Contributions
Abstract: EP1462
Type: ePoster
Abstract Category: Pathology and pathogenesis of MS - 13 Experimental models
Neuromyelitis optica (NMO) is a heterogeneous condition with the histopathological hallmarks inflammation, demyelination and focal loss of aquaporin 4 (AQP4). While antibodies targeting AQP4 are believed to be central to NMO pathogenicity, anti-AQP4 immunoglobulin is absent in approximately one-fourth of NMO patients. Two distinct pathological entities might mediate tissue damage in NMO: innate and adaptive inflammation. We assume that innate and adaptive immunity cascades differentially regulate AQP4, and specifically contribute to the development of destructive NMO lesions.
Innate inflammation was triggered by feeding young mice with 0.25% Cuprizone (Cup) mixed into ground rodent chow for 5 weeks. The liaison of innate and adaptive immunity was realized by combining the cuprizone model with active Experimental Autoimmune Encephalomyelitis (i.e. Cup/EAE). AQP4 distribution was further characterized in post mortem samples of progressive MS patients. ELISA was performed to screen for anti-AQP4 antibodies in our model. Discrimination of microglia and recruited monocytes was done using CX3CR1+/eGFP CCR2+/RFP mice.
Activation of innate immunity by cuprizone resulted in a pronounced diffuse AQP4 deposition within the demyelinated white matter. The same staining pattern was found in lesions of progressive MS patients. In the grey matter cortex, polarized AQP4 expression on astrocytic foot processes was lost, paralleled by a modest increase of diffuse staining intensity. Such lesions were characterized by reactive gliosis and pronounced microglia activation, but absence of T-cells and granulocytes. In Cup/EAE mice, several perivascular inflammatory infiltrates were found, and these were intensively populated by CCR2+ monocytes, CD4+ T-cells and granulocytes. Interestingly, anti-AQP4 staining intensity dramatically reduced at the close vicinity of perivascular infiltrates. Furthermore, some of these lesions showed retraction of perivascular astrocyte processes. These pathological changes occurred despite the absence of anti-AQP4 antibodies or focal complement deposition.
This study highlights the simultaneous effects of innate and adaptive immunity on AQP4 pathology. We propose that tissue damage in seronegative NMO patients begins with innate immune activation followed by secondary peripheral immune cell recruitment. The relation to types 4-6 lesions (Misu, Lassmann, Acta. Neuropathol. 2013) remains to be clarified.
Disclosure:
Sven Olaf Rohr: Nothing to disclosure.
Peter Ponsaerts: Nothing to disclosure.
Markus Kipp: Nothing to disclosure.
Abstract: EP1462
Type: ePoster
Abstract Category: Pathology and pathogenesis of MS - 13 Experimental models
Neuromyelitis optica (NMO) is a heterogeneous condition with the histopathological hallmarks inflammation, demyelination and focal loss of aquaporin 4 (AQP4). While antibodies targeting AQP4 are believed to be central to NMO pathogenicity, anti-AQP4 immunoglobulin is absent in approximately one-fourth of NMO patients. Two distinct pathological entities might mediate tissue damage in NMO: innate and adaptive inflammation. We assume that innate and adaptive immunity cascades differentially regulate AQP4, and specifically contribute to the development of destructive NMO lesions.
Innate inflammation was triggered by feeding young mice with 0.25% Cuprizone (Cup) mixed into ground rodent chow for 5 weeks. The liaison of innate and adaptive immunity was realized by combining the cuprizone model with active Experimental Autoimmune Encephalomyelitis (i.e. Cup/EAE). AQP4 distribution was further characterized in post mortem samples of progressive MS patients. ELISA was performed to screen for anti-AQP4 antibodies in our model. Discrimination of microglia and recruited monocytes was done using CX3CR1+/eGFP CCR2+/RFP mice.
Activation of innate immunity by cuprizone resulted in a pronounced diffuse AQP4 deposition within the demyelinated white matter. The same staining pattern was found in lesions of progressive MS patients. In the grey matter cortex, polarized AQP4 expression on astrocytic foot processes was lost, paralleled by a modest increase of diffuse staining intensity. Such lesions were characterized by reactive gliosis and pronounced microglia activation, but absence of T-cells and granulocytes. In Cup/EAE mice, several perivascular inflammatory infiltrates were found, and these were intensively populated by CCR2+ monocytes, CD4+ T-cells and granulocytes. Interestingly, anti-AQP4 staining intensity dramatically reduced at the close vicinity of perivascular infiltrates. Furthermore, some of these lesions showed retraction of perivascular astrocyte processes. These pathological changes occurred despite the absence of anti-AQP4 antibodies or focal complement deposition.
This study highlights the simultaneous effects of innate and adaptive immunity on AQP4 pathology. We propose that tissue damage in seronegative NMO patients begins with innate immune activation followed by secondary peripheral immune cell recruitment. The relation to types 4-6 lesions (Misu, Lassmann, Acta. Neuropathol. 2013) remains to be clarified.
Disclosure:
Sven Olaf Rohr: Nothing to disclosure.
Peter Ponsaerts: Nothing to disclosure.
Markus Kipp: Nothing to disclosure.