Genetic Variants Found to Play a Role in Antibody Production and Disease Severity in Multiple Sclerosis Patients

Dr. Jose Álvarez-Cermeño and Dr. Luisa Villar from Instituto Ramón y Cajal de Investigación Sanitaria in Madrid, Spain recently published in the journal Nature Reviews Neurology a review on the work developed by Dr. An Goris and colleagues on the link between genetic factors and multiple sclerosis (MS), published in January 2015 – Genetic variants are major determinants of CSF antibody levels in multiple sclerosis; Brain 138, 632-643. The review is entitled “Multiple sclerosis: Genetic variability affects CNS IgG production in MS.”

MS is a chronic, progressive neurodegenerative disorder that results from the attack on the central nervous system by the body’s own immune system, causing inflammation and damage to the myelin layer that covers and protects neurons. Myelin loss leads to impairment in signal transmission along nerve fibers, affecting motor function (e.g. walking, speaking) and causing irreversible neurological disability. It is thought that both genetic and environmental factors can contribute to the risk of developing MS.

According to the authors, MS has traditionally been considered a T-cell-mediated autoimmune disease, but studies have suggested that other types of immune cells, namely B cells and B-cell-produced antibodies, play a role in MS. In fact, more than 90% of MS patients have in their central nervous systems local synthesis of IgG, the most common type of antibody produced by B cells in circulation in the body. This phenomenon indicates that the central nervous system in MS patients suffers aberrant immune system activation.

Dr. Goris and colleagues have conducted a genome-wide association study (GWAS) to assess the role played by genetic factors in IgG antibody production and clinical disease features in the cerebrospinal fluid (CSF) of a cohort of over 6,000 MS patients. A higher IgG synthesis (determined by the presence of oligoclonal IgG bands in the CSF and through a high IgG index) was found to be linked to specific genetic variants, more specifically to single nucleotide polymorphisms (SNPs) in the HLA-DRB01*15:01 allele and in a locus near the SMAD4 gene, both genetic variants that have been previously associated to MS development. On the other hand, a SNP in HLA-DQA1*0301 was found to be linked to a lack of IgG production.

Antibody production within the central nervous system was also found to be associated with certain epidemiological and clinical features. IgG synthesis was observed to be associated with a younger age at onset and female gender. In terms of disease severity, oligoclonal IgG band status did not correlate with disease course, duration or progression, but a high IgG index was found to be associated with a more aggressive MS disease course.

The authors concluded that the genetic background of an individual contributes to the heterogeneity in disease course and treatment response seen in MS patients. Previous studies have identified both serum and CSF biomarkers linked to MS pathophysiology — now the authors suggest that the combination of such biomarkers with the genetic markers that have been reported to also be linked to MS could potentially allow a better understanding of the different ‘immunophenotypes’ seen in MS patients and its relation to the different clinical features presented.

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