title: Activation-induced cytidine deaminase and aberrant germinal center selection in the development of humoral autoimmunities.
abstract: Humoral immunity, which is the branch of the immune system governed by B cells, protects the body from extracellular pathogens through the secretion of immunoglobulins. Given the unpredictability of exogenous antigens, B cells must be accommodating to numerous genetic alterations to mold immunoglobulin specificity to recognize offending pathogens. Abnormalities in this process leave the host susceptible to permanent pathological modifications and in particular humoral autoimmunities in which secreted immunoglobulins mistake host proteins as pathogenic targets. Underlying the development of self-reactive immunoglobulins is activation-induced cytidine deaminase (AID), a mutagenic enzyme responsible for modifying the specificity of B cells by producing point mutations at the immunoglobulin gene locus. Ideally, these mutations result in an increased affinity for exogenous antigens. However, in pathological scenarios, these mutations produce or enhance a B cell's ability to target the host. AID-induced mutations occur in the germinal center microenvironment of peripheral lymphoid tissue, where pathogenic B-cell clones must evade overwhelming selection pressures to be released systemically. Recent research has revealed numerous genes and pathways responsible for eliminating self-reactive clones within the germinal center. On the basis of these studies, this review aims to clarify the link between AID and the generation of pathogenic immunoglobulins. Furthermore, it describes the selective pressures that pathogenic B cells must bypass within the germinal center to secrete immunoglobulins that ultimately result in disease.
authors.affiliation: Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Zaheen
authors.forename: Alberto
authors.initials: A
authors.lastname: Martin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D003564:Cytidine Deaminase / Q000378:metabolism*; D018858:Germinal Center / Q000276:immunology*; D006801:Humans; D056724:Immunity, Humoral / Q000276:immunology*; D007136:Immunoglobulins / Q000235:genetics / Q000276:immunology; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D007136:Immunoglobulins; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase