Contributions
Abstract: P982
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - MS and infections
Natalizumab (NTZ), a humanized monoclonal antibody directed against alpha4 integrin, is a very effective treatment for patients with highly active multiple sclerosis (MS), but rebound of MS disease activity after NTZ discontinuation has emerged. Because NTZ interferes with CNS immune surveillance and our previous studies suggest that a deregulated EBV infection could be the main stimulus for cytotoxic lymphocyte recruitment and activation in the MS brain, in this study we verified the hypothesis that severe MS rebound after NTZ discontinuation might result from devastating immune-mediated inflammation stimulated by uncontrolled EBV expansion and reactivation in CNS-infiltrating B cells.
We have analysed post-mortem brain tissue from a 50-year-old male MS patient who developed a fatal relapse 3 months after NTZ withdrawal, with numerous new active lesions on MRI, CSF lymphocytosis but no evidence of JCV infection (Rigau et al. Neurology 2012;79:2214). Sections cut from 4 brain tissue blocks (2 from the cerebral hemispheres and 2 from the brain stem) were analysed using immunohistochemistry and in situ hybridization. Chronic inactive (n=3), chronic active (n=3) and actively demyelinating white matter lesions (n=3) with different degrees of perivascular and parenchymal lymphocytic infiltration (mainly CD20+ B cells, CD138+ plasma cells and CD8+ T cells) were analyzed.
Cells expressing markers of EBV latent infection (EBER, LMP2A) were detected in most perivascular infiltrates in all lesions analyzed. Cells expressing proteins associated with the immediate early (BZLF1) and early (BFRF1) phases of the EBV lytic cycle were more frequent in chronic active and actively demyelinating lesions. Cells expressing the structural viral proteins p160 and gp350/220 were also detected in all lesions analyzed, being strikingly more numerous in actively demyelinating lesions. CD8+ T cells represented 70-80% of total infiltrating CD3+ T cells; the percentage of CD8+ cells co-expressing granzyme B ranged between 5% and 50% in chronic inactive and actively demyelinating lesions, respectively.
These findings suggest that massive entry of EBV infected cells in the CNS after NTZ withdrawal, or previous intracerebral EBV spreading during NTZ treatment, may have triggered a highly destructive, cytotoxic immune response causing lethal MS rebound after NTZ discontinuation.
This study is funded by grant Ricerca Finalizzata 2011-02347228 of the Italian Ministry of Health to FA.
Disclosure: The authors have nothing to disclose.
Abstract: P982
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - MS and infections
Natalizumab (NTZ), a humanized monoclonal antibody directed against alpha4 integrin, is a very effective treatment for patients with highly active multiple sclerosis (MS), but rebound of MS disease activity after NTZ discontinuation has emerged. Because NTZ interferes with CNS immune surveillance and our previous studies suggest that a deregulated EBV infection could be the main stimulus for cytotoxic lymphocyte recruitment and activation in the MS brain, in this study we verified the hypothesis that severe MS rebound after NTZ discontinuation might result from devastating immune-mediated inflammation stimulated by uncontrolled EBV expansion and reactivation in CNS-infiltrating B cells.
We have analysed post-mortem brain tissue from a 50-year-old male MS patient who developed a fatal relapse 3 months after NTZ withdrawal, with numerous new active lesions on MRI, CSF lymphocytosis but no evidence of JCV infection (Rigau et al. Neurology 2012;79:2214). Sections cut from 4 brain tissue blocks (2 from the cerebral hemispheres and 2 from the brain stem) were analysed using immunohistochemistry and in situ hybridization. Chronic inactive (n=3), chronic active (n=3) and actively demyelinating white matter lesions (n=3) with different degrees of perivascular and parenchymal lymphocytic infiltration (mainly CD20+ B cells, CD138+ plasma cells and CD8+ T cells) were analyzed.
Cells expressing markers of EBV latent infection (EBER, LMP2A) were detected in most perivascular infiltrates in all lesions analyzed. Cells expressing proteins associated with the immediate early (BZLF1) and early (BFRF1) phases of the EBV lytic cycle were more frequent in chronic active and actively demyelinating lesions. Cells expressing the structural viral proteins p160 and gp350/220 were also detected in all lesions analyzed, being strikingly more numerous in actively demyelinating lesions. CD8+ T cells represented 70-80% of total infiltrating CD3+ T cells; the percentage of CD8+ cells co-expressing granzyme B ranged between 5% and 50% in chronic inactive and actively demyelinating lesions, respectively.
These findings suggest that massive entry of EBV infected cells in the CNS after NTZ withdrawal, or previous intracerebral EBV spreading during NTZ treatment, may have triggered a highly destructive, cytotoxic immune response causing lethal MS rebound after NTZ discontinuation.
This study is funded by grant Ricerca Finalizzata 2011-02347228 of the Italian Ministry of Health to FA.
Disclosure: The authors have nothing to disclose.