Amyloid-like Behavior of Site-Specifically Citrullinated Myelin Oligodendrocyte Protein (MOG) Peptide Fragments inside EBV-Infected B-Cells Influences Their Cytotoxicity and Autoimmunogenicity

Abstract

Multiple sclerosis (MS) is an autoimmune disorder manifested via chronic inflammation, demyelination, and neurodegeneration inside the central nervous system. The progressive phase of MS is characterized by neurodegeneration, but unlike classical neurodegenerative diseases, amyloid-like aggregation of self-proteins has not been documented. There is evidence that citrullination protects an immunodominant peptide of human myelin oligodendrocyte glycoprotein (MOG34–56) against destructive processing in Epstein-Barr virus-infected B-lymphocytes (EBV-BLCs) in marmosets and causes exacerbation of ongoing MS-like encephalopathies in mice. Here we collected evidence that citrullination of MOG can also lead to amyloid-like behavior shifting the disease pathogenesis toward neurodegeneration. We observed that an immunodominant MOG peptide, MOG35–55, displays amyloid-like behavior upon site-specific citrullination at positions 41, 46, and/or 52. These amyloid aggregates are shown to be toxic to the EBV-BLCs and to dendritic cells at concentrations favored for antigen presentation, suggesting a role of amyloid-like aggregation in the pathogenesis of progressive MS.

The Atypical Fibrin Fibre Network in Rheumatoid Arthritis and its Relation to Autoimmunity, Inflammation and Thrombosis

“…There is evidence to suggest that the processes of citrullination and amyloidogenesis may overlap. Citrullination has been shown to affect the aggregation and oligomerization of β -amyloid proteins (142) and that citrullination of human myelin oligodendrocyte glycoprotein (MOG) can lead to amyloid-like behavior shift that has pathogenic implications for multiple sclerosis (143).…”

Environmental Influencers, MicroRNA, and Multiple Sclerosis

“…EBV infection in MS is documented in several articles. [69][70][71][72][73][74][75][76][77] Hassani et al have shown the presence of EBV in 90% of the tested MS cases (n = 101) compared with that in only 24% of the non-MS control cases (n = 24). EBV infection is associated with B cells, CD8 + T cells, astrocytes, and microglia.…”

Experimental autoimmune encephalomyelitis in the common marmoset: a translationally relevant model for the cause and course of multiple sclerosis

“…Genomewide association studies (GWASs) reveal that the vast majority of genetic risk factors have a function in the immune system, although the individual contribution of each gene to the pathogenic process is often not clear. Environmental risk factors are diverse and include exposure to infectious (with Epstein-Barr virus) as well as noninfectious factors (smoking, sunshine exposure) (Ascherio and Munger, 2007;Ascherio et al, 2012). In the course of our research the question of whether MS might be triggered by an endogenous factor or process emerged.…”

“…We observed the following: (1) replacement of these residues by citrulline protects the MOG34-56 peptide against cleavage by catG and (2) that citrullination promotes spontaneous aggregation of the peptide in the following order: MOG34-56 < MOG34-56c41,46 MOG34-56c46,52. Moreover, the oligomeric aggregates show amyloid-like seeding behavior (Araman et al, 2019).…”

“…Primary immunology data of the model can be found in references Brok et al (2000), Kap et al (2008) and Jagessar et al (2010Jagessar et al ( , 2012d. Papers presenting primary data on the pathogenic role of EBV-infected B cells are Jagessar et al (2013a), (2016) and Morandi (2017b) and Araman et al (2019).…”