title: B cell autophagy mediates TLR7-dependent autoimmunity and inflammation.
abstract: Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease, defined by loss of B cell self-tolerance that results in production of antinuclear antibodies (ANA) and chronic inflammation. While the initiating events in lupus development are not well defined, overexpression of the RNA-recognizing toll-like receptor (TLR)7 has been linked to SLE in humans and mice. We postulated that autophagy plays an essential role in TLR7 activation of B cells for the induction of SLE by delivering RNA ligands to the endosomes, where this innate immune receptor resides. To test this hypothesis, we compared SLE development in Tlr7 transgenic (Tg) mice with or without B cell-specific ablation of autophagy (Cd19-Cre Atg5(f/f)). We observed that in the absence of B cell autophagy the 2 hallmarks of SLE, ANA and inflammation, were eliminated, thus curing these mice of lupus. This was also evident in the significantly extended survival of the autophagy-deficient mice compared to Tlr7.1 Tg mice. Furthermore, glomerulonephritis was ameliorated, and the serum levels of inflammatory cytokines in the knockout (KO) mice were indistinguishable from those of control mice. These data provide direct evidence that B cells require TLR7-dependent priming through an autophagy-dependent mechanism before autoimmunity is induced, thereafter involving many cell types. Surprisingly, hyper-IgM production persisted in Tlr7.1 Tg mice in the absence of autophagy, likely involving a different activation pathway than the production of autoantibodies. Furthermore, these mice still presented with anemia, but responded with a striking increase in extramedullary hematopoiesis (EMH), possibly due to the absence of pro-inflammatory cytokines.
authors.affiliation: a Graduate Program in Genetics; Sackler School of Graduate Biomedical Sciences; Tufts University School of Medicine ; Boston , MA , USA.
authors.forename: Chi G
authors.initials: CG
authors.lastname: Weindel
authors.forename: Lauren J
authors.initials: LJ
authors.lastname: Richey
authors.forename: Silvia
authors.initials: S
authors.lastname: Bolland
authors.forename: Abhiruchi J
authors.initials: AJ
authors.lastname: Mehta
authors.forename: John F
authors.initials: JF
authors.lastname: Kearney
authors.forename: Brigitte T
authors.initials: BT
authors.lastname: Huber
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D001343:Autophagy / Q000276:immunology*; D000071187:Autophagy-Related Protein 5; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D001947:Breeding; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism; D005838:Genotype; D006410:Hematopoiesis; D007075:Immunoglobulin M / Q000378:metabolism; D007249:Inflammation / Q000276:immunology* / Q000473:pathology*; D008099:Liver / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000819:agonists / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D013154:Spleen / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000819:agonists / Q000378:metabolism*
chemical_list: C495773:Atg5 protein, mouse; D001323:Autoantibodies; D000071187:Autophagy-Related Protein 5; D016207:Cytokines; D007075:Immunoglobulin M; D008562:Membrane Glycoproteins; D008869:Microtubule-Associated Proteins; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7
keywords: ANA, anti-nuclear Ab; Ab, antibody; Atg5 KO; B cells; B6, C57BL/6J; BM, bone marrow; BMD, BM derived; BMDM, BMD macrophages; BMDmDCs, BMD myeloid dendritic cells; BMDpDCs, BMD plasmacytoid dendritic cells; CFS3, colony stimulating factor 3 (granulocyte); CSF2, colony stimulating factor 2 (granulocyte-macrophage); DC, dendritic cell; ELISA, enzyme-linked immunosorbent assay; ELISpot, enzyme-linked immunospot assay; EMH, extramedullary hematopoiesis; FOB, follicular B cells; GMP, granulocyte-macrophage progenitor; H&E, hematoxylin and eosin stain; IFN, interferon; IHC, immunohistochemistry; IL, interleukin; Irf7, interferon regulatory factor 7; KO, knockout; LAP, LC3-associated phagocytosis; LPS, lipopolysaccharide; MZB, marginal zone B cells; MZP, marginal zone precursor B cells; NEAA, nonessential amino acids; O/N, overnight; PAS, periodic acid-Schiff; PC, phosphocholine; PCV, packed cell volume; PEMs, peritoneal macrophages; RBC, red blood cell; RT, room temperature; SLE, systemic lupus erythematosus; T1B, transitional 1 B cells; TLR, toll-like receptor; TLR7; Tg, transgenic; WT, wild type; YAA, Y-linked autoimmune accelerator; autoimmunity; ds, double stranded; inflammation; lupus; mDC, myeloid DC; pDC, plasmacytoid DC; ss, single stranded