Alpha-2-macroglobulin (A2M) is a proteinase inhibitor involved in deactivation of cytokines and modulation of antigen-mediated immune responses. Based on its role in inflammatory and neurodegenerative disorders, we investigated the role of A2M and its receptor low-density lipoprotein receptor-related protein (LRP) for the development of multiple sclerosis (MS). We analyzed the frequency of two polymorphisms in the A2M (Val 1000 Ile, Exon 18 del), and one polymorphism in the LRP (A216V) gene in a case control study involving 326 MS patients, and 290 controls, all defined for the expression of HLA-DR15. No association was found for any of the three polymorphism with MS. Furthermore, no differences in serum A2M levels were detected between MS patients and controls. The results do not suggest a contribution of A2M and LRP to the development of MS.

Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system. It is widely accepted that a dysregulated immune response against brain resident antigens is central to its yet unknown pathogenesis 1 , 2 , 3 , 4 . Although there is evidence that the development of MS has a genetic component, specific genetic factors are largely unknown 5 , 6 , 7 . Here we investigated the role of a point mutation in the gene ( PTPRC ) encoding protein-tyrosine phosphatase, receptor-type C (also known as CD45) in the heterozygous state in the development of MS. The nucleotide transition in exon 4 of the gene locus interferes with mRNA splicing and results in altered expression of CD45 isoforms on immune cells. In three of four independent case-control studies, we demonstrated an association of the mutation with MS. We found the PTPRC mutation to be linked to and associated with the disease in three MS nuclear families. In one additional family, we found the same variant CD45 phenotype, with an as-yet-unknown origin, among the members affected with MS. Our findings suggest an association of the mutation in PTPRC with the development of MS in some families.