Defective germinal center B-cell response and reduced arthritic pathology in microRNA-29a-deficient mice

Abstract

MicroRNA (miR) are short non-coding RNA sequences of 19-24 nucleotides that regulate gene expression by binding to mRNA target sequences. The miR-29 family of miR (miR-29a, b-1, b-2 and c) is a key player in T-cell differentiation and effector function, with deficiency causing thymic involution and a more inflammatory T-cell profile. However, the relative roles of different miR-29 family members in these processes have not been dissected. We studied the immunological role of the individual members of the miR-29 family using mice deficient for miR-29a/b-1 or miR-29b-2/c in homeostasis and during collagen-induced arthritis. We found a definitive hierarchy of immunological function, with the strong phenotype of miR-29a-deficiency in thymic involution and T-cell activation being reduced or absent in miR-29c-deficient mice. Strikingly, despite elevating the Th1 and Th17 responses, loss of miR-29a conferred near-complete protection from collagen-induced arthritis (CIA), with profound defects in B-cell proliferation and antibody production. Our results identify the hierarchical structure of the miR-29 family in T-cell biology, and identify miR-29a in B cells as a potential therapeutic target in arthritis.

Germinal Center B Cells Are Essential for Collagen‐Induced Arthritis

“…Clearly, however, a critical function of GC B cells in CIA is the production of anti‐CII antibodies. This is further supported by studies showing that mice that lack GCs and additionally have broader immune defects also have reduced responses to CII , albeit on an MHC H‐2 b background. Importantly, however, the B6 mouse model of CIA does not involve CII‐reactive T cells, because the immune response is more likely to be triggered by heterologous proteins contaminating the CII preparations and will therefore be different from classic CIA in A q ‐expressing mice .…”

miR-29b directly targets activation-induced cytidine deaminase in human B cells and can limit its inappropriate expression in naïve B cells

“…Interrogation of data from other papers that analysed the human B cell miRNome (Basso et al, 2009;Tan et al, 2009; confirmed this observation. The miR-29 family of miRNAs are known to be particularly important in T cells, where they control aspects of development and effector function (Ma et al, 2011;Papadopoulou et al, 2011;Steiner et al, 2011), and in B cells have recently been shown to regulate germinal centre dynamics in a murine model of collagen-induced arthritis (Nieuwenhuijze, 2017).…”

Molecular regulation of peripheral B cells and their progeny in immunity

“…For instance, the microRNA miR-148a promotes the plasma cell fate by decreasing mRNA encoding BACH2 and an inhibitor of IRF4, MITF (Porstner et al 2015). Although their mechanisms remain to be established, yet further microRNAs (miR-29a and miR-217) appear to enhance or restrain the GC reaction and its outputs (de Yebenes et al 2014;van Nieuwenhuijze et al 2017), and almost nothing is yet known about long noncoding RNA that can regulate gene expression.…”