LYN deficiency affects B cell maturation as well as survival

The Mina and Everard Goodman Faculty of Life Sciences, Bar Ilan University, Ramat-Gan, Israel.
European Journal of Immunology (Impact Factor: 4.03). 02/2012; 42(2):511-21. DOI: 10.1002/eji.201141940
Source: PubMed

ABSTRACT Lyn, an Src-family protein tyrosine kinase expressed in B lymphocytes, contributes to initiation of BCR signaling and is also responsible for feedback inhibition of BCR signaling. Lyn-deficient mice have a decreased number of follicular B cells and also spontaneously develop a lupus-like autoimmunity. We used flow cytometric analysis, BrdU labeling and our mathematical models of B-cell population dynamics, to analyze how Lyn deficiency impacts B-cell maturation and survival. We found that Lyn-deficient transitional 1 (T1) cells develop normally, but T2 cells develop primarily from the T1 subset in the spleen and fail to also develop directly from BM immature B cells. Lyn-deficient T2 cells either mature to the follicular B-cell type at a close to normal rate, or die in this compartment rather than access the T3 anergic subset. The ≈ 40% of WT follicular cells that were short-lived exited primarily by joining the T3 anergic subset, whereas the ≈ 15% Lyn(-/-) follicular cells that were not long lived had a high death rate and died in this compartment rather than entering the T3 subset. We hypothesize that exaggerated BCR signaling resulting from weak interactions with self-antigens is largely responsible for these alterations in Lyn-deficient B cells.

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    • "For personal use only. BCR Signaling Inhibitors, Autoimmunity, and B-Cell Malignancies  [165]. This highlights the role of Lyn as a negative regulator of BCR signaling that acts by phosphorylating membrane proteins such as CD22, which then recruit phosphatases that limit the initial events in BCR signaling. "
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    ABSTRACT: Objective To investigate why the level of Lyn is significantly decreased in B cells from a majority of patients with systemic lupus erythematosus (SLE) and to determine the role of microRNA-30a (miR-30a) in SLE B cell hyperactivity. Methods Luciferase reporter gene assays were performed to identify the interaction between miR-30a and the 3′-untranslated region (3′-UTR) of Lyn. Levels of miR-30a in B cells were determined by TaqMan quantitative polymerase chain reaction (qPCR), Lyn messenger RNA levels were tested with real-time qPCR, and protein levels of Lyn were determined using Western blotting. The quantity of IgG was determined by enzyme-linked immunosorbent assay. The proliferation of B cells was measured using 3H-thymidine incorporation. ResultsIn B cell lines, miR-30a, but not miR-30b, miR-30c, miR-30d, or miR-30e, could specifically bind the 3′-UTR of Lyn, and overexpression of miR-30a inhibited the levels of Lyn. The level of miR-30a in B cells was significantly higher in SLE patients compared to healthy donors. The level of miR-30a was negatively associated with the level of Lyn in B cells. Overexpression of miR-30a was found to promote B cell proliferation and the production of IgG antibodies. The effect of miR-30a could be abrogated by inducing overexpression of Lyn in B cells. Conclusion These results reveal that elevated expression of miR-30a is responsible for the reduction in levels of Lyn in B cells from patients with SLE, suggesting that miR-30a plays an important role in B cell hyperactivity.
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