Multiple Sclerosis (MS) is an autoimmune disease that affects the brain and spinal cord, otherwise known as the central nervous system (CNS). Though common symptoms include numbness in limbs, paralysis, and vision impairment, the progression of the disease varies person to person. Additional symptoms such as seizures may accompany pediatric MS which affects 8,000-10,000 children in the United States. Pediatric MS is a difficult area to study because of its low prevalence and differences from adult MS.
The autoimmune component of MS refers to the degradation of the myelin sheath, a lipid-rich tissue that encapsulates our neuron’s axons and mediates the conduction of signals throughout our body. The attack on myelin is carried out by T cells, a type of white blood cell, which recognize our myelin as a foreign entity and subsequently destroy it. This autoimmune response is further characterized by the production of myelin specific antibodies, that is, proteins secreted by B cells to target specific pathogens (1). Without myelin, the body develops the aforementioned symptoms. In a study published by O’Connor and colleagues in the journal of neuroimmunology, researchers examined the levels and binding characteristics of antibodies for immature (pediatric) and mature (adult) human MBP (a protein that makes up myelin) in the serum of children with MS and controls in an effort to better understand the contribution of antibodies in early MS onset and how it further illuminates the differences between pediatric and adult MS.
Researchers began by using mass cytometry to make a direct comparison of pediatric and adult-derived MBP. Higher levels of citrullination and phosphorylated species were observed in immature pediatric-derived MBP but not in adult-derived MBP. Citrullination and phosphorylation are noteworthy because these types of post-translational modifications alter the function of MBP. Therefore, these antibodies may be behaving differently in pediatric MS patients than in adults. However, researchers then found that the serum reactivity to immature and mature MBP did not differ significantly from pediatric MS patients and controls. Additionally, anti-myelin antibodies were present (seropositivity) in similar frequencies in serum levels of both MS children and controls which suggests that these molecules are a part of the normal immune response in children.
However, it’s important to note that the methods used so far (ELISA/DELFIA) did not examine antibodies in their soluble form which sometimes changes their conformation. Researchers therefore examined the binding characteristics of soluble anti-MBP antibodies in seropositive samples of MS and control children. These samples contained IgG and IgM anti-MBP antibodies which are different varieties, or isotype, of antibody. Nonetheless, the binding affinities were quantified and no differences were found in these solution binding experiments although very slow dissociation rates in children were consistent with high-affinity anti-MBP binding. The majority of MBP specific antibodies detected were of the IgG1 antibody, a further subclass of this isotype. These antibodies were almost exclusively found in the serum which accurately reflected the presence of antibodies in the CSF at the same time.
Researchers were able to find a remarkable relationship between anti-MBP antibodies measured in children with MS and the clinical phenotype of this disease. Of the MS children who harbored serum anti-MBP antibodies, 36% of them had experienced an acute disseminated encephalomyelitis (ADEM) episode. ADEM is an inflammatory mediating disease commonly coupled with MS and considered a borderline form of MS. This is in contrast to 12% of MS children who had experienced an ADEM episode but did not harbor anti-MBP antibodies suggesting an increased risk of these ADEM-like episodes when anti-MBP antibodies are present. Furthermore, there was a significant correlation between higher concentrations of of IgG anti-MBP antibodies and both younger age at onset and higher number of relapses.
To quickly summarize, O’Connor and colleagues found that circulating anti-MBP antibodies can be present as a normal childhood humoral immune repertoire. Additionally, these antibodies tend to be of the IgG1 subclass and display high binding affinities for their MBP target myelin antigen. Finally, the presence of these high-affinity anti-myelin antibodies was found to be equal in both serum and CSF of children with MS and was associated with a significantly higher incidence of ADEM episodes. Researchers suggest that the presence of these anti-MBP antibodies exhibit disease modifying abilities in MS and aren’t a result of ADEM episodes seeing as controls ruled out that possibility. This is interesting because it suggest that these anti-MBP antibodies must be able to access the CNS and then subsequently engage in tissue damage.
This study highlights the differences in antibody circulation between children and adults with MS. O'Connor and colleagues found differences in binding characteristics and properties of anti-MBP antibodies. This adds to the growing amount of literature dedicated to these differences, such as a recent study that looked at the high proportion of MOG (another myelin protein) autoantibodies in children with MS but not adults (2)(3). It is also the first study to examine the circulating antibodies for both immature and mature forms of myelin in patients with MS though no significant differences were found in this area. Understanding these differences not only allows us to help treat pediatric MS, but in turn, adult MS as well
Reference: O’Connor, K.C., et al. (2010). Anti-myelin antibodies modulate clinical expression of childhood multiple sclerosis. Journal of Neuroimmunology. 1-2, 92-99.
Brilot, R. C. et al. (2009). Antibodies to native myelin oligodendrocyte glycoprotein in children with inflammatory demyelinating central nervous system disease. Annals of Neurology. 66, 8333-842
McLaughlin, K.A., et al., 2009. Age-dependent B cell autoimmunity to a myelin surface antigen in pediatric multiple sclerosis. Journal of Immunology. 183, 4067-4076.