombination , Clonal Selection, Antigen-Mediated/genetics , Clonal Selection, Antigen-Mediated/immunology
Curr Opin Immunol ; 72: 286-297, 2021 10.
Article in English | MEDLINE | ID: covidwho-1606955


Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is caused by mutations in the Autoimmune Regulator (AIRE) gene, which impair the thymic negative selection of self-reactive T-cells and underlie the development of autoimmunity that targets multiple endocrine and non-endocrine tissues. Beyond autoimmunity, APECED features heightened susceptibility to certain specific infections, which is mediated by anti-cytokine autoantibodies and/or T-cell driven autoimmune tissue injury. These include the 'signature' APECED infection chronic mucocutaneous candidiasis (CMC), but also life-threatening coronavirus disease 2019 (COVID-19) pneumonia, bronchiectasis-associated bacterial pneumonia, and sepsis by encapsulated bacteria. Here we discuss the expanding understanding of the immunological mechanisms that contribute to infection susceptibility in this prototypic syndrome of impaired central tolerance, which provide the foundation for devising improved diagnostic and therapeutic strategies for affected patients.

COVID-19/immunology , Candidiasis, Cutaneous/immunology , Polyendocrinopathies, Autoimmune/immunology , T-Lymphocytes/immunology , Transcription Factors/genetics , Animals , Autoimmunity , Bronchiectasis , COVID-19/epidemiology , COVID-19/genetics , Candidiasis, Cutaneous/epidemiology , Candidiasis, Cutaneous/genetics , Clonal Selection, Antigen-Mediated/genetics , Disease Susceptibility , Humans , Immune Tolerance/genetics , Polyendocrinopathies, Autoimmune/epidemiology , Polyendocrinopathies, Autoimmune/genetics