Contributions
Abstract: P446
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - MS and infections
Epstein-Barr virus (EBV) is widely recognized as a major environmental risk factor for multiple sclerosis (MS) but the mechanisms linking this ubiquitous virus to chronic central nervous system (CNS) inflammation are debated. One of the current hypotheses proposes that immune responses primarily directed toward EBV-infected B cells, the preferred cellular reservoir of the virus, cause bystander damage in the CNS. The goal of this study has been to explore further the hypothesized link between EBV deregulation and immune activation in the MS brain.
Immunohistochemistry, laser capture microdissection and advanced polymerase chain reaction (PCR) methods were combined to study gene expression of well characterized immune infiltrates isolated from post-mortem brain tissue of persons with secondary progressive (SP) MS. Brain tissue was provided by the UK MS Tissue Bank. White matter perivascular cuffs (n=39) and meningeal infiltrates (n=36), including ectopic B-cell follicles, were isolated from brain sections of 11 SPMS cases and analyzed for expression of 78 immune-related genes and 6 EBV genes.
EBV transcripts were detected in CNS immune infiltrates from 9 of 11 SPMS cases, more frequently in meningeal infiltrates and with a pattern consistent with profound viral deregulation (latency disruption and entry into the lytic cycle). As to cellular genes, transcripts associated with type 1 immunity (mediated by Th1/Tc1/NK cells) predominated over transcripts associated with type 2 and type 3 immunity in both meningeal and white matter infiltrates. RNA signals related to B-cell growth/differentiation (BCMA, BAFF), lymphoid tissue formation (CCL19, CCL21), cell proliferation (Ki76), antigen presentation (CD1a), myeloid cell recruitment (CCL2) and type 1 immunity (IFN-gamma) were also significantly higher in meningeal than in white matter infiltrates. A strong association was found in the meninges between EBV transcripts indicative of viral latency disruption (latency II and III programmes) and cellular genes involved in pathogen recognition (TLR9, RIG-1), B-cell growth/differentiation (IL6, CD138), type-1 IFN pathway (IRF7, MxA), antigen presentation (CD1a, MHC class II), immunoregulation (p35/EBI3, FoxP3) and cytotoxic cell recruitment and expansion (CD8, Tbet, IL2, CXCL10, CXCR3).
These findings strengthen the link between EBV deregulation, B-cell activation/formation of ectopic B-cell follicles and antiviral immunity in the MS brain.
Disclosure:
Caterina Veroni: nothing to disclose
Barbara Serafini: nothing to disclose
Barbara Rosicarelli: nothing to disclose
Corrado Fagnani: nothing to disclose
Francesca Aloisi: nothing to disclose
This study is funded by Italian Multiple Sclerosis Foundation (grant 2013/R/22 to BS) and Italian Ministry of Health (grant RF 2011-02347228 to FA).
Abstract: P446
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - MS and infections
Epstein-Barr virus (EBV) is widely recognized as a major environmental risk factor for multiple sclerosis (MS) but the mechanisms linking this ubiquitous virus to chronic central nervous system (CNS) inflammation are debated. One of the current hypotheses proposes that immune responses primarily directed toward EBV-infected B cells, the preferred cellular reservoir of the virus, cause bystander damage in the CNS. The goal of this study has been to explore further the hypothesized link between EBV deregulation and immune activation in the MS brain.
Immunohistochemistry, laser capture microdissection and advanced polymerase chain reaction (PCR) methods were combined to study gene expression of well characterized immune infiltrates isolated from post-mortem brain tissue of persons with secondary progressive (SP) MS. Brain tissue was provided by the UK MS Tissue Bank. White matter perivascular cuffs (n=39) and meningeal infiltrates (n=36), including ectopic B-cell follicles, were isolated from brain sections of 11 SPMS cases and analyzed for expression of 78 immune-related genes and 6 EBV genes.
EBV transcripts were detected in CNS immune infiltrates from 9 of 11 SPMS cases, more frequently in meningeal infiltrates and with a pattern consistent with profound viral deregulation (latency disruption and entry into the lytic cycle). As to cellular genes, transcripts associated with type 1 immunity (mediated by Th1/Tc1/NK cells) predominated over transcripts associated with type 2 and type 3 immunity in both meningeal and white matter infiltrates. RNA signals related to B-cell growth/differentiation (BCMA, BAFF), lymphoid tissue formation (CCL19, CCL21), cell proliferation (Ki76), antigen presentation (CD1a), myeloid cell recruitment (CCL2) and type 1 immunity (IFN-gamma) were also significantly higher in meningeal than in white matter infiltrates. A strong association was found in the meninges between EBV transcripts indicative of viral latency disruption (latency II and III programmes) and cellular genes involved in pathogen recognition (TLR9, RIG-1), B-cell growth/differentiation (IL6, CD138), type-1 IFN pathway (IRF7, MxA), antigen presentation (CD1a, MHC class II), immunoregulation (p35/EBI3, FoxP3) and cytotoxic cell recruitment and expansion (CD8, Tbet, IL2, CXCL10, CXCR3).
These findings strengthen the link between EBV deregulation, B-cell activation/formation of ectopic B-cell follicles and antiviral immunity in the MS brain.
Disclosure:
Caterina Veroni: nothing to disclose
Barbara Serafini: nothing to disclose
Barbara Rosicarelli: nothing to disclose
Corrado Fagnani: nothing to disclose
Francesca Aloisi: nothing to disclose
This study is funded by Italian Multiple Sclerosis Foundation (grant 2013/R/22 to BS) and Italian Ministry of Health (grant RF 2011-02347228 to FA).