The lupus-related Lmb3 locus contains a disease-suppressing Coronin-1A gene mutation.
Here, we show that a lupus-suppressing locus is caused by a nonsense mutation of the filamentous actin-inhibiting Coronin-1A gene. This mutation was associated with developmental and functional alterations in T cells including reduced migration, survival, activation, and Ca2+ flux. T-dependent humoral responses were impaired, but no intrinsic B cell defects were detected. By transfer of T cells, it was shown that suppression of autoimmunity could be accounted for by the presence of the Coro1a(Lmb3) mutation in T cells. Our results demonstrate that Coronin-1A is required for the development of systemic lupus and identify actin-cytoskeleton regulatory proteins as potential targets for modulating autoimmune diseases.
Haraldsson
M Katarina
MK
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Louis-Dit-Sully
Christine A
CA
Lawson
Brian R
BR
Sternik
Gabriel
G
Santiago-Raber
Marie-Laure
ML
Gascoigne
Nicholas R J
NR
Theofilopoulos
Argyrios N
AN
Kono
Dwight H
DH
D000199:Actins / Q000378:metabolism; D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D049109:Cell Proliferation; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D018389:Codon, Nonsense; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D020022:Genetic Predisposition to Disease; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D007150:Immunohistochemistry; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology*; D014162:Transfection
D000199:Actins; D001323:Autoantibodies; D018389:Codon, Nonsense; D007074:Immunoglobulin G; D008840:Microfilament Proteins; C072061:coronin proteins