Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.


An Intrinsic B Cell Defect That Affects Toll-Like Receptor Signaling Supports Autoimmunity in New Zealand Black Chromosome 13 Congenic Mice.

Loh2,  Christina, Pau3,  Evelyn, Chang1,  Nan-Hua, Wither2,  Joan E.

University Health Network
University of Toronto, Toronto, ON, Canada
University of Toronto

Purpose:

Introgression of a New Zealand Black (NZB) chromosome 13 interval onto the B6 background (denoted, c13) is sufficient to produce many of the hallmarks of lupus, including, high titre anti-chromatin antibody (Ab) production, abnormal B and T cell activation, and renal disease. In this study we sought to characterize the immune defects leading to these pathogenic abnormalities.

Methods:

Bone marrow (BM) chimeras were generated by reconstituting lethally irradiated B6, B6.Thy1aIgHa, or B6.CD45.1 mice with B6, B6.Thy1aIgHa, B6.CD45.1, c13, c13.Ig, or various mixtures of BM cells. Anti-hen egg lysozyme (HEL) immunoglobulin (Ig) and/or soluble HEL transgenes (Tg) were crossed onto the c13 mouse strain (denoted, c13.Ig and c13.Ig.sHEL) to assess B cell tolerance. Antibody production was measured by ELISA and splenic cellular profiles were examined by flow cytometry. For Toll-like receptor (TLR) stimulation, splenocytes from 10–14 week old B6, c13, B6.Ig, or c13.Ig mice were cultured in the presence of poly(I:C) (TLR3), imiquimod (TLR7), or ODN1826 (TLR9) and/or HEL for 72 hrs. Proliferation was measured by CFSE dilution.

Results:

Serologic and cellular characterization of hematopoietic radiation chimeras and anti-HEL Ig transgenic mice revealed that the autoimmune phenotype in c13 mice could be transferred by BM cells. Assessment of mixed hematopoietic chimeric and c13.Ig mice indicated that autoreactive congenic B cells were required for disease initiation. Examination of c13.Ig.sHEL mice, a classic model of B cell anergy, revealed that B cell anergy was intact in congenic mice. However, there was enhanced selection and/or survival of endogenous B cells resulting in high titer anti-chromatin and -Sm/RNP antibody production in these mice. Given the preferential generation of anti-nuclear over anti-HEL antibodies, we examined whether nucleic-acid sensing TLR signaling was altered in these mice. Congenic B cells were hyper-responsive to the TLR3 ligand, polyinosine-polycytidylic acid (poly(I:C)), a double stranded RNA analogue, demonstrating enhanced proliferation, survival, and induction of intracellular TLR3 expression as compared to control B cells. Using mixed cell cultures, this response was found to be intrinsic to congenic B cells.

Conclusions:

An intrinsic defect affecting self-reactive B cell selection and/or function that is associated with TLR3-hyper-responsiveness is required for initiation of autoimmunity in NZB chromosome 13 congenic mice.

To cite this abstract, please use the following information:
Loh, Christina, Pau, Evelyn, Chang, Nan-Hua, Wither, Joan E.; An Intrinsic B Cell Defect That Affects Toll-Like Receptor Signaling Supports Autoimmunity in New Zealand Black Chromosome 13 Congenic Mice. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :424
DOI: 10.1002/art.28193

Abstract Supplement

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