Multiple sclerosis (MS) is an autoimmune disease of unknown etiology characterized by the inflammatory demyelination of the central nervous system (CNS) and breakdown of the blood-brain barrier (BBB). The gMS anti-GAGA4 diagnostic test is based on the detection of circulating IgM antibodies directed against the glycan antigen Glucose(α1,4)Glucose(α). Relapsing remitting MS patients have significantly higher blood levels of the IgM antibody anti-GAGA4 than patients suffering from other neurological diseases.
The biological basis of immune response to a α-glucose antigen is still somewhat unclear, but it is of interest that this particular glycan is found within the BBB. This glycan is also found to be an important immunogenic antigen in other autoimmune diseases. It is believed that when immune cells traverse the BBB, the collagen matrix collapses, possibly leading to the release of glycans antigens and a potential immune response. Interestingly, deposits of the BBB can also be found within MS active plaques.
Alpha-glucose based glycans are also found in the cell wall of several pathogenic fungi and bacteria. This homology between known pathogens and a human α-glucose glycan may suggest that these IgM antibodies could develop via a mechanism called molecular mimicry where a cross-reactive response targets the same glycan as found in the BBB.
The production of IgM antibodies against the GAGA4 glycan antigen is most likely produced by self-replenishing B-1 B-cells. These cells respond much better to glycan antigens than proteins. Interestingly, B1 B-cells require a high amount of antigen for induction and play an important role as a first line of defense against invading pathogens and removal of self antigens.