Recent studies show that immunoglobulin G3 (IgG3) heavy chain polymorphisms strongly associate with susceptibility to developing multiple sclerosis (MS). A study conducted by Kennedy et al, published in the Journal of Neuroimmune Pharmacology, concurs, reporting that higher levels of total immunoglobulin (IgG) and IgG3 occur in MS patients but not in patients with other neurological disorders.

A historically distinguishing feature of MS is the increasing IgG production along with oligoclonal bands (OCBs) in the cerebrospinal fluid (CSF). OCBs correlate with disease activity, brain atrophy, and cortical lesion load. Nevertheless, levels of OCBs do not correlate with CSF IgG concentration, in contrast to the link between serum and CSF levels of IgG.

IgG antibodies comprise 4 subclasses, from IgG1 to IgG4, with IgG1 and IgG3 being predominant within CSF of MS patients. IgG1 and IgG3 structurally differ as the latter has a larger hinge region, which may explain why this specific antibody is more effective as an effector (ie, neutralization) but may hinder its detection by standard enzyme-linked immunosorbent assay (ELISA) as it depends on the exposition of fragment crystallizable (FC) portions.

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Interestingly, the authors found no difference by using commercial human IgG subclass ELISA kits in any IgG subclasses between MS and control sera, aligning with previous studies. Nonetheless, by using direct and capture ELISAs, authors found a higher level of total IgG and IgG3 only in MS patients sera, distinguishing them from other neurological disorders. 

“The assay-dependent feature of MS serum antibodies may suggest a complex nature of these antibodies which needs further investigations,” they wrote.

The CSF IgG antibodies originate from a systemic source. These serum antibodies target microvessels from the brain tissue, disrupt the blood-brain barrier, and correlate with brain MRI MS severity.

Likewise, B-cell clusters corresponding to OCBs exist only within the blood.

“Although we did not necessarily reveal mechanisms of MS, we provide novel findings that MS serum IgG antibodies are unique, which may provide a stepping stone for future investigations for mechanisms,” the authors concluded.


Kennedy PG, Graner MW, Fringuello A, et al. Higher levels of IgG3 antibodies in serum, but not in CSF, distinguish multiple sclerosis from other neurological disorders. J Neuroimmune Pharmacol. Published online January 6, 2022. doi:10.1007/s11481-021-10048-x