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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.

SUBMITTER: Kang HK

PROVIDER: S-EPMC3370101 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Megakaryocyte progenitors are the main APCs inducing Th17 response to lupus autoantigens and foreign antigens.

Kang Hee-Kap HK Chiang Ming-Yi MY Ecklund Diane D Zhang Li L Ramsey-Goldman Rosalind R Datta Syamal K SK

Journal of immunology (Baltimore, Md. : 1950) 20120504 12

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 pro ...[more]

PMID: 22561152

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Project description:Systemic lupus erythematosus (SLE) is characterized by production of a variety of autoantibodies. Although anti-double-stranded DNA (anti-dsDNA) antibodies contribute to the pathogenesis of lupus nephritis (LN), they are not sufficient for diagnosis and evaluation of disease activity. To obtain other autoantibodies associated with LN, we screened autoantigens reacting with the sera of LN patients by using an N-terminal biotinylated protein library created from a wheat cell-free protein production system. We screened 17 proteins that showed higher positive signals in the active phase than in the inactive phase of SLE, and higher positive signals in the serum of SLE patient with nephritis than in that of patient without nephritis. Of these, two LN-associated autoantigens, ribosomal RNA-processing protein 8 (RRP8) and spermatid nuclear transition protein 1 (TNP1) were identified by immunoprecipitation and immunofluorescence of renal tissues. Circulating anti-RRP8 and anti-TNP1 autoantibodies were recognized and deposited as an immune complex (IC) in glomeruli. IC was deposited preferentially in glomeruli rather than in other organs in C57BL/6 mice injected with RRP8 or TNP1. ELISA analysis of sera from patients with various rheumatic diseases demonstrated reactivity for RRP8 and TNP1 in 20% and 14.7% of SLE patients, respectively, whereas there was little or no reactivity in patients with other rheumatic diseases. Among SLE patients, 63.6% and 45.5% of those with LN were positive for anti-RRP8 and anti-TNP1 antibodies, compared with 12.5% and 9.4% of SLE patients without nephritis, respectively. Both proteins are cationic, and their respective antibodies did not cross-react with dsDNA. These proteins released from apoptotic cells form ICs with each autoantibody, and their ICs may become trapped at anionic sites in the glomerular basement membrane, leading to deposition in glomeruli. These autoantibodies may be useful for prediction of LN in subsets of SLE patients who are negative for anti-dsDNA antibodies.

Project description:BACKGROUND:Recent advances in single-cell techniques have provided the opportunity to finely dissect cellular heterogeneity within populations previously defined by "bulk" assays and to uncover rare cell types. In human hematopoiesis, megakaryocytes and erythroid cells differentiate from a shared precursor, the megakaryocyte-erythroid progenitor (MEP), which remains poorly defined. RESULTS:To clarify the cellular pathway in erythro-megakaryocyte differentiation, we correlate the surface immunophenotype, transcriptional profile, and differentiation potential of individual MEP cells. Highly purified, single MEP cells were analyzed using index fluorescence-activated cell sorting and parallel targeted transcriptional profiling of the same cells was performed using a specifically designed panel of genes. Differentiation potential was tested in novel, single-cell differentiation assays. Our results demonstrate that immunophenotypic MEP comprise three distinct subpopulations: "Pre-MEP," enriched for erythroid/megakaryocyte progenitors but with residual myeloid differentiation capacity; "E-MEP," strongly biased towards erythroid differentiation; and "MK-MEP," a previously undescribed, rare population of cells that are bipotent but primarily generate megakaryocytic progeny. Therefore, conventionally defined MEP are a mixed population, as a minority give rise to mixed-lineage colonies while the majority of cells are transcriptionally primed to generate exclusively single-lineage output. CONCLUSIONS:Our study clarifies the cellular hierarchy in human megakaryocyte/erythroid lineage commitment and highlights the importance of using a combination of single-cell approaches to dissect cellular heterogeneity and identify rare cell types within a population. We present a novel immunophenotyping strategy that enables the prospective identification of specific intermediate progenitor populations in erythro-megakaryopoiesis, allowing for in-depth study of disorders including inherited cytopenias, myeloproliferative disorders, and erythromegakaryocytic leukemias.

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Megakaryocyte progenitors are the main APCs inducing Th17 response to lupus autoantigens and foreign antigens.

Publications

Megakaryocyte progenitors are the main APCs inducing Th17 response to lupus autoantigens and foreign antigens.

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