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La Presse Médicale
Volume 42, n° 4P2
page 760 (avril 2013)
Doi : 10.1016/j.lpm.2013.02.256

ANCA reactive B cells and neutrophils cross-talk in the pathogenesis of AAV: A model proposal

P.R. Hurtado, J. Nitschke, E. Hurtado-Perez, C.A. Peh
The Royal Adelaide Hospital, Adelaide, Australia 

Introduction .– The current model of AAV pathogenesis is based on the role of circulating ANCA and its effect on primed neutrophils. However, published data of patients with AAV treated with Rituximab, which remove circulating B cells, shows that clinical remission correlates more to the decreasing number of circulating B cells than decrease in ANCA titre. Given that ANCA reactive B cells can be found in circulation in patients with AAV, we would like to hypothesize that these cells play a direct role in AAV pathogenesis. Here, we propose a model whereby activated neutrophils and ANCA-reactive B cells engage in intercellular cross-talk, which could potentially lead not only to neutrophil degranulation and inflammation but also to the proliferation and differentiation of ANCA-reactive B cells. The model is based on the expression of complementary molecules on activated B cells and Neutrophils, such as Lymphotoxin A (LTa) and ICAM-1 (CD54) on B cells, and LTBR, LAF-1 and BAFF (CD268) molecules on neutrophils. Membrane expression of ANCA antigens on activated neutrophils or in NETs would act as an additional activation signal for B cell differentiation and ANCA production.

Methods .– PBMC from healthy individuals, as well as purified Neutrophils and B cells were cultures in the presence of TLR ligands for 24 and 48hours. Phenotype studies of B cells and Neutrophils were carried out using directly labelled monoclonal antibodies and analyzed by flow cytometry while the gene expression was studies by RT-PCR.

Results .– Preliminary results show expression of LTa and CD54 on B cells and LTBR and LAF-1 on Neutrophils are modulated by TLR-ligands such as LPS, viral RNA and CpG oligonucleotides. Given the role of these molecules on cell adhesion and activation it is reasonable to speculate on the possibility of neutrophil-B cell and the resulting cell activation. If proven to be true, the model would potentially open new opportunities for disease monitoring and novel targets for therapeutic intervention of AAV.

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