title: Critical role of CD4 T cells in PF4/heparin antibody production in mice.
abstract: Antibodies specific for platelet factor 4 (PF4)/heparin complexes are central to the pathogenesis of heparin-induced thrombocytopenia. Marginal zone B cells appear to be the source of such antibodies, but whether T-cell help is required is unclear. Here, we showed that induction of PF4/heparin-specific antibodies by PF4/heparin complexes was markedly impaired in mice depleted of CD4 T cells by anti-CD4 antibodies. Furthermore, Rag1-deficient recipient mice produced PF4/heparin-specific antibodies upon PF4/heparin challenge when reconstituted with a mixture of wild-type splenic B cells and splenocytes from B-cell-deficient (μMT) mice but not splenocytes from T- and B-cell-deficient (Rag1 knockout) mice. Lastly, mice with B cells lacking CD40, a B-cell costimulatory molecule that helps T-cell-dependent B-cell responses, displayed a marked reduction of PF4/heparin-specific antibody production following PF4/heparin challenge. Together, these findings show that helper T cells play a critical role in production of PF4/heparin-specific antibodies.
authors.affiliation: Key Laboratory of Developmental Genes and Human Disease, Ministry of Education, Institute of Life Science, Southeast University, Nanjing, People's Republic of China; and Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI.
authors.forename: Yongwei
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI.
authors.forename: Mei
authors.initials: M
authors.lastname: Yu
authors.affiliation: Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI.
authors.forename: Anand
authors.initials: A
authors.lastname: Padmanabhan
authors.affiliation: Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Aster
authors.affiliation: Key Laboratory of Developmental Genes and Human Disease, Ministry of Education, Institute of Life Science, Southeast University, Nanjing, People's Republic of China; and.
authors.forename: Liudi
authors.initials: L
authors.lastname: Yuan
authors.affiliation: Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI.
authors.forename: Renren
authors.initials: R
authors.lastname: Wen
authors.affiliation: Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI.
authors.forename: Demin
authors.identifier: http://orcid.org/0000-0001-5549-3795
authors.initials: D
authors.lastname: Wang
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000917:Antibody Formation; D000918:Antibody Specificity; D001402:B-Lymphocytes / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D004195:Disease Models, Animal; D006493:Heparin / Q000009:adverse effects / Q000737:chemistry / Q000276:immunology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology; D006801:Humans; D007114:Immunization; D008212:Lymphocyte Depletion; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010978:Platelet Factor 4 / Q000737:chemistry / Q000276:immunology*; D013921:Thrombocytopenia / Q000097:blood / Q000209:etiology / Q000276:immunology; D018183:Transplantation Chimera
chemical_list: D018398:Homeodomain Proteins; C064658:RAG-1 protein; D010978:Platelet Factor 4; D006493:Heparin