A hallmark of multiple sclerosis (MS), a chronic inflammatory autoimmune disease of the central nervous system, is demyelination and the presence of primary immune cells that have crossed the blood-brain barrier. Despite several decades of research, the cause of MS remains poorly understood; however, the disease is likely due to a combination of environmental and genetic factors. Mononucleosis due to Epstein-Barr virus (EBV) infection, for example, is considered a risk factor and a prerequisite for a diagnosis of MS. Like MS, mononucleosis also arises from both genetic and environmental risk factors. Although more than 90% of the world‘s population is likely to have been infected with EBV, only a small proportion of individuals will subsequently develop MS.
Previously, the researchers in the present study reported that antibodies directed against specific regions of EBNA1 were strongly associated with MS. Anoctamin 2 (ANO2) autoantigen, which is one of two highly associated protein fragments of EBNA1, also shows cross-reactivity with antibodies produced in MS patients. In a recent study published in the journal Science Advances, researchers explore the association between Epstein-Barr virus nuclear antigen 1 (EBNA1) cross-reactive immunity and multiple sclerosis. In the research, scientists investigated the immune reactivity targeting CRYAB, the gene encoding the protein alphaB-crystallin, expressed by SM oligodendrocytes, and its potential cross-reactivity with EBNA1.
Plasma samples from 713 participants with MS and 722 controls were obtained from the Swedish National Epidemiological Survey on a patient cohort. Controls in the study were selected on a population basis and were matched to MS patients by gender, age, and geographic region. Immunoglobulin G (IgG) anti-CRYAB antibodies directed against the CRYAB 2-16 and CRYAB 7-21 fragments are increased in plasma samples of MS patients compared to controls. Similar trends were observed for the adjacent peptides CRYAB 1-15, CRYAB 8-22 and CRYAB 9-23, with the highest odds ratio (OR) for MS observed with CRYAB 3-17 reactivity at 13.3% vs. 7.2% of controls. Importantly, few other positive signals were observed for other CRYAB peptides and proteins.
CRYAB antibodies were similar in individuals with relapsing-remitting, secondary progressive, and primary progressive MS. Age, disease duration, and gender also did not affect anti-CRYAB reactivity. Individuals with reactivity to the CRYAB 3-17 fragment also showed positive reactivity to the EBNA1 fragment 393-412. Comparatively, ANO2 134-153 reactivity was strongly correlated with EBNA1 425-444, but not with the non-homologous fragment EBNA1 393-412. Next, the researchers immunized the mice with CRYAB or EBNA1 380-641 and determined the antigenic reactivity of the isolated T cells. To this end, CD4+ T lymphocytes of EBNA1 380-641 immunized mice produced an increased amount of interferon γ (IFN-γ) upon exposure to full-length CRYAB.
Similarly, CD4+ T cells from CRYAB-immunized mice reacted to EBNA1 380-641 and EBNA1 1-120 but not to other MS-related autoantigens. No specific reactivity was observed between CD8+ T cells of mice immunized with CRYAB or EBNA1380-641. T cells were also obtained from natalizumab-treated MS patients and compared with those of MS patients before treatment initiation and healthy controls. Increased levels of IFN-γ cells, interleukin 17A (IL-17A), and IL-22 responding to CRYAB, EBNA1 1-120, and EBNA1 380-641 were observed in natalizumab-treated MS patients compared to the other two patient groups . Similarly, increased levels of effector memory and central memory CD4+ T lymphocytes responded to both CRYAB and EBNA1 antibodies.
Thus, the researchers confirm the responsiveness of CRYAB to EBNA1, thus elucidating a possible mechanism by which EBV infection elicits an adaptive immune response that ultimately contributes to the development of MS. Importantly, only about 20% of MS patients show autoreactivity between EBV and MS autoantigens. It is possible that CRYAB has a neuroprotective function, which could explain its therapeutic effect in neuroinflammatory models, while autoreactivity against it could reverse this role as noted above. Thus, a role for CRYAB in both neuroprotection and also as an autoantigenic target driving autoimmunity is not mutually exclusive.
Therefore, some underlying factors such as human leukocyte antigen (HLA), previous immune responses to environmental stimuli or other as yet undiscovered risk factors may be involved in the pathogenesis of multiple sclerosis.
- By Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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