A Complex Role of Herpes Viruses in the Disease Process of Multiple Sclerosis

Abstract

Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system (CNS). Neither the antigenic target(s) nor the cell population(s) responsible for CNS tissue destruction in MS have been fully defined. The objective of this study was to simultaneously determine the antigen (Ag)-specificity and phenotype of un-manipulated intrathecal CD4+ and CD8+ T cells of patients with relapsing-remitting and progressive MS compared to subjects with other inflammatory neurological diseases. We applied a novel Ag-recognition assay based on co-cultures of freshly obtained cerebrospinal fluid T cells and autologous dendritic cells pre-loaded with complex candidate Ag's. We observed comparably low T cell responses to complex auto-Ag's including human myelin, brain homogenate, and cell lysates of apoptotically modified oligodendroglial and neuronal cells in all cohorts and both compartments. Conversely, we detected a strong intrathecal enrichment of Epstein-Barr virus- and human herpes virus 6-specific (but not cytomegalovirus-specific) reactivities of the Th1-phenotype throughout all patients. Qualitatively, the intrathecal enrichment of herpes virus reactivities was more pronounced in MS patients. This enrichment was completely reversed by long-term treatment with the IL-2 modulating antibody daclizumab, which strongly inhibits MS disease activity. Finally, we observed a striking discrepancy between diminished intrathecal T cell proliferation and enhanced cytokine production of herpes virus-specific T cells among progressive MS patients, consistent with the phenotype of terminally differentiated cells. The data suggest that intrathecal administration of novel therapeutic agents targeting immune cells outside of the proliferation cycle may be necessary to effectively eliminate intrathecal inflammation in progressive MS.

Intrathecal CD4+ and CD8+ T‐cell responses to endogenously synthesized candidate disease‐associated human autoantigens in multiple sclerosis patients

“…Whereas antigen processing and presentation may differ between BLCL and the currently undefined local APC in MS lesions, the use of cMSAg-transduced autoBLCL as artificial APC represents a reasonable compromise to detect intrathecal cMSAg-specific T cells. Congruent to our findings, Wuest and colleagues also did not observe significant reactivity of CSF-derived T cells toward self-antigens using cell-, myelin-, and brain-derived lysate pulsed autologous dendritic cells used as APC [12]. Still, a cautious interpretation of our data is warranted, as there are a few limitations.…”

Cerebrospinal fluid markers reveal intrathecal inflammation in progressive multiple sclerosis

“…Previously published functional data indicate that intrathecal T cells in progressive MS have phenotypes of terminally differentiated cells, 45 making them resistant to immunosuppressive agents that target cells in the proliferation cycle. Together with insight obtained from the current paper, we conclude that the observed lack of efficacy of current therapeutic agents in progressive MS may be due to inadequate penetrance of large molecules (such as biologicals) to CNS tissue and preferential targeting of proliferating cells by small molecules, such as classical immunosuppressive/cancer therapeutics.…”

Intrathecal CD8 T-cells of multiple sclerosis patients recognize lytic Epstein-Barr virus proteins

“…17,19,20 They were either restricted to the analysis of a selective set of known immunodominant EBV peptides or used autologous dendritic cells pulsed with EBV or BLCL protein lysates as APC. [19][20][21][22] Besides the limited number of peptides tested, which discounts issues like inter-HLA allele peptide affinity and post-translational peptide modifications, the caveat of the latter strategy is restriction to structural viral proteins and potential contamination of host proteins in case of EBV and BLCL protein lysates, respectively. 13,14,30 The artificial APC system applied here overcomes these potential drawbacks, by assaying CD8 T-cell reactivity on cells that both endogenously express individual EBV proteins or human CRYAB, along with the HLA-I alleles that are involved in autoBLCL CD8 T-cell recognition.…”