title: Megakaryocyte progenitors are the main APCs inducing Th17 response to lupus autoantigens and foreign antigens.
abstract: In search of autoantigen-presenting cells that prime the pathogenic autoantibody-inducing Th cells of lupus, we found that CD41(+)CD151(+) cells among Lineage(-) (Lin(-)) CD117(+) (c-Kit(+)) CX3CR1(-) splenocytes depleted of known APCs were most proficient in presenting nuclear autoantigens from apoptotic cells to induce selectively an autoimmune Th17 response in different lupus-prone mouse strains. The new APCs have properties resembling megakaryocyte and/or bipotent megakaryocyte/erythroid progenitors of bone marrow, hence they are referred to as MM cells in this study. The MM cells produce requisite cytokines, but they require contact for optimal Th17 induction upon nucleosome feeding, and can induce Th17 only before undergoing differentiation to become c-Kit(-)CD41(+) cells. The MM cells expand up to 10-fold in peripheral blood of lupus patients and 49-fold in spleens of lupus mice preceding disease activity; they accelerate lupus in vivo and break tolerance in normal mice, inducing autoimmune Th17 cells. MM cells also cause Th17 skewing to foreign Ag in normal mice without Th17-polarizing culture conditions. Several molecules in MM cells are targets for blocking of autoimmunization. This study advances our understanding of lupus pathogenesis and Th17 differentiation biology by characterizing a novel category of APC.
authors.affiliation: Division of Rheumatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Hee-Kap
authors.initials: HK
authors.lastname: Kang
authors.forename: Ming-Yi
authors.initials: MY
authors.lastname: Chiang
authors.forename: Diane
authors.initials: D
authors.lastname: Ecklund
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Rosalind
authors.initials: R
authors.lastname: Ramsey-Goldman
authors.forename: Syamal K
authors.initials: SK
authors.lastname: Datta
mesh_terms: D000328:Adult; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D000938:Antigen-Presenting Cells / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002469:Cell Separation; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D055016:Megakaryocyte Progenitor Cells / Q000276:immunology*; D051379:Mice; D008817:Mice, Mutant Strains; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D001324:Autoantigens