Researchers from Singapore’s leading science institute, A*STAR, found that a group of small noncoding RNAs, called mir-17-92, regulate B-cell function and antibodies in mice. The results may help pave the way for new lupus treatments and other diseases linked to B-cell dysfunction.
Antibody-producing B-cells are a crucial part of our defense against pathogens. In autoimmune diseases such as systemic lupus erythematosus (SLE), antibodies are directed at the body’s own proteins. Researchers have known that mir-17-92 regulates the early development of B-cells, but the RNA cluster’s role in mature B-cells has been elusive.
Short noncoding RNAs, like mir-17-92, control gene expression by binding to a matching mRNA strand – the transcript of the DNA code that is used as a blueprint for making proteins. This binding causes the mRNA to become unstable or to lose its ability to be translated into a protein.
Shengli Xu and colleagues from the Bioprocessing Technology Institute at A*STAR engineered a mouse that lacked mir-17-92 only in mature B-cells. According to their publication, entitled “Mir-17-92 regulates bone marrow homing of plasma cells and production of immunoglobulin G2c,“ the researchers found that plasma cells – a type of B-cell producing antibodies – were directed to the bone marrow during an immune response. In normal mice, these cells were retained in the spleen to a higher degree.
The research team found that this altered location of plasma cells was mediated through a receptor called S1PR1. The receptor is known to direct plasma cells to the bone marrow, but mir-17-92 normally reduces the expression of the receptor, blocking the movement of the cells. When mir-17-92 was absent, S1PR1 numbers increased, and more cells were sent to the bone marrow.
Results, published in the journal Nature Communications, also show that mice lacking mir-17-92 produced less of the IgG2c class of antibodies, the most common type of antibody involved in autoimmune reactions in mouse models of lupus. The team also found the mediator behind the observed effect: the protein IKAROS, whose levels were elevated in the mutant mice. After normalization, IgG2c production increased to normal levels.
The research team also looked at how the absence of mir-17-92 affected disease in a lupus mouse model. As they had suspected, the levels of autoantibodies were decreased, as was the extent of kidney injury in mice. “These findings lead to better understanding of the role of mir-17-92 for normal B-cell function, and also pave the way for development of new treatments for some B-cell related diseases in humans, such as multiple myeloma and lupus,” lead author Xu said in a press release.
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