title: Loss of anergic B cells in prediabetic and new-onset type 1 diabetic patients.
abstract: Although dogma predicts that under normal circumstances, potentially offensive autoreactive cells are silenced by mechanisms of immune tolerance, islet antigen-reactive B lymphocytes are known to play a crucial role in the development of autoimmunity in type 1 diabetes (T1D). Thus, participation of these cells in T1D may reflect escape from silencing mechanisms. Consistent with this concept, we found that in healthy subjects, high-affinity insulin-binding B cells occur exclusively in the anergic naive IgD(+), IgM(-) B-cell (BND) compartment. Antigen receptors expressed by these cells are polyreactive and have N-region additions, Vh usage, and charged complementarity-determining region 3 consistent with autoreactivity. Consistent with a potential early role in autoimmunity, these high-affinity insulin-binding B cells are absent from the anergic compartment of some first-degree relatives and all prediabetic and new-onset (<1 year) T1D patients tested, but return to normal levels in individuals diabetic for >1 year. Interestingly, these changes were correlated by transient loss of the entire BND compartment. These findings suggest that environmental events such as infection or injury may, by disrupting B-cell anergy, dispose individuals toward autoimmunity, the precise nature of which is specified by genetic risk factors, such as HLA alleles.
authors.affiliation: Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO.
authors.forename: Mia J
authors.initials: MJ
authors.lastname: Smith
authors.affiliation: Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Packard
authors.affiliation: Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO.
authors.forename: Shannon K
authors.initials: SK
authors.lastname: O'Neill
authors.affiliation: Section of Rheumatology, Department of Medicine, University of Chicago, Chicago, IL.
authors.forename: Carole J
authors.initials: CJ
authors.lastname: Henry Dunand
authors.affiliation: Section of Rheumatology, Department of Medicine, University of Chicago, Chicago, IL.
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.affiliation: Barbara Davis Center, University of Colorado School of Medicine, Aurora, CO.
authors.forename: Lisa
authors.initials: L
authors.lastname: Fitzgerald-Miller
authors.affiliation: Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO.
authors.forename: Daniel
authors.initials: D
authors.lastname: Stowell
authors.affiliation: Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO.
authors.forename: Rochelle M
authors.initials: RM
authors.lastname: Hinman
authors.affiliation: Section of Rheumatology, Department of Medicine, University of Chicago, Chicago, IL.
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Wilson
authors.affiliation: Barbara Davis Center, University of Colorado School of Medicine, Aurora, CO.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Gottlieb
authors.affiliation: Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO john.cambier@ucdenver.edu.
authors.forename: John C
authors.initials: JC
authors.lastname: Cambier
mesh_terms: D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D001324:Autoantigens; D001402:B-Lymphocytes / Q000276:immunology / Q000502:physiology*; D017635:Clonal Anergy / Q000502:physiology*; D003001:Cloning, Molecular; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics / Q000378:metabolism; D011236:Prediabetic State
chemical_list: D015703:Antigens, CD; D001324:Autoantigens; D007136:Immunoglobulins