title: Separate checkpoints regulate splenic plasma cell accumulation and IgG autoantibody production in Lyn-deficient mice.
abstract: Accumulation of plasma cells and autoantibodies against nuclear antigens characterize both human and murine lupus. Understanding how these processes are controlled may reveal novel therapeutic targets for this disease. Mice deficient in Lyn, a negative regulator of B and myeloid cell activity, develop lupus-like autoimmune disease. Here, we show that lyn(-) (/) (-) mice exhibit increased splenic plasmablasts and plasma cells and produce IgM against a wide range of self-antigens. Both events require Btk, a target of Lyn-dependent inhibitory pathways. A Btk-dependent increase in the expression of the plasma cell survival factor IL-6 by lyn(-) (/) (-) splenic myeloid cells was also observed. Surprisingly, IL-6 was not required for plasma cell accumulation or polyclonal IgM autoreactivity in lyn(-/-) mice. IL-6 was, however, necessary for the production of IgG autoantibodies, which we show are focused towards a limited set of nucleic acid-containing and glomerular autoantigens in lyn(-) (/) (-) mice. A similar uncoupling of plasma cell accumulation from IgG autoantibodies was seen in lyn(+/-) mice. Plasma cell accumulation and polyclonal IgM autoreactivity are therefore controlled separately from, and are insufficient for, the production of IgG against lupus-associated autoantigens. Regulators of either of these two checkpoints may be attractive therapeutic targets for lupus.
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Toni
authors.initials: T
authors.lastname: Gutierrez
authors.forename: Kristina E
authors.initials: KE
authors.lastname: Halcomb
authors.forename: Alanna J
authors.initials: AJ
authors.lastname: Coughran
authors.forename: Quan-Zhen
authors.initials: QZ
authors.lastname: Li
authors.forename: Anne B
authors.initials: AB
authors.lastname: Satterthwaite
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D001324:Autoantigens / Q000276:immunology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046228:Microarray Analysis; D010950:Plasma Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D013154:Spleen / Q000473:pathology*; D019061:src-Family Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D000974:Antibodies, Antinuclear; D001324:Autoantigens; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D015850:Interleukin-6; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases
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