title: A mutated B cell chronic lymphocytic leukemia subset that recognizes and responds to fungi.
abstract: B cell chronic lymphocytic leukemia (CLL), the most common leukemia in adults, is a clonal expansion of CD5(+)CD19(+) B lymphocytes. Two types of CLLs are being distinguished as carrying either unmutated or somatically mutated immunoglobulins (Igs), which are associated with unfavorable and favorable prognoses, respectively. More than 30% of CLLs can be grouped based on their expression of stereotypic B cell receptors (BCRs), strongly suggesting that distinctive antigens are involved in the development of CLL. Unmutated CLLs, carrying Ig heavy chain variable (IGHV) genes in germline configuration, express low-affinity, poly-, and self-reactive BCRs. However, the antigenic specificity of CLLs with mutated IGHV-genes (M-CLL) remained elusive. In this study, we describe a new subset of M-CLL, expressing stereotypic BCRs highly specific for β-(1,6)-glucan, a major antigenic determinant of yeasts and filamentous fungi. β-(1,6)-glucan binding depended on both the stereotypic Ig heavy and light chains, as well as on a distinct amino acid in the IGHV-CDR3. Reversion of IGHV mutations to germline configuration reduced the affinity for β-(1,6)-glucan, indicating that these BCRs are indeed affinity-selected for their cognate antigen. Moreover, CLL cells expressing these stereotypic receptors proliferate in response to β-(1,6)-glucan. This study establishes a class of common pathogens as functional ligands for a subset of somatically mutated human B cell lymphomas.
authors.affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, 1012 ZA Amsterdam, The Netherlands.
authors.forename: Robbert
authors.initials: R
authors.lastname: Hoogeboom
authors.forename: Kok P M
authors.initials: KP
authors.lastname: van Kessel
authors.forename: Frans
authors.initials: F
authors.lastname: Hochstenbach
authors.forename: Thera A
authors.initials: TA
authors.lastname: Wormhoudt
authors.forename: Roy J A
authors.initials: RJ
authors.lastname: Reinten
authors.forename: Koen
authors.initials: K
authors.lastname: Wagner
authors.forename: Arnon P
authors.initials: AP
authors.lastname: Kater
authors.forename: Jeroen E J
authors.initials: JE
authors.lastname: Guikema
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Bende
authors.forename: Carel J M
authors.initials: CJ
authors.lastname: van Noesel
mesh_terms: D001230:Aspergillus / Q000378:metabolism; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism; D002175:Candida / Q000378:metabolism; D016022:Case-Control Studies; D049109:Cell Proliferation; D000939:Epitopes / Q000378:metabolism*; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007075:Immunoglobulin M / Q000235:genetics / Q000378:metabolism; D007135:Immunoglobulin Variable Region / Q000235:genetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D009154:Mutation; D011947:Receptors, Antigen, B-Cell / Q000235:genetics* / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012440:Saccharomyces / Q000378:metabolism; D014250:Trichosporon / Q000378:metabolism; D015003:Yeasts / Q000378:metabolism*; D047071:beta-Glucans / Q000276:immunology / Q000378:metabolism*
chemical_list: D000939:Epitopes; D007143:Immunoglobulin Heavy Chains; D007075:Immunoglobulin M; D007135:Immunoglobulin Variable Region; D011947:Receptors, Antigen, B-Cell; D011994:Recombinant Proteins; D047071:beta-Glucans; C064197:beta-1,6-glucan