Separate checkpoints regulate splenic plasma cell accumulation and IgG autoantibody production in Lyn-deficient mice.
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.
Gutierrez
Toni
T
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Halcomb
Kristina E
KE
Coughran
Alanna J
AJ
Li
Quan-Zhen
QZ
Satterthwaite
Anne B
AB
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*
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
Immunity. 2008 Jul 18;29(1):138-49
18599325
Immunity. 1998 Apr;8(4):509-16
9586640
J Immunol. 2003 Aug 15;171(4):1850-8
12902486
Proc Natl Acad Sci U S A. 1989 Oct;86(19):7547-51
2798426
Nat Immunol. 2007 Sep;8(9):967-74
17581537
J Immunol. 2005 Jul 1;175(1):37-41
15972629
J Immunol. 2003 Aug 1;171(3):1319-27
12874221
Blood. 2009 May 7;113(19):4534-40
19224760
Immunity. 1997 Jul;7(1):69-81
9252121
J Clin Invest. 1994 Aug;94(2):585-91
8040314
Cell. 1995 Oct 20;83(2):301-11
7585947
Int Immunol. 2005 Sep;17(9):1179-91
16051621
J Immunol. 2002 Mar 15;168(6):2914-21
11884462
J Investig Med. 2001 Mar;49(2):157-65
11288756
Oncogene. 1999 Apr 8;18(14):2291-7
10327049
Nat Immunol. 2007 Apr;8(4):419-29
17322888
J Immunol. 2006 Mar 15;176(6):3635-41
16517732
Immunity. 1998 Apr;8(4):497-508
9586639
Proc Natl Acad Sci U S A. 2006 Jan 3;103(1):153-8
16371463
Nat Immunol. 2008 Feb;9(2):166-75
18157131
Immunol Rev. 2000 Jun;175:120-7
10933597
J Immunol. 2007 Jan 1;178(1):271-9
17182564
J Immunol. 2008 Dec 1;181(11):7770-7
19017966
J Exp Med. 1998 Sep 7;188(5):833-44
9730885
Clin Exp Immunol. 2007 Jan;147(1):60-70
17177964
J Immunol. 1991 Jul 1;147(1):117-23
2051017
J Exp Med. 2009 Jan 16;206(1):69-78
19139170
Immunity. 1995 Nov;3(5):549-60
7584145
Clin Exp Immunol. 1993 Feb;91(2):220-5
8428389
Eur J Immunol. 2007 Oct;37(10):2734-43
17853409
J Immunol. 2005 Sep 1;175(5):2880-9
16116174
Immunity. 2001 Oct;15(4):603-15
11672542
J Exp Med. 1997 May 5;185(9):1661-70
9151903
J Exp Med. 2004 Jun 7;199(11):1577-84
15173206
Cell Immunol. 2009;258(1):90-7
19393603
Nat Genet. 2008 Feb;40(2):204-10
18204446
Nature. 2005 May 26;435(7041):452-8
15917799
Int Immunol. 1991 Mar;3(3):273-8
2049341
Int Immunol. 1998 Apr;10(4):435-44
9620599
Immunity. 2005 Jan;22(1):9-18
15664155
Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):12905-10
14555759
J Immunol. 2002 Oct 15;169(8):4213-21
12370351
J Exp Med. 2007 Aug 6;204(8):1959-71
17664289
Immunity. 2002 Apr;16(4):535-46
11970877
J Immunol. 2000 Aug 1;165(3):1210-9
10903718
J Exp Med. 2009 Mar 16;206(3):561-76
19221396
J Immunol. 2006 Nov 15;177(10):7203-10
17082638
J Immunol. 2003 Aug 15;171(4):1684-90
12902466
J Immunol. 2001 Aug 15;167(4):2361-9
11490026