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J Immunol. 2011 Dec 15;187(12):6550-63. doi: 10.4049/jimmunol.1102022. Epub 2011 Nov 14.

Expansion of functionally anergic CD21-/low marginal zone-like B cell clones in hepatitis C virus infection-related autoimmunity.

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Laboratoire I3 Immunologie, Immunopathologie, Immunothérapeutique, Centre National de la Recherche Scientifique Unité Mixte de Recherche 7211 et INSERM U959, Groupe Hospitalier Pitié-Salpétrière, Université Pierre et Marie Curie, F-75013 Paris, France.


Homeostasis of peripheral B cell subsets is disturbed during chronic hepatitis C virus (HCV) infection, leading to the occurrence of autoimmunity and B cell lymphoproliferation. However, mechanisms by which HCV causes lymphoproliferation remain controversial. We report in this article on the elevated number of clonal CD21(-/low)IgM(+)CD27(+) marginal zone (MZ)-like B cells, which correlates with autoimmunity and lymphoproliferation in HCV patients. We found an increase in autoreactive BCRs using V(H)1-69 and V(H)4-34 genes in CD21(-/low) MZ B cells. CD21(-/low) MZ B cells showed impaired calcium-mediated signaling, did not upregulate activation markers, and did not proliferate in response to BCR triggering. CD21(-/low) MZ B cells also were prone to dying faster than their CD21(+) counterparts, suggesting that these B cells were anergic. CD21(-/low) MZ B cells, in contrast, remained responsive to TLR9 stimulation. Gene array analyses revealed the critical role of Early growth response 2 and Cbl-b in the induction of anergy. Therefore, HCV patients who display high frequencies of unresponsive CD21(-/low) MZ B cells are more susceptible to developing autoimmunity and/or lymphoproliferation. These cells remain in peripheral blood controlled by functional anergy instead of being eliminated, and chronic antigenic stimulation through TLR stimulation may create a favorable environment for breaking tolerance and activating these cells.

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