SLAP deficiency decreases dsDNA autoantibody production.
Src-like adaptor protein (SLAP) adapts c-Cbl, an E3 ubiquitin ligase, to activated components of the BCR signaling complex regulating BCR levels and signaling in developing B cells. Based on this function, we asked whether SLAP deficiency could decrease the threshold for tolerance and eliminate development of autoreactive B cells in two models of autoantibody production. First, we sensitized mice with a dsDNA mimetope that causes an anti-dsDNA response. Despite equivalent production of anti-peptide antibodies compared to BALB/c controls, SLAP(-/-) mice did not produce anti-dsDNA. Second, we used the 56R tolerance model. SLAP(-/-) 56R mice had decreased levels of dsDNA-reactive antibodies compared to 56R mice due to skewed light chain usage. Thus, SLAP is a critical regulator of B-cell development and function and its deficiency leads to decreased autoreactive B cells that are otherwise maintained by inefficient receptor editing or failed negative selection.
Department of Pediatrics, National Jewish Health, 1400 Jackson Street, Denver, CO 80206, USA.
Lisa K
LK
Peterson
Department of Pediatrics, National Jewish Health, 1400 Jackson Street, Denver, CO 80206, USA.
Luke F
LF
Pennington
Department of Pediatrics, National Jewish Health, 1400 Jackson Street, Denver, CO 80206, USA.
Laura A
LA
Shaw
Department of Pediatrics, National Jewish Health, 1400 Jackson Street, Denver, CO 80206, USA.
Meredith
M
Brown
Department of Pediatrics, National Jewish Health, 1400 Jackson Street, Denver, CO 80206, USA.
Eric C
EC
Treacy
Department of Pediatrics, University of Colorado Denver, 13001 E. 17th Place, Aurora, CO 80045, USA; Department of Immunology, National Jewish Health, 1400 Jackson Street, Denver, CO 80206, USA.
Samantha F
SF
Friend
Department of Pediatrics, National Jewish Health, 1400 Jackson Street, Denver, CO 80206, USA.
Øyvind
Ø
Hatlevik
Department of Immunology, National Jewish Health, 1400 Jackson Street, Denver, CO 80206, USA.
Kira
K
Rubtsova
Department of Immunology, National Jewish Health, 1400 Jackson Street, Denver, CO 80206, USA.
Anatoly V
AV
Rubtsov
Department of Pediatrics, National Jewish Health, 1400 Jackson Street, Denver, CO 80206, USA; Department of Pediatrics, University of Colorado Denver, 13001 E. 17th Place, Aurora, CO 80045, USA; Department of Immunology, National Jewish Health, 1400 Jackson Street, Denver, CO 80206, USA; Division of Rheumatology, Colorado Children's Hospital, 13123 E. 16th Ave., Aurora, CO 80045, USA. Electronic address: dragonel@njhealth.org.
Leonard L
LL
Dragone
D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis* / Q000276:immunology; D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D004247:DNA / Q000276:immunology*; D005260:Female; D007143:Immunoglobulin Heavy Chains / Q000276:immunology / Q000378:metabolism; D007145:Immunoglobulin kappa-Chains / Q000276:immunology / Q000378:metabolism; D007146:Immunoglobulin lambda-Chains / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000172:deficiency* / Q000235:genetics; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism
D000974:Antibodies, Antinuclear; D007143:Immunoglobulin Heavy Chains; D007145:Immunoglobulin kappa-Chains; D007146:Immunoglobulin lambda-Chains; D011947:Receptors, Antigen, B-Cell; C095148:Sla protein, mouse; D004247:DNA; D016392:Proto-Oncogene Proteins pp60(c-src)
Autoantibodies; Autoimmunity; B cells