Elevated serum IgG3 is associated with accelerated progression from clinically isolated syndrome to multiple sclerosis — ASN Events
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  3. Elevated serum IgG3 is associated with accelerated progression from clinically isolated syndrome to multiple sclerosis

Elevated serum IgG3 is associated with accelerated progression from clinically isolated syndrome to multiple sclerosis (#179)

Lilian Cha 1 , Stephanie Trend 1 , Anderson P Jones 1 , Scott N Byrne 2 3 , Marzena J Fabis-Pedrini 4 , David R Booth 3 , Robyn M Lucas 5 6 , Allan G Kermode 4 7 , Martyn A French 8 , Prue H Hart 1
  1. Telethon Kids Institute, Subiaco, Western Australia, Australia
  2. Infectious Diseases & Immunology, Charles Perkins Centre, Sydney, New South Wales, Australia
  3. Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, Sydney, New South Wales, Australia
  4. Centre for Neuromuscular and Neurological Disorders, Perron Institute for Neurological and Translational Science, Perth, Western Australia, Australia
  5. National Centre for Epidemiology & Population Health, Australian National University, Canberra, Australian Capital Territory, Australia
  6. Centre for Ophthalmology and Visual Science, University of Western Australia, Perth, Western Australia, Australia
  7. Institute for Immunology and Infectious Disease, Murdoch University, Perth, Western Australia, Australia
  8. Medical School and School of Biomedical Sciences, University of Western Australia, Perth, Western Australia, Australia

Clinically isolated syndrome (CIS) is the first clinical episode suggestive of multiple sclerosis (MS), an immune-mediated degenerative neurological condition. Damage to the central nervous system occurs via complex inflammatory processes, including deposition of IgG3 and IgG1 (‘upstream’ IgG subclasses) in the brain. The association between these IgG subclasses and antibodies to Epstein-Barr virus (EBV), which is implicated in MS, led us to hypothesise that dysregulated immunoglobulin class switching in CIS contributes to disease pathogenesis, and could be a predictor for conversion to MS.

Peripheral blood samples were collected from individuals with recently diagnosed CIS (n=20) and healthy controls (n=10). Immunophenotyping of B-cell subsets was performed by flow cytometry and serum levels of total IgM, IgG and IgA, and IgG1, IgG2, IgG3 and IgG4 subclasses were measured by ELISA or cytometric bead array. Serum EBV-specific antibodies (anti-EBNA IgG, anti-VCA IgG and IgM) were also measured.

EBV-specific antibodies did not correlate with serum immunoglobulins, thus non-specific serum immunoglobulin levels are not associated with EBV serology status in CIS. Individuals with CIS had significantly lower levels of total IgM and IgG compared with controls. Assessment of serum IgG subclass levels showed lower levels of IgG2 (a ‘downstream’ subclass) in the CIS group compared with healthy controls (p<0.05). Comparison of the ratio of upstream and downstream IgG subclasses (IgG3/IgG1:IgG2/IgG4 as % total IgG) displayed a broad range in CIS, where four individuals with a higher ratio converted to MS <3 months of CIS diagnosis. Moreover, IgG3 (proportion of total IgG) correlated with the frequency of antibody secreting cells (CD20loCD27hiCD38hiCD24-) (r=0.5, p=0.02) and negatively correlated with time until conversion to MS (n=16; r=-0.7, p=0.001). These data suggest that CIS is associated with B-cell dysfunction and that IgG3 may be a useful prognostic marker in determining who will rapidly progress to MS.

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