Contributions
Abstract: P418
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - 12 Pathology
Progressive multifocal leukoencephalopathy (PML) is an opportunistic brain infection caused by the JC virus (JCV) in immunosuppressed patients, e.g. in natalizumab treated MS patients. When the immune system recovers, an immune reconstitution inflammatory syndrome (IRIS) may occur, accompanied by a profound inflammatory reaction. A sufficient immune response is necessary for viral clearance, but can also cause life-threatening brain damage.
The aim of our study was to characterize non-inflammatory (n=7) and inflammatory PML lesions (n=15; >500 lymphoid cells/mm²) histologically to identify the role different immune cell populations play in viral elimination.
Up to 2000 lymphoid cells/mm2 were found in inflammatory PML lesions; these were mainly CD8+ cytotoxic T cells (44%), followed by CD138+ plasma cells (24%), CD4+ T cells (24%) and B cells (8%). The lymphoid infiltrate correlated negatively with the number of virally infected cells, suggesting an effective viral clearance (r=-0.5; p=0.01). The strongest correlation was found for plasma cells (r=-0.7; p=0.0001) and CD8+ T cells (r=-0.5; p=0.01), but not for CD4+ T cells. Patients who survived the PML showed significantly higher numbers of cytotoxic T cells (median 666 cells/mm2) und plasma cells (median 399 cells/mm2) compared to patients who succumbed (median 275 cells/mm2; p=0.04, and 67 cells/mm2; p=0.04). The number of JCV-infected cells correlated negatively with the disease duration (r=-0.6; p=0.01). After a disease duration of 4 months, no or only single virally infected cells were present (median 0.2 infected cells/mm²). PML was suspected in these cases due to highly inflammatory demyelinating lesions, and the diagnosis was finally confirmed by tissue-based PCR. Analysis of B cell/plasma cell clonality revealed biclonal peaks in two different lesions of one patient, indicating a strongly directed immune response.
In conclusion, our results suggest that a strong immune response by plasma cells and cytotoxic T cells is associated with viral elimination in PML. An effective reduction of JCV-infected cells was observed 4 months after diagnosis and the lesions showed a prominent lymphoid infiltrate. Neuropathologists should thus be aware that PML lesions may not always show immunohistochemical evidence of JCV-infected cells. A better understanding of the pathomechanisms of viral clearance may improve our clinical guidance of PML patients.
Disclosure:
Lidia Stork: nothing to disclose
Wolfgang Brück: funding by N-RENNT; honoraria for lectures by Bayer Vital, Biogen, Merck Serono, Teva Pharma, Genzyme, Sanofi-Aventis and Novartis and is a member of scientific advisory boards for Teva Pharma, Biogen, Novartis and Genzyme. He received funding for research projects by Teva Pharma, Biogen, Novartis and Genzyme. Dr Brück serves on the editorial boards of Neuropathology and Applied Neurobiology, Multiple Sclerosis International and Therapeutic Advances in Neurological Disorders.
Wolfram Klapper: nothing to disclose
Caroline Ryschkewitsch: nothing to disclose
Imke Metz: funding by N-RENNT; reports grants from German Ministry for Education and Research (BMBF, ''German Competence Network Multiple Sclerosis'' (KKNMS), Pattern MS/NMO), during the conduct of the study; personal fees from BiogenIdec, Bayer Healthcare, TEVA, Serono, Novartis, grants from BiogenIdec, outside the submitted work.
Abstract: P418
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - 12 Pathology
Progressive multifocal leukoencephalopathy (PML) is an opportunistic brain infection caused by the JC virus (JCV) in immunosuppressed patients, e.g. in natalizumab treated MS patients. When the immune system recovers, an immune reconstitution inflammatory syndrome (IRIS) may occur, accompanied by a profound inflammatory reaction. A sufficient immune response is necessary for viral clearance, but can also cause life-threatening brain damage.
The aim of our study was to characterize non-inflammatory (n=7) and inflammatory PML lesions (n=15; >500 lymphoid cells/mm²) histologically to identify the role different immune cell populations play in viral elimination.
Up to 2000 lymphoid cells/mm2 were found in inflammatory PML lesions; these were mainly CD8+ cytotoxic T cells (44%), followed by CD138+ plasma cells (24%), CD4+ T cells (24%) and B cells (8%). The lymphoid infiltrate correlated negatively with the number of virally infected cells, suggesting an effective viral clearance (r=-0.5; p=0.01). The strongest correlation was found for plasma cells (r=-0.7; p=0.0001) and CD8+ T cells (r=-0.5; p=0.01), but not for CD4+ T cells. Patients who survived the PML showed significantly higher numbers of cytotoxic T cells (median 666 cells/mm2) und plasma cells (median 399 cells/mm2) compared to patients who succumbed (median 275 cells/mm2; p=0.04, and 67 cells/mm2; p=0.04). The number of JCV-infected cells correlated negatively with the disease duration (r=-0.6; p=0.01). After a disease duration of 4 months, no or only single virally infected cells were present (median 0.2 infected cells/mm²). PML was suspected in these cases due to highly inflammatory demyelinating lesions, and the diagnosis was finally confirmed by tissue-based PCR. Analysis of B cell/plasma cell clonality revealed biclonal peaks in two different lesions of one patient, indicating a strongly directed immune response.
In conclusion, our results suggest that a strong immune response by plasma cells and cytotoxic T cells is associated with viral elimination in PML. An effective reduction of JCV-infected cells was observed 4 months after diagnosis and the lesions showed a prominent lymphoid infiltrate. Neuropathologists should thus be aware that PML lesions may not always show immunohistochemical evidence of JCV-infected cells. A better understanding of the pathomechanisms of viral clearance may improve our clinical guidance of PML patients.
Disclosure:
Lidia Stork: nothing to disclose
Wolfgang Brück: funding by N-RENNT; honoraria for lectures by Bayer Vital, Biogen, Merck Serono, Teva Pharma, Genzyme, Sanofi-Aventis and Novartis and is a member of scientific advisory boards for Teva Pharma, Biogen, Novartis and Genzyme. He received funding for research projects by Teva Pharma, Biogen, Novartis and Genzyme. Dr Brück serves on the editorial boards of Neuropathology and Applied Neurobiology, Multiple Sclerosis International and Therapeutic Advances in Neurological Disorders.
Wolfram Klapper: nothing to disclose
Caroline Ryschkewitsch: nothing to disclose
Imke Metz: funding by N-RENNT; reports grants from German Ministry for Education and Research (BMBF, ''German Competence Network Multiple Sclerosis'' (KKNMS), Pattern MS/NMO), during the conduct of the study; personal fees from BiogenIdec, Bayer Healthcare, TEVA, Serono, Novartis, grants from BiogenIdec, outside the submitted work.