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* Department of Internal Medicine, Section of Allergy and Clinical Immunology, Yale University School of Medicine, New Haven, CT 06520;
Department of Human Developmental Biology, Jagiellonian University, College of Medicine, Krakow, Poland; and
Department of Genetics, Stanford School of Medicine, Stanford University, Stanford, CA 94305
Contact sensitivity (CS) is related to delayed-type hypersensitivity and is a well-characterized prototype of T cell-mediated inflammation. However, the inflammatory response associated with CS is additionally dependent on Ag-specific IgM produced by a subpopulation of B cells in response to sensitization. Upon re-exposure to hapten, this IgM mediates rapid vascular activation and subsequent recruitment of proinflammatory T cells to the local site. Interference with this pathway prevents the full development of the classic delayed inflammatory response and is therefore termed the "CS initiation" pathway. In this study, we show that CS initiation is defective in mice deficient in activation-induced deaminase, an enzyme central to the process of somatic hypermutation. Using adoptive transfer experiments, we demonstrate that the defect is specific to a B-1-like population of B cells and that transfer of WT cells reconstitutes CS initiation mechanisms in deficient recipients. We went on to identify a novel subpopulation of Ag-binding B cells in the spleens of sensitized mice that possess initiation activity (CD19+CD5+Thy-1intIgMhighIgDhigh) that we name "initiator B cells." Analysis of BCR H chain genes isolated from these cells revealed evidence of activation-induced deaminase-mediated somatic hypermutation. The sensitivity of CS initiation to very low amounts of sensitizing hapten suggests that the responsible B cells have increased IgM receptor gene mutations enabling selection to generate Abs with sufficient affinity to mediate the response.
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1 This work was supported in part by grants from the National Institutes of Health (AI-59801), the American Academy of Allergy Asthma and Immunology, and the Polish Committee of Scientific Research. S.M.K. is funded by a fellowship from the Canadian Institutes of Health Research.
2 Current address: One Breakthrough Way, Nevada Cancer Institute, Las Vegas, NV 89135. E-mail address: jtung{at}nvcancer.org
3 Address correspondence and reprint requests to Dr. Philip Askenase, Department of Internal Medicine, Section of Allergy and Clinical Immunology, Yale University School of Medicine, 333 Cedar Street, P.O. Box 208013, New Haven, CT 06520. E-mail address: Philip.Askenase{at}yale.edu
4 Abbreviations used in this paper: DTH, delayed-type hypersensitivity; AID, activation-induced deaminase; CS, contact sensitivity; DNFB, 2,4-dinitro-1-fluorobenzene; PerC, peritoneal cavity; SHM, somatic hypermutation; TNP-Cl, picryl chloride; PI, propidium iodide; WT, wild type.
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