Btk regulates localization, in vivo activation, and class switching of anti-DNA B cells.
The autoimmune disease systemic lupus erythematosus (SLE) is characterized by loss of tolerance to nuclear antigens such as chromatin, DNA, and RNA. This focused autoreactivity is thought to arise from the ability of DNA or RNA specific B cells to receive dual signals from the BCR and TLR9 or TLR7, respectively. The Tec kinase Btk is necessary for the production of anti-DNA antibodies in several murine models of SLE. To assess the role of Btk in the fate of DNA reactive B cells, we generated Btk-/- mice carrying the 56R anti-DNA Ig transgene on the C57BL/6 background. dsDNA specific B cells were present in 56R.Btk-/- mice, although they were not preferentially localized to the marginal zone. These cells were able to proliferate in response to large CpG DNA containing fragments that require BCR-induced internalization to access TLR9. However, anti-DNA antibodies were not observed in the serum of 56R.Btk-/- mice. A transgene expressing a low level of Btk in B cells (Btk(lo)) restored anti-DNA IgM in these mice. This correlated with partial rescue of proliferative response to BCR engagement and TLR9-induced IL-10 secretion in Btk(lo) B cells. anti-DNA IgG was not observed in 56R.Btk(lo) mice, however. This was likely due, at least in part, to a role for Btk in controlling the expression of T-bet and AID in cells stimulated with CpG DNA. Thus, Btk is required for the initial loss of tolerance to DNA and the subsequent production of pathogenic autoantibodies once tolerance is breached.
Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, United States.
Kristina E
KE
Halcomb
Sandirai
S
Musuka
Toni
T
Gutierrez
Heather L
HL
Wright
Anne B
AB
Satterthwaite
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D000974:Antibodies, Antinuclear / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D034961:Antigens, Nuclear / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D001402:B-Lymphocytes / Q000201:enzymology / Q000276:immunology*; D049109:Cell Proliferation; D018899:CpG Islands / Q000276:immunology; D055879:Gene Knock-In Techniques; D015322:Gene Rearrangement, B-Lymphocyte / Q000235:genetics / Q000276:immunology*; D018858:Germinal Center / Q000201:enzymology / Q000276:immunology; D007108:Immune Tolerance; D007075:Immunoglobulin M / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000276:immunology / Q000378:metabolism
D000974:Antibodies, Antinuclear; D034961:Antigens, Nuclear; D007075:Immunoglobulin M; D008562:Membrane Glycoproteins; D011947:Receptors, Antigen, B-Cell; C477038:Tlr7 protein, mouse; C495370:Tlr9 protein, mouse; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase