In:
The Journal of Immunology, The American Association of Immunologists, Vol. 192, No. 1_Supplement ( 2014-05-01), p. 46.7-46.7
Abstract:
Systemic lupus erythematosus (SLE) is an autoimmune disease with a high incidence in females and a complex phenotype. Using 564Igi mice, a model of SLE with knock-in genes encoding an auto-reactive anti-RNA antibody, we investigated how expression of Toll-like receptors (TLRs) in B cells and neutrophils affects pathogenesis. We established that TLR signaling through MyD88 is necessary for disease. Autoantibody was produced in mice with single deletions of Tlr7, Tlr8 or Tlr9. Autoantibody was produced in female mice with the combined deletions of Tlr7 and 9, but not in male mice. Autoantibody was not produced in the combined absence of Tlr7 and 8 in either sex, indicating that TLR8 contributes to the break in tolerance in females. Furthermore, TLR8 was sufficient for the loss of B cell tolerance, the production of class-switched autoantibody, heightened granulopoiesis, and increased production of type I interferon (IFN-I) by neutrophils as well as glomerulonephritis and death. We show that dosage of X-linked Tlr8 plays a major role in the high incidence of disease in female mice. In addition, we show that the negative regulation of disease by TLR9 is exerted primarily on granulopoiesis and IFN-I production by neutrophils. Collectively, we suggest that individual TLRs play unique roles in the pathogenesis of SLE, suggesting new targets for treatment.
Type of Medium:
Online Resource
ISSN:
0022-1767
,
1550-6606
DOI:
10.4049/jimmunol.192.Supp.46.7
Language:
English
Publisher:
The American Association of Immunologists
Publication Date:
2014
detail.hit.zdb_id:
1475085-5
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