In a recent study published in the journal Nature Communications, LMU clinicians have clarified the lifespan of antibody-producing cells and have also identified a novel biomarker that could be used to monitor autoimmune conditions such as multiple sclerosis and lupus erythematous.
The humoral immune response is mediated by cells in plasma and is responsible for fighting infections. Plasma cells secrete antibodies, proteins that that are able to identify pathogens and destroy them. However, antibodies with specific characteristics sometimes attack their host tissues causing autoimmune conditions like multiple sclerosis (MS) or lupus erythematosus(SLE). “Balanced regulation of the production and activity of plasma cells is therefore vital,” Professor Edgar Meinl (LMU Medical Center) said in a recent news release.
The researchers were able to identify a mechanism of action involved in the regulation of these antibody producing cells’ lifespan. Specifically, the researchers found that a cell-surface receptor, called BCMA, can be a useful biomarker for monitoring the severity of autoimmune diseases.
The cells in the plasma are produced by B-cells, which carry certain membrane-bound receptors that are able to identify antigens. When B-cells recognize an antigen, they are able to differentiate it into a clone of plasma cells that secrete the antigen-binding protein in soluble form as antibody. But the life-span of these antibodies is dependent on the BCMA receptor survival.
The extension of the lifespan of the plasma cells is activated by the BAFF and APRIL survival factors, BCMA ligands.. “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,” Meinl explained in the news release. “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 extended the cell’s membrane and is projected in the extracellular medium. Gamma-secretase removes the exposed portion by cutting the protein inside of the plasma membrane. That this enzyme cleaves the 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 Meinl in the news release, “and probably reflects the fact that the extracellular segment of the receptor is unusually short.”
The cleaved fragment is constant, and can be detected in fluid of the body as soluble BCMA (sBCMA). The evidence from this new study showed that in patients with Lupus, the sBCMA levels in the blood are high and associated correlated with the disease severity.
Multiple sclerosis is an organ-specific condition that is triggered in the central nervous system. “Correspondingly, in MS patients sBCMA levels were increased specifically in the cerebrospinal fluid, which bathes the brain and the spinal cord,” said Meinl. “So, 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.”
Results from this study could trigger the development of treatments, with both B cells and the BCMA/BAFF/APRIL mechanism being targets for lupus and multiple sclerosis, treatment.