A study led by researchers at Ludwig Maximilians University Munich in Germany revealed a promising new biomarker linked to the lifespan control of important antibody-producing cells and relevant for autoimmune diseases like systemic lupus erythematosus (SLE). The study was recently published in the journal Nature Communications and is entitled “Gamma-secretase directly sheds the survival receptor BCMA from plasma cells”.
The humoral immune response refers to the antibody-mediated immunity provided by plasma cells and it plays a key role against infections. Plasma cells produce antibodies, a class of proteins able to specifically recognize infectious pathogens. Antibodies with certain specificities may, however, mistakenly attack the healthy tissues of the body, leading to the development of autoimmune diseases like SLE, a disorder were healthy joints and organs are attacked by autoantibodies resulting in inflammation, swelling, pain, disability and often in tissue destruction in multiple organs. “Balanced regulation of the production and activity of plasma cells is therefore vital,” noted the study’s senior author Dr. Edgar Meinl.
B-cells are the progenitors of plasma cells, and they contain specific membrane-bound receptors able to recognize foreign proteins (antigens). When a B-cell finds its corresponding antigen, it differentiates into a clone of plasma cells that secrete the antigen-binding protein in an antibody form.
The time that an antibody-producing plasma cell survives in the body mainly depends on a survival receptor called BCMA (B-cell maturation antigen). BCMA binds to survival factors (like BAFF and APRIL), activating a program that effectively extends the lifespan of the plasma cell. “However, the lifetime of plasma cells cannot be prolonged indefinitely. Otherwise the organism would become swamped with antibodies, increasing the risk of an autoimmune reaction,” explained Dr. Meinl. “We have now shown, in cooperation with colleagues in Munich, Berlin and Stockholm, that the membrane-bound enzyme gamma-secretase acts as a brake on immune reactions by fragmenting BCMA.”
BCMA is present at the cell-surface and projected into the extracellular environment. Researchers have now found that a protein called gamma-secretase is able to cut the exposed portion of BCMA, reducing cell survival and controlling the immune response. The fact that gamma-secretase cleaves the BCMA receptor directly was a surprise: “Up to now, it was only known to be involved in the degradation of membrane proteins that had already been cleaved by other enzymes. BCMA is the first natural substrate of gamma-secretase to be identified that is directly cleaved by the enzyme,” said Dr. Meinl.
The released fragment that is cut off from the BCMA receptor is stable and can be detected in circulation as soluble BCMA (sBCMA). This fragment was found to act as a decoy, neutralizing survival factors like APRIL that bind to BCMA prolonging cells’ lifespan. Inhibition of gamma-secretase was found to enhance BCMA expression in plasma cells, increasing their number in the bone marrow. Analysis of sBCMA levels in patients with SLE and other autoimmune diseases like multiple sclerosis, led the team to suggest that sBCMA could be used as a biomarker for monitoring the severity of autoimmune conditions. In lupus patients in particular, sBCMA levels were found to be abnormally high in the blood, and to be correlated with disease severity.
“sBCMA is an indicator of the intensity of ongoing immune reactions. sBCMA is therefore well suited to serve as an informative clinical parameter for the assessment of the therapeutic effects of different treatment regimes on plasma cells.” said Dr. Meinl. The team concluded that the cleavage of BCMA by gamma-secretase controls plasma cells in the bone marrow and can be used as a biomarker for B-cell involvement and disease severity in autoimmune diseases.
B cells and the BCMA/BAFF/APRIL system represent promising therapeutic targets for lupus, as blocking their activity can inhibit autoimmune antibody production. Clinical trials testing therapeutic agents that target these elements are currently being conducted.