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BBA - Molecular Basis of Disease (v.1812, #2)
Viral triggers of multiple sclerosis by Kristina Kakalacheva; Munz Christian Münz; Lunemann Jan D. Lünemann (pp. 132-140).
Genetic and environmental factors jointly determine the susceptibility to develop Multiple Sclerosis (MS). Collaborative efforts during the past years achieved substantial progress in defining the genetic architecture, underlying susceptibility to MS. Similar to other autoimmune diseases, HLA-DR and HLA-DQ alleles within the HLA class II region on chromosome 6p21 are the highest-risk-conferring genes. Less-robust susceptibility effects have been identified for MHC class I alleles and for non-MHC regions. The role of environmental risk factors and their interaction with genetic susceptibility alleles are much less well defined, despite the fact that infections have long been associated with MS development. Current data suggest that infectious triggers are most likely ubiquitous, i.e., highly prevalent in the general population, and that they require a permissive genetic trait which predisposes for MS development. In this review article, we illustrate mechanisms of infection-induced immunopathologies in experimental animal models of autoimmune CNS inflammation, discuss challenges for the translation of these experimental data into human immunology research, and provide future perspectives on how novel model systems could be utilized to better define the role of viral pathogens in MS.
Keywords: Epstein–Barr virus; Human endogenous retrovirus; HHV; Adjuvant; T cells
Viral triggers of multiple sclerosis by Kristina Kakalacheva; Munz Christian Münz; Lunemann Jan D. Lünemann (pp. 132-140).
Genetic and environmental factors jointly determine the susceptibility to develop Multiple Sclerosis (MS). Collaborative efforts during the past years achieved substantial progress in defining the genetic architecture, underlying susceptibility to MS. Similar to other autoimmune diseases, HLA-DR and HLA-DQ alleles within the HLA class II region on chromosome 6p21 are the highest-risk-conferring genes. Less-robust susceptibility effects have been identified for MHC class I alleles and for non-MHC regions. The role of environmental risk factors and their interaction with genetic susceptibility alleles are much less well defined, despite the fact that infections have long been associated with MS development. Current data suggest that infectious triggers are most likely ubiquitous, i.e., highly prevalent in the general population, and that they require a permissive genetic trait which predisposes for MS development. In this review article, we illustrate mechanisms of infection-induced immunopathologies in experimental animal models of autoimmune CNS inflammation, discuss challenges for the translation of these experimental data into human immunology research, and provide future perspectives on how novel model systems could be utilized to better define the role of viral pathogens in MS.
Keywords: Epstein–Barr virus; Human endogenous retrovirus; HHV; Adjuvant; T cells
Radical changes in multiple sclerosis pathogenesis by Jack van Horssen; Maarten E. Witte; Gerty Schreibelt; Helga E. de Vries (pp. 141-150).
Reactive oxygen species (ROS) contain one or more unpaired electrons and are formed as intermediates in a variety of normal biochemical reactions. However, when generated in excess amounts or not appropriately controlled, ROS initiate extensive cellular damage and tissue injury. ROS have been implicated in the progression of cancer, cardiovascular disease and neurodegenerative and neuroinflammatory disorders, such as multiple sclerosis (MS). In the last decade there has been a major interest in the involvement of ROS in MS pathogenesis and evidence is emerging that free radicals play a key role in various processes underlying MS pathology. To counteract ROS-mediated damage, the central nervous system is equipped with an intrinsic defense mechanism consisting of endogenous antioxidant enzymes. Here, we provide a comprehensive overview on the (sub)cellular origin of ROS during neuroinflammation as well as the detrimental effects of ROS in processing underlying MS lesion development and persistence. In addition, we will discuss clinical and experimental studies highlighting the therapeutic potential of antioxidant protection in the pathogenesis of MS.
Keywords: Antioxidants; Multiple sclerosis; Neurodegeneration; Neuroinflammation; Oxidative damage; Reactive oxygen species
Radical changes in multiple sclerosis pathogenesis by Jack van Horssen; Maarten E. Witte; Gerty Schreibelt; Helga E. de Vries (pp. 141-150).
Reactive oxygen species (ROS) contain one or more unpaired electrons and are formed as intermediates in a variety of normal biochemical reactions. However, when generated in excess amounts or not appropriately controlled, ROS initiate extensive cellular damage and tissue injury. ROS have been implicated in the progression of cancer, cardiovascular disease and neurodegenerative and neuroinflammatory disorders, such as multiple sclerosis (MS). In the last decade there has been a major interest in the involvement of ROS in MS pathogenesis and evidence is emerging that free radicals play a key role in various processes underlying MS pathology. To counteract ROS-mediated damage, the central nervous system is equipped with an intrinsic defense mechanism consisting of endogenous antioxidant enzymes. Here, we provide a comprehensive overview on the (sub)cellular origin of ROS during neuroinflammation as well as the detrimental effects of ROS in processing underlying MS lesion development and persistence. In addition, we will discuss clinical and experimental studies highlighting the therapeutic potential of antioxidant protection in the pathogenesis of MS.
Keywords: Antioxidants; Multiple sclerosis; Neurodegeneration; Neuroinflammation; Oxidative damage; Reactive oxygen species
Contribution of CD8 T lymphocytes to the immuno-pathogenesis of multiple sclerosis and its animal models by Lennart T. Mars; Philippe Saikali; Roland S. Liblau; Nathalie Arbour (pp. 151-161).
Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) characterized by multi-focal demyelination, axonal loss, and immune cell infiltration. Numerous immune mediators are detected within MS lesions, including CD4+ and CD8+ T lymphocytes suggesting that they participate in the related pathogenesis. Although CD4+ T lymphocytes are traditionally considered the main actors in MS immunopathology, multiple lines of evidence suggest that CD8+ T lymphocytes are also implicated in the pathogenesis. In this review, we outline the recent literature pertaining to the potential roles of CD8+ T lymphocytes both in MS and its animal models. The CD8+ T lymphocytes detected in MS lesions demonstrate characteristics of activated and clonally expanded cells supporting the notion that these cells actively contribute to the observed injury. Moreover, several experimental in vivo models mediated by CD8+ T lymphocytes recapitulate important features of the human disease. Whether the CD8+ T cells can induce or aggravate tissue destruction in the CNS needs to be fully explored. Strengthening our understanding of the pathogenic potential of CD8+ T cells in MS should provide promising new avenues for the treatment of this disabling inflammatory disease.
Keywords: T lymphocyte; Cytotoxic T cell; Autoimmunity; Central nervous system; Demyelination; Suppressor cell
Contribution of CD8 T lymphocytes to the immuno-pathogenesis of multiple sclerosis and its animal models by Lennart T. Mars; Philippe Saikali; Roland S. Liblau; Nathalie Arbour (pp. 151-161).
Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) characterized by multi-focal demyelination, axonal loss, and immune cell infiltration. Numerous immune mediators are detected within MS lesions, including CD4+ and CD8+ T lymphocytes suggesting that they participate in the related pathogenesis. Although CD4+ T lymphocytes are traditionally considered the main actors in MS immunopathology, multiple lines of evidence suggest that CD8+ T lymphocytes are also implicated in the pathogenesis. In this review, we outline the recent literature pertaining to the potential roles of CD8+ T lymphocytes both in MS and its animal models. The CD8+ T lymphocytes detected in MS lesions demonstrate characteristics of activated and clonally expanded cells supporting the notion that these cells actively contribute to the observed injury. Moreover, several experimental in vivo models mediated by CD8+ T lymphocytes recapitulate important features of the human disease. Whether the CD8+ T cells can induce or aggravate tissue destruction in the CNS needs to be fully explored. Strengthening our understanding of the pathogenic potential of CD8+ T cells in MS should provide promising new avenues for the treatment of this disabling inflammatory disease.
Keywords: T lymphocyte; Cytotoxic T cell; Autoimmunity; Central nervous system; Demyelination; Suppressor cell
Human endogenous retroviruses and multiple sclerosis: Innocent bystanders or disease determinants? by Joseph M. Antony; Andre M. DesLauriers; Rakesh K. Bhat; Kristofer K. Ellestad; Christopher Power (pp. 162-176).
Human endogenous retroviruses (HERVs) constitute 5–8% of human genomic DNA and are replication incompetent despite expression of individual HERV genes from different chromosomal loci depending on the specific tissue. Several HERV genes have been detected as transcripts and proteins in the central nervous system, frequently in the context of neuroinflammation. The HERV-W family has received substantial attention in large part because of associations with diverse syndromes including multiple sclerosis (MS) and several psychiatric disorders. A HERV-W-related retroelement, multiple sclerosis retrovirus (MSRV), has been reported in MS patients to be both a biomarker as well as an effector of aberrant immune responses. HERV-H and HERV-K have also been implicated in MS and other neurological diseases but await delineation of their contributions to disease. The HERV-W envelope-encoded glycosylated protein, syncytin-1, is encoded by chromosome 7q21 and exhibits increased glial expression within MS lesions. Overexpression of syncytin-1 in glia induces endoplasmic reticulum stress leading to neuroinflammation and the induction of free radicals, which damage proximate cells. Syncytin-1's receptor, ASCT1 is a neutral amino acid transporter expressed on glia and is suppressed in white matter of MS patients. Of interest, antioxidants ameliorate syncytin-1's neuropathogenic effects raising the possibility of using these agents as therapeutics for neuroinflammatory diseases. Given the multiple insertion sites of HERV genes as complete and incomplete open reading frames, together with their differing capacity to be expressed and the complexities of individual HERVs as both disease markers and bioactive effectors, HERV biology is a compelling area for understanding neuropathogenic mechanisms and developing new therapeutic strategies.►HERVs express proteins in the brain. ►HERVs represent 8% of the human genome. ►The HERV-W envelope protein protein, Syncytin-1, is found in MS lesions. ►Syncytin-1 induces endoplasmic reticulum (ER) stress in astrocytes.
Keywords: Human endogenous retrovirus; Multiple sclerosis; Neuroinflammation; Neurodegeneration; MSRV; Syncytin-1; Endoplasmic reticulum stress
Human endogenous retroviruses and multiple sclerosis: Innocent bystanders or disease determinants? by Joseph M. Antony; Andre M. DesLauriers; Rakesh K. Bhat; Kristofer K. Ellestad; Christopher Power (pp. 162-176).
Human endogenous retroviruses (HERVs) constitute 5–8% of human genomic DNA and are replication incompetent despite expression of individual HERV genes from different chromosomal loci depending on the specific tissue. Several HERV genes have been detected as transcripts and proteins in the central nervous system, frequently in the context of neuroinflammation. The HERV-W family has received substantial attention in large part because of associations with diverse syndromes including multiple sclerosis (MS) and several psychiatric disorders. A HERV-W-related retroelement, multiple sclerosis retrovirus (MSRV), has been reported in MS patients to be both a biomarker as well as an effector of aberrant immune responses. HERV-H and HERV-K have also been implicated in MS and other neurological diseases but await delineation of their contributions to disease. The HERV-W envelope-encoded glycosylated protein, syncytin-1, is encoded by chromosome 7q21 and exhibits increased glial expression within MS lesions. Overexpression of syncytin-1 in glia induces endoplasmic reticulum stress leading to neuroinflammation and the induction of free radicals, which damage proximate cells. Syncytin-1's receptor, ASCT1 is a neutral amino acid transporter expressed on glia and is suppressed in white matter of MS patients. Of interest, antioxidants ameliorate syncytin-1's neuropathogenic effects raising the possibility of using these agents as therapeutics for neuroinflammatory diseases. Given the multiple insertion sites of HERV genes as complete and incomplete open reading frames, together with their differing capacity to be expressed and the complexities of individual HERVs as both disease markers and bioactive effectors, HERV biology is a compelling area for understanding neuropathogenic mechanisms and developing new therapeutic strategies.►HERVs express proteins in the brain. ►HERVs represent 8% of the human genome. ►The HERV-W envelope protein protein, Syncytin-1, is found in MS lesions. ►Syncytin-1 induces endoplasmic reticulum (ER) stress in astrocytes.
Keywords: Human endogenous retrovirus; Multiple sclerosis; Neuroinflammation; Neurodegeneration; MSRV; Syncytin-1; Endoplasmic reticulum stress
Mouse models for multiple sclerosis: Historical facts and future implications by Andrew L. Croxford; Florian C. Kurschus; Ari Waisman (pp. 177-183).
Multiple sclerosis (MS) is an inflammatory and demyelinating condition of the CNS, characterized by perivascular infiltrates composed largely of T lymphocytes and macrophages. Although the precise cause remains unknown, numerous avenues of research support the hypothesis that autoimmune mechanisms play a major role in the development of the disease. Pathologically similar lesions to those seen in MS can be induced in laboratory rodents by immunization with CNS-derived antigens. This form of disease induction, broadly termed experimental autoimmune encephalomyelitis, is frequently the starting point in MS research with respect to studying pathogenesis and creating novel treatments. Many different EAE models are available, each mimicking a particular facet of MS. These models all have common ancestry, and have developed from a single concept of immunization with self-antigen. We will discuss the major changes in immunology research, which have shaped the EAE models we use today, and discuss how current animal models of MS have resulted in successful treatments and more open questions for researchers to address.
Keywords: Multiple sclerosis; Experimental autoimmune encephalomyelitis
Mouse models for multiple sclerosis: Historical facts and future implications by Andrew L. Croxford; Florian C. Kurschus; Ari Waisman (pp. 177-183).
Multiple sclerosis (MS) is an inflammatory and demyelinating condition of the CNS, characterized by perivascular infiltrates composed largely of T lymphocytes and macrophages. Although the precise cause remains unknown, numerous avenues of research support the hypothesis that autoimmune mechanisms play a major role in the development of the disease. Pathologically similar lesions to those seen in MS can be induced in laboratory rodents by immunization with CNS-derived antigens. This form of disease induction, broadly termed experimental autoimmune encephalomyelitis, is frequently the starting point in MS research with respect to studying pathogenesis and creating novel treatments. Many different EAE models are available, each mimicking a particular facet of MS. These models all have common ancestry, and have developed from a single concept of immunization with self-antigen. We will discuss the major changes in immunology research, which have shaped the EAE models we use today, and discuss how current animal models of MS have resulted in successful treatments and more open questions for researchers to address.
Keywords: Multiple sclerosis; Experimental autoimmune encephalomyelitis
Cells of the oligodendroglial lineage, myelination, and remyelination by Veronique E. Miron; Tanja Kuhlmann; Jack P. Antel (pp. 184-193).
Myelin is critical in maintaining electrical impulse conduction in the central nervous system. The oligodendrocyte is the cell type responsible for myelin production within this compartment. The mutual supply of trophic support between oligodendrocytes and the underlying axons may indicate why demyelinated axons undergo degeneration more readily; the latter contributes to the neural decline in multiple sclerosis (MS). Myelin repair, termed remyelination, occurs in acute inflammatory lesions in MS and is associated with functional recovery and clinical remittances. Animal models have demonstrated that remyelination is mediated by oligodendrocyte progenitor cells (OPCs) which have responded to chemotactic cues, migrated into the lesion, proliferated, differentiated into mature oligodendrocytes, and ensheathed demyelinated axons. The limited remyelination observed in more chronic MS lesions may reflect intrinsic properties of neural cells or extrinsic deterrents. Therapeutic strategies currently under development include transplantation of exogenous OPCs and promotion of remyelination by endogenous OPCs. All currently approved MS therapies are aimed at dampening the immune response and are not directly targeting neural processes.► The oligodendrocyte is the CNS cell type responsible for production of the myelin sheath. ► Newly differentiated oligodendrocyte progenitor cells mediate myelin repair (remyelination). ► Transplantation of exogenous progenitors or targeting endogenous ones may enhance remyelination.
Keywords: Myelin; Remyelination; Oligodendrocyte; Oligodendrocyte progenitor cell; Multiple sclerosis; Repair
Cells of the oligodendroglial lineage, myelination, and remyelination by Veronique E. Miron; Tanja Kuhlmann; Jack P. Antel (pp. 184-193).
Myelin is critical in maintaining electrical impulse conduction in the central nervous system. The oligodendrocyte is the cell type responsible for myelin production within this compartment. The mutual supply of trophic support between oligodendrocytes and the underlying axons may indicate why demyelinated axons undergo degeneration more readily; the latter contributes to the neural decline in multiple sclerosis (MS). Myelin repair, termed remyelination, occurs in acute inflammatory lesions in MS and is associated with functional recovery and clinical remittances. Animal models have demonstrated that remyelination is mediated by oligodendrocyte progenitor cells (OPCs) which have responded to chemotactic cues, migrated into the lesion, proliferated, differentiated into mature oligodendrocytes, and ensheathed demyelinated axons. The limited remyelination observed in more chronic MS lesions may reflect intrinsic properties of neural cells or extrinsic deterrents. Therapeutic strategies currently under development include transplantation of exogenous OPCs and promotion of remyelination by endogenous OPCs. All currently approved MS therapies are aimed at dampening the immune response and are not directly targeting neural processes.► The oligodendrocyte is the CNS cell type responsible for production of the myelin sheath. ► Newly differentiated oligodendrocyte progenitor cells mediate myelin repair (remyelination). ► Transplantation of exogenous progenitors or targeting endogenous ones may enhance remyelination.
Keywords: Myelin; Remyelination; Oligodendrocyte; Oligodendrocyte progenitor cell; Multiple sclerosis; Repair
Genetics of multiple sclerosis by Ilse A. Hoppenbrouwers; Rogier Q. Hintzen (pp. 194-201).
► Maternal transmission of MS. ► Non-HLA MS risk variants. ► Identifying risk genes results in better understanding MS.
Keywords: MS; Genes; Pathogenesis; SNP; Autoimmunity; HLA
Genetics of multiple sclerosis by Ilse A. Hoppenbrouwers; Rogier Q. Hintzen (pp. 194-201).
► Maternal transmission of MS. ► Non-HLA MS risk variants. ► Identifying risk genes results in better understanding MS.
Keywords: MS; Genes; Pathogenesis; SNP; Autoimmunity; HLA
Assessment of evidence for a protective role of vitamin D in multiple sclerosis by Heather E.C. Hanwell; Brenda Banwell (pp. 202-212).
Evidence for a role of vitamin D insufficiency in determining risk in Multiple Sclerosis (MS) is supported by studies in both pediatric- and adult-onset patients. The potential role of vitamin D in modulating MS disease activity is an area of active clinical trials research, and the possibility of primary disease prevention with vitamin D supplementation in early life is an emerging concept. With Sir Austin Bradford Hill's criteria as a framework, the present review assesses the evidence for a causal relationship between vitamin D insufficiency and the pathobiology of MS, and discusses rationale for future clinical trials with vitamin D.
Keywords: Vitamin D; Multiple Sclerosis; Hill's Criteria
Assessment of evidence for a protective role of vitamin D in multiple sclerosis by Heather E.C. Hanwell; Brenda Banwell (pp. 202-212).
Evidence for a role of vitamin D insufficiency in determining risk in Multiple Sclerosis (MS) is supported by studies in both pediatric- and adult-onset patients. The potential role of vitamin D in modulating MS disease activity is an area of active clinical trials research, and the possibility of primary disease prevention with vitamin D supplementation in early life is an emerging concept. With Sir Austin Bradford Hill's criteria as a framework, the present review assesses the evidence for a causal relationship between vitamin D insufficiency and the pathobiology of MS, and discusses rationale for future clinical trials with vitamin D.
Keywords: Vitamin D; Multiple Sclerosis; Hill's Criteria
The many faces of EMMPRIN—Roles in neuroinflammation by Smriti M. Agrawal; V. Wee Yong (pp. 213-219).
The central nervous system (CNS) is a relatively immune-privileged organ, wherein a well-instated barrier system (the blood–brain barrier) prevents the entry of blood cells into the brain with the exception of regular immune surveillance cells. Despite this tight security immune cells are successful in entering the CNS tissue where they result in states of neuroinflammation, tissue damage and cell death. Various components of the blood–brain barrier and infiltrating cells have been examined to better understand how blood cells are able to breach this secure barrier. Proteases, specifically matrix metalloproteinases (MMP), have been found to be the common culprits in most diseases involving neuroinflammation. MMPs secreted by infiltrating cells act specifically upon targets on various components of the blood–brain barrier, compromising this barrier and allowing cell infiltration into the CNS. Extracellular matrix metalloproteinase inducer (EMMPRIN) is an upstream inducer of several MMPs and is suggested to be the master regulator of MMP production in disease states such as cancer metastasis. EMMPRIN in the context of the CNS is still relatively understudied. In this review we will introduce EMMPRIN, discuss its ligands and roles in non-CNS conditions that can help implicate its involvement in CNS disorders, showcase its expression within the CNS in healthy and disease conditions, elucidate its ligands and receptors, and briefly discuss the emerging roles it plays in various diseases of the CNS involving inflammation.
Keywords: Extracellular matrix metalloproteinase inducer (EMMPRIN); Central nervous system disease; Multiple Sclerosis
The many faces of EMMPRIN—Roles in neuroinflammation by Smriti M. Agrawal; V. Wee Yong (pp. 213-219).
The central nervous system (CNS) is a relatively immune-privileged organ, wherein a well-instated barrier system (the blood–brain barrier) prevents the entry of blood cells into the brain with the exception of regular immune surveillance cells. Despite this tight security immune cells are successful in entering the CNS tissue where they result in states of neuroinflammation, tissue damage and cell death. Various components of the blood–brain barrier and infiltrating cells have been examined to better understand how blood cells are able to breach this secure barrier. Proteases, specifically matrix metalloproteinases (MMP), have been found to be the common culprits in most diseases involving neuroinflammation. MMPs secreted by infiltrating cells act specifically upon targets on various components of the blood–brain barrier, compromising this barrier and allowing cell infiltration into the CNS. Extracellular matrix metalloproteinase inducer (EMMPRIN) is an upstream inducer of several MMPs and is suggested to be the master regulator of MMP production in disease states such as cancer metastasis. EMMPRIN in the context of the CNS is still relatively understudied. In this review we will introduce EMMPRIN, discuss its ligands and roles in non-CNS conditions that can help implicate its involvement in CNS disorders, showcase its expression within the CNS in healthy and disease conditions, elucidate its ligands and receptors, and briefly discuss the emerging roles it plays in various diseases of the CNS involving inflammation.
Keywords: Extracellular matrix metalloproteinase inducer (EMMPRIN); Central nervous system disease; Multiple Sclerosis
The blood–brain barrier, chemokines and multiple sclerosis by David W. Holman; Robyn S. Klein; Richard M. Ransohoff (pp. 220-230).
The infiltration of leukocytes into the central nervous system (CNS) is an essential step in the neuropathogenesis of multiple sclerosis (MS). Leukocyte extravasation from the bloodstream is a multistep process that depends on several factors including fluid dynamics within the vasculature and molecular interactions between circulating leukocytes and the vascular endothelium. An important step in this cascade is the presence of chemokines on the vascular endothelial cell surface. Chemokines displayed along the endothelial lumen bind chemokine receptors on circulating leukocytes, initiating intracellular signaling that culminates in integrin activation, leukocyte arrest, and extravasation. The presence of chemokines at the endothelial lumen can help guide the movement of leukocytes through peripheral tissues during normal immune surveillance, host defense or inflammation. The expression and display of homeostatic or inflammatory chemokines therefore critically determine which leukocyte subsets extravasate and enter the peripheral tissues. Within the CNS, however, infiltrating leukocytes that cross the endothelium face additional boundaries to parenchymal entry, including the abluminal presence of localizing cues that prevent egress from perivascular spaces. This review focuses on the differential display of chemokines along endothelial surfaces and how they impact leukocyte extravasation into parenchymal tissues, especially within the CNS. In particular, the display of chemokines by endothelial cells of the blood brain barrier may be altered during CNS autoimmune disease, promoting leukocyte entry into this immunologically distinct site. Recent advances in microscopic techniques, including two-photon and intravital imaging have provided new insights into the mechanisms of chemokine-mediated capture of leukocytes within the CNS.► Leukocyte extravasation from the bloodstream into peripheral tissues is a multistep process. ► Chemokines displayed along endothelial surfaces provide guiding cues to circulating leukocytes and intiate intracellular signalling cascades. ► The central nervous system is considered an immunologically specialized site and leukocyte trafficking is tightly regulated by anatomical and biochemical specializations. ► The central nervous system is considered an immunologically specialized site and leukocyte trafficking is tightly regulated by anatomical and biochemical specializations.
Keywords: Blood–brain barrier; Chemokine; Leukocyte; Inflammation
The blood–brain barrier, chemokines and multiple sclerosis by David W. Holman; Robyn S. Klein; Richard M. Ransohoff (pp. 220-230).
The infiltration of leukocytes into the central nervous system (CNS) is an essential step in the neuropathogenesis of multiple sclerosis (MS). Leukocyte extravasation from the bloodstream is a multistep process that depends on several factors including fluid dynamics within the vasculature and molecular interactions between circulating leukocytes and the vascular endothelium. An important step in this cascade is the presence of chemokines on the vascular endothelial cell surface. Chemokines displayed along the endothelial lumen bind chemokine receptors on circulating leukocytes, initiating intracellular signaling that culminates in integrin activation, leukocyte arrest, and extravasation. The presence of chemokines at the endothelial lumen can help guide the movement of leukocytes through peripheral tissues during normal immune surveillance, host defense or inflammation. The expression and display of homeostatic or inflammatory chemokines therefore critically determine which leukocyte subsets extravasate and enter the peripheral tissues. Within the CNS, however, infiltrating leukocytes that cross the endothelium face additional boundaries to parenchymal entry, including the abluminal presence of localizing cues that prevent egress from perivascular spaces. This review focuses on the differential display of chemokines along endothelial surfaces and how they impact leukocyte extravasation into parenchymal tissues, especially within the CNS. In particular, the display of chemokines by endothelial cells of the blood brain barrier may be altered during CNS autoimmune disease, promoting leukocyte entry into this immunologically distinct site. Recent advances in microscopic techniques, including two-photon and intravital imaging have provided new insights into the mechanisms of chemokine-mediated capture of leukocytes within the CNS.► Leukocyte extravasation from the bloodstream into peripheral tissues is a multistep process. ► Chemokines displayed along endothelial surfaces provide guiding cues to circulating leukocytes and intiate intracellular signalling cascades. ► The central nervous system is considered an immunologically specialized site and leukocyte trafficking is tightly regulated by anatomical and biochemical specializations. ► The central nervous system is considered an immunologically specialized site and leukocyte trafficking is tightly regulated by anatomical and biochemical specializations.
Keywords: Blood–brain barrier; Chemokine; Leukocyte; Inflammation
MS and the B cell controversy by Anne H. Cross; Emmanuelle Waubant (pp. 231-238).
The contribution of B cells and their products to the pathogenesis of MS has long been debated. The presence of B cells, plasma cells and excess immunoglobulins in MS lesions and in the cerebrospinal fluid of MS patients implicate the humoral immune system in the disease. Correlations of higher levels of CSF B cells and immunoglobulins found in some studies with a more aggressive clinical course of MS have bolstered the notion that the humoral immune system is involved in MS pathogenesis. However, until the advent of rituximab, a monoclonal antibody therapy that specifically lyses B cells, confirmation of the key role of B cells and their products in MS had been lacking. Development of this therapeutic monoclonal antibody to CD20, a cell surface molecule confined to B cells, allowed determination of the effects of B cell depletion. Perhaps somewhat unexpectedly, depletion of circulating B cells led to rapid and profound reduction in gadolinium enhancing lesions on brain MRI in three separate studies in relapsing MS subjects. When examined, depletion of B cells in the blood was accompanied by depletion of B cells in CSF. Notably, reduction of enhancing brain lesions was not accompanied by reduction in CSF immunoglobulins. Whether the critical role of B cells occurs in the periphery, in the CNS, or in both locations has not yet been determined.
Keywords: Multiple sclerosis; B lymphocyte; Antibody; Rituximab; Therapy
MS and the B cell controversy by Anne H. Cross; Emmanuelle Waubant (pp. 231-238).
The contribution of B cells and their products to the pathogenesis of MS has long been debated. The presence of B cells, plasma cells and excess immunoglobulins in MS lesions and in the cerebrospinal fluid of MS patients implicate the humoral immune system in the disease. Correlations of higher levels of CSF B cells and immunoglobulins found in some studies with a more aggressive clinical course of MS have bolstered the notion that the humoral immune system is involved in MS pathogenesis. However, until the advent of rituximab, a monoclonal antibody therapy that specifically lyses B cells, confirmation of the key role of B cells and their products in MS had been lacking. Development of this therapeutic monoclonal antibody to CD20, a cell surface molecule confined to B cells, allowed determination of the effects of B cell depletion. Perhaps somewhat unexpectedly, depletion of circulating B cells led to rapid and profound reduction in gadolinium enhancing lesions on brain MRI in three separate studies in relapsing MS subjects. When examined, depletion of B cells in the blood was accompanied by depletion of B cells in CSF. Notably, reduction of enhancing brain lesions was not accompanied by reduction in CSF immunoglobulins. Whether the critical role of B cells occurs in the periphery, in the CNS, or in both locations has not yet been determined.
Keywords: Multiple sclerosis; B lymphocyte; Antibody; Rituximab; Therapy
The role of antibodies in multiple sclerosis by Martin S. Weber; Bernhard Hemmer; Sabine Cepok (pp. 239-245).
B cells, plasma cells, and antibodies are commonly found in active central nervous system (CNS) lesions in patients with multiple sclerosis (MS). B cells isolated from CNS lesions as well as from the cerebrospinal fluid (CSF) show signs of clonal expansion and hypermutation, suggesting their local activation. Plasma blasts and plasma cells maturating from these B cells were recently identified to contribute to the development of oligoclonal antibodies produced within the CSF, which remain a diagnostic hallmark finding in MS. Within the CNS, antibody deposition is associated with complement activation and demyelination, indicating antigen recognition-associated effector function. While some studies indeed implied a disease-intrinsic and possibly pathogenic role of antibodies directed against components of the myelin sheath, no unequivocal results on a decisive target antigen within the CNS persisted to date. The notion of a pathogenic role for antibodies in MS is nevertheless empirically supported by the clinical benefit of plasma exchange in patients with histologic signs of antibody deposition within the CNS. Further, such evidence derives from the animal model of MS, experimental autoimmune encephalomyelitis (EAE). In transgenic mice endogenously producing myelin-specific antibodies, EAE severity was substantially increased accompanied by enhanced CNS demyelination. Further, genetic engineering in mice adding T cells that recognize the same myelin antigen resulted in spontaneous EAE development, indicating that the coexistence of myelin-specific B cells, T cells, and antibodies was sufficient to trigger CNS autoimmune disease. In conclusion, various pathological, clinical, immunological, and experimental findings collectively indicate a pathogenic role of antibodies in MS, whereas several conceptual challenges, above all uncovering potential target antigens of the antibody response within the CNS, remain to be overcome.
Keywords: Antibody; B cell; Multiple sclerosis; Experimental autoimmune encephalomyelitis
The role of antibodies in multiple sclerosis by Martin S. Weber; Bernhard Hemmer; Sabine Cepok (pp. 239-245).
B cells, plasma cells, and antibodies are commonly found in active central nervous system (CNS) lesions in patients with multiple sclerosis (MS). B cells isolated from CNS lesions as well as from the cerebrospinal fluid (CSF) show signs of clonal expansion and hypermutation, suggesting their local activation. Plasma blasts and plasma cells maturating from these B cells were recently identified to contribute to the development of oligoclonal antibodies produced within the CSF, which remain a diagnostic hallmark finding in MS. Within the CNS, antibody deposition is associated with complement activation and demyelination, indicating antigen recognition-associated effector function. While some studies indeed implied a disease-intrinsic and possibly pathogenic role of antibodies directed against components of the myelin sheath, no unequivocal results on a decisive target antigen within the CNS persisted to date. The notion of a pathogenic role for antibodies in MS is nevertheless empirically supported by the clinical benefit of plasma exchange in patients with histologic signs of antibody deposition within the CNS. Further, such evidence derives from the animal model of MS, experimental autoimmune encephalomyelitis (EAE). In transgenic mice endogenously producing myelin-specific antibodies, EAE severity was substantially increased accompanied by enhanced CNS demyelination. Further, genetic engineering in mice adding T cells that recognize the same myelin antigen resulted in spontaneous EAE development, indicating that the coexistence of myelin-specific B cells, T cells, and antibodies was sufficient to trigger CNS autoimmune disease. In conclusion, various pathological, clinical, immunological, and experimental findings collectively indicate a pathogenic role of antibodies in MS, whereas several conceptual challenges, above all uncovering potential target antigens of the antibody response within the CNS, remain to be overcome.
Keywords: Antibody; B cell; Multiple sclerosis; Experimental autoimmune encephalomyelitis
Th1 versus Th17: Are T cell cytokines relevant in multiple sclerosis? by Amy E. Lovett-Racke; Yuhong Yang; Michael K. Racke (pp. 246-251).
Our understanding of the pathophysiology of multiple sclerosis (MS) has evolved significantly over the past two decades as the fields of immunology and neurobiology provide new avenues of exploration into the cause and mechanism of the disease. It has been known for decades that T cells have different cytokine phenotypes, yet the cytokine phenotype of pathogenic T cells in MS is still an area of debate. In EAE, it appears that IFNγ and IL-17, produced by Th1 and Th17 cells respectively, are not the critical factor that determines T cell encephalitogenicity. However, there are molecules such as IL-23, T-bet and STAT4, that appear to be critical, yet it is unclear whether all these molecules contribute to a common, yet undefined pathway, or act in a synergistic manner which culminates in encephalitogenicity has still to be determined. Therefore, the focus of research on effector T cells in MS should focus on pathways upstream of the cytokines that define Th1 and Th17 cells, since downstream products, such as IFNγ and IL-17, probably are not critical determinants of whether an effector T cells is capable of trafficking to the CNS and inducing inflammatory demyelination.
Keywords: Multiple sclerosis; Experimental autoimmune encephalomyelitis; Interferon-gamma; Interleukin-17
Th1 versus Th17: Are T cell cytokines relevant in multiple sclerosis? by Amy E. Lovett-Racke; Yuhong Yang; Michael K. Racke (pp. 246-251).
Our understanding of the pathophysiology of multiple sclerosis (MS) has evolved significantly over the past two decades as the fields of immunology and neurobiology provide new avenues of exploration into the cause and mechanism of the disease. It has been known for decades that T cells have different cytokine phenotypes, yet the cytokine phenotype of pathogenic T cells in MS is still an area of debate. In EAE, it appears that IFNγ and IL-17, produced by Th1 and Th17 cells respectively, are not the critical factor that determines T cell encephalitogenicity. However, there are molecules such as IL-23, T-bet and STAT4, that appear to be critical, yet it is unclear whether all these molecules contribute to a common, yet undefined pathway, or act in a synergistic manner which culminates in encephalitogenicity has still to be determined. Therefore, the focus of research on effector T cells in MS should focus on pathways upstream of the cytokines that define Th1 and Th17 cells, since downstream products, such as IFNγ and IL-17, probably are not critical determinants of whether an effector T cells is capable of trafficking to the CNS and inducing inflammatory demyelination.
Keywords: Multiple sclerosis; Experimental autoimmune encephalomyelitis; Interferon-gamma; Interleukin-17
Disruption of central nervous system barriers in multiple sclerosis by Jorge Ivan Alvarez; Romain Cayrol; Alexandre Prat (pp. 252-264).
The delicate microenvironment of the central nervous system (CNS) is protected by the blood–brain barrier (BBB) and the blood–cerebrospinal fluid barrier (BCB). These barriers function in distinct CNS compartments and their anatomical basis lay on the junctional proteins present in endothelial cells for the BBB and in the choroidal epithelium for the BCB. During neuroinflammatory conditions like multiple sclerosis (MS) and its murine model experimental autoimmune encephalomyelitis (EAE), activation or damage of the various cellular components of these barriers facilitate leukocyte infiltration leading to oligodendrocyte death, axonal damage, demyelination and lesion development. This manuscript will review in detail the features of these barriers under physiological and pathological conditions, particularly when focal immune activation promotes the loss of the BBB and BCB phenotype, the upregulation of cell adhesion molecules (CAMs) and the recruitment of immune cells.
Keywords: BBB; BCB; MS; EAE; CAMs; Transmigration; Neuroinflammation; Choroid plexus; Basal lamina; Basement membrane; Endothelial cells; Tight junctions; Adherens junctions; Astrocyte; Chemokine; ECM; Pericyte; ICAM-1; VCAM-1; ALCAM; VLA-4; P-selectin; Ependyma
Disruption of central nervous system barriers in multiple sclerosis by Jorge Ivan Alvarez; Romain Cayrol; Alexandre Prat (pp. 252-264).
The delicate microenvironment of the central nervous system (CNS) is protected by the blood–brain barrier (BBB) and the blood–cerebrospinal fluid barrier (BCB). These barriers function in distinct CNS compartments and their anatomical basis lay on the junctional proteins present in endothelial cells for the BBB and in the choroidal epithelium for the BCB. During neuroinflammatory conditions like multiple sclerosis (MS) and its murine model experimental autoimmune encephalomyelitis (EAE), activation or damage of the various cellular components of these barriers facilitate leukocyte infiltration leading to oligodendrocyte death, axonal damage, demyelination and lesion development. This manuscript will review in detail the features of these barriers under physiological and pathological conditions, particularly when focal immune activation promotes the loss of the BBB and BCB phenotype, the upregulation of cell adhesion molecules (CAMs) and the recruitment of immune cells.
Keywords: BBB; BCB; MS; EAE; CAMs; Transmigration; Neuroinflammation; Choroid plexus; Basal lamina; Basement membrane; Endothelial cells; Tight junctions; Adherens junctions; Astrocyte; Chemokine; ECM; Pericyte; ICAM-1; VCAM-1; ALCAM; VLA-4; P-selectin; Ependyma
The role of antigen presenting cells in multiple sclerosis by Emily M.L. Chastain; D'Anne S. Duncan; Jane M. Rodgers; Stephen D. Miller (pp. 265-274).
Multiple sclerosis (MS) is a debilitating T cell mediated autoimmune disease of the central nervous system (CNS). Animal models of MS, such as experimental autoimmune encephalomyelitis (EAE) and Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) have given light to cellular mechanisms involved in the initiation and progression of this organ-specific autoimmune disease. Within the CNS, antigen presenting cells (APC) such as microglia and astrocytes participate as first line defenders against infections or inflammation. However, during chronic inflammation they can participate in perpetuating the self-destructive environment by secretion of inflammatory factors and/or presentation of myelin epitopes to autoreactive T cells. Dendritic cells (DC) are also participants in the presentation of antigen to T cells, even within the CNS. While the APCs alone are not solely responsible for mediating the destruction to the myelin sheath, they are critical players in perpetuating the inflammatory milieu. This review will highlight relevant studies which have provided insight to the roles played by microglia, DCs and astrocytes in the context of CNS autoimmunity.
Keywords: Multiple sclerosis; EAE; TMEV-IDD; Microglia; Astrocyte; Dendritic cell
The role of antigen presenting cells in multiple sclerosis by Emily M.L. Chastain; D'Anne S. Duncan; Jane M. Rodgers; Stephen D. Miller (pp. 265-274).
Multiple sclerosis (MS) is a debilitating T cell mediated autoimmune disease of the central nervous system (CNS). Animal models of MS, such as experimental autoimmune encephalomyelitis (EAE) and Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) have given light to cellular mechanisms involved in the initiation and progression of this organ-specific autoimmune disease. Within the CNS, antigen presenting cells (APC) such as microglia and astrocytes participate as first line defenders against infections or inflammation. However, during chronic inflammation they can participate in perpetuating the self-destructive environment by secretion of inflammatory factors and/or presentation of myelin epitopes to autoreactive T cells. Dendritic cells (DC) are also participants in the presentation of antigen to T cells, even within the CNS. While the APCs alone are not solely responsible for mediating the destruction to the myelin sheath, they are critical players in perpetuating the inflammatory milieu. This review will highlight relevant studies which have provided insight to the roles played by microglia, DCs and astrocytes in the context of CNS autoimmunity.
Keywords: Multiple sclerosis; EAE; TMEV-IDD; Microglia; Astrocyte; Dendritic cell
Inflammation, demyelination, and degeneration — Recent insights from MS pathology by Christine Stadelmann; Christiane Wegner; Bruck Wolfgang Brück (pp. 275-282).
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system which responds to anti-inflammatory treatments in the early disease phase. However, the pathogenesis of the progressive disease phase is less well understood, and inflammatory as well as neurodegenerative mechanisms of tissue damage are currently being discussed. This review summarizes current knowledge on the interrelation between inflammation, demyelination, and neurodegeneration derived from the study of human autopsy and biopsy brain tissue and experimental models of MS.
Keywords: Multiple sclerosis; Pathogenesis; Pathology; Neuroaxonal damage; Autoimmunity; Progressive disease
Inflammation, demyelination, and degeneration — Recent insights from MS pathology by Christine Stadelmann; Christiane Wegner; Bruck Wolfgang Brück (pp. 275-282).
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system which responds to anti-inflammatory treatments in the early disease phase. However, the pathogenesis of the progressive disease phase is less well understood, and inflammatory as well as neurodegenerative mechanisms of tissue damage are currently being discussed. This review summarizes current knowledge on the interrelation between inflammation, demyelination, and neurodegeneration derived from the study of human autopsy and biopsy brain tissue and experimental models of MS.
Keywords: Multiple sclerosis; Pathogenesis; Pathology; Neuroaxonal damage; Autoimmunity; Progressive disease