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Eur J Immunol. 2013 Sep;43(9):2441-2450. doi: 10.1002/eji.201343412. Epub 2013 Jul 3.

Complement C4 maintains peripheral B-cell tolerance in a myeloid cell dependent manner.

Author information

1
Program in Cellular and Molecular Medicine, Childrens Hospital, Harvard Medical School, Boston, MA, USA.
2
Graduate Program in Immunology, Division of Medical Sciences, Harvard Medical School, Boston, MA, USA.
3
MD-PhD Program, Harvard Medical School, Boston, MA, USA.
4
Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
#
Contributed equally

Abstract

The factors that allow self-reactive B cells to escape negative selection and become activated remain poorly defined. Using a BCR knock-in mouse strain, we identify a pathway by which B-cell selection to nucleolar self-antigens is complement dependent. Deficiency in complement component C4 led to a breakdown in the elimination of autoreactive B-cell clones at the transitional stage, characterized by a relative increase in their response to a range of stimuli, entrance into follicles, and a greater propensity to form self-reactive GCs. Using mixed BM chimeras, we found that the myeloid compartment was sufficient to restore negative selection in the autoreactive mice. A model is proposed in which in the absence of complement C4, inappropriate clearance of apoptotic debris promotes chronic activation of myeloid cells, allowing the maturation and activation of self-reactive B-cell clones leading to increased spontaneous formation of GCs.

KEYWORDS:

Autoimmunity; Germinal center; Lupus nucleolar antigen; Negative selection

PMID:
23749435
PMCID:
PMC4086186
DOI:
10.1002/eji.201343412
[Indexed for MEDLINE]
Free PMC Article

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