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


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.


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.


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.


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

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