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Immunopathology of multiple sclerosis

Key Points

  • Two decades of clinical experience with the immunomodulatory treatment of multiple sclerosis points to distinct immunological pathways that drive disease relapses and progression. Although the immunomodulatory drugs reduce the frequency of relapses, the trade-off of efficacy is a range of side effects, and the long-standing drugs approved for multiple sclerosis do not ultimately halt neurodegeneration.

  • Dissecting the distinct roles of the immune system in multiple sclerosis is complicated by one, the multicellular pathophysiology that involves infiltrating adaptive and innate immune cells, as well as central nervous system (CNS)-resident innate cells with inflammatory capacity; and two, the chronic nature of the disease that unfolds over a period of many decades.

  • Multiple sclerosis is associated with more than 100 different genetic variants that promote disease predisposition and with environmental influences that alter disease penetrance and stochastic occurrences, although the exact triggering events may vary from one patient to the next. Despite the progress in identifying the genetic determinants of the disease, their phenotypic consequences remain to be elucidated, and a substantial understanding of environmental contributors is lacking.

  • Dysregulation of immune effector–suppressor cell interactions occurs in multiple sclerosis, ultimately resulting in autoreactive adaptive immune cells that are capable of infiltrating and promoting damage within the CNS. However, these cells may not be the main drivers of more chronic, progressive neurodegeneration.

  • Chronic inflammation in multiple sclerosis may reflect a long-term stress response to homeostatic dysregulation in the CNS by tissue-resident innate cells that exceedingly burdens the system, leading to progressive and irreversible neurodegenerative decline.

  • The most imminent goal for future treatment is the concomitant improved targeting of relapses and progression, potentially through combinatorial therapies that modulate both arms of the disease. Improved disease prognosis and potential patient stratification for more directed healthcare provision are also much-anticipated prospects and may become tangible as we move into the immune informatics era and as large-scale, organized health resources become increasingly accessible.

Abstract

Two decades of clinical experience with immunomodulatory treatments for multiple sclerosis point to distinct immunological pathways that drive disease relapses and progression. In light of this, we discuss our current understanding of multiple sclerosis immunopathology, evaluate long-standing hypotheses regarding the role of the immune system in the disease and delineate key questions that are still unanswered. Recent and anticipated advances in the field of immunology, and the increasing recognition of inflammation as an important component of neurodegeneration, are shaping our conceptualization of disease pathophysiology, and we explore the potential implications for improved healthcare provision to patients in the future.

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Figure 1: Immune system dysregulation outside the CNS.
Figure 2: Immune system dysregulation inside the CNS in early and late multiple sclerosis.

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Acknowledgements

This work was supported by the Wellcome Trust, the Medical Research Council, the Alan and Babette Sainsbury Charitable Fund, and the Rosetrees Trust (L.F.).

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Correspondence to Lars Fugger.

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Approved drugs for the treatment of multiple sclerosis (PDF 134 kb)

Supplementary information S2 (table)

Murine EAE models. (PDF 180 kb)

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Glossary

Demyelination

Damage to the myelin sheath surrounding nerves in the brain and spinal cord, which affects the function of the nerves involved. Demyelination occurs in multiple sclerosis and in experimental autoimmune encephalomyelitis, which is an animal model of multiple sclerosis.

Gliosis

The proliferation and activation of glial cells (microglia, oligodendrocytes and astrocytes) in response to damage in the central nervous system.

Tumefactive multiple sclerosis

A subtype of multiple sclerosis characterized by atypical, large demyelinated lesions that appear tumour-like and oedematous and can exert pressure on the surrounding central nervous system tissue due to their size.

Molecular mimicry

A mechanism by which a peptide from a foreign antigen that is presented to a T cell closely resembles part of a self-protein, thereby triggering an autoimmune reaction.

Choroid plexus

The site of production of cerebrospinal fluid in the adult brain. It is formed by invagination of ependymal cells into the ventricles, which become highly vascularized.

Primary neurodegeneration

The process of progressive dysfunction and loss of axons and neurons, triggered by mechanisms involving central nervous system-resident cells, as opposed to cells infiltrating from the periphery.

Candidate genes

Genes assumed to be affected by disease-associated genetic polymorphisms, based on their functional relevance and/or their physical proximity to the polymorphisms in question. The determination of whether the assigned candidates are truly affected by the polymorphisms and how they influence disease susceptibility typically requires functional follow-up investigations at the molecular, cellular and systemic levels.

Interactome networks

Maps of molecular interactions, often segregated by cell type, and used as a framework to simplify cellular organization and to help address systems biology questions at the cellular level. These networks may reflect sets of physical intermolecular interactions as well as other molecules that indirectly act together in specific pathways.

Central tolerance

Self-tolerance that is created at the level of the central lymphoid organs. Developing T cells (in the thymus) and B cells (in the bone marrow) that strongly recognize self-antigen must undergo further rearrangement of antigen-receptor genes to become self-tolerant, or they face deletion.

Immune-privileged site

An area in the body with a decreased immune response to foreign antigens, including tissue grafts. These sites include the brain, eye, testis and placenta.

Dural sinuses

Venous channels located between layers of the brain dura mater. These sinuses receive blood from both internal and external brain veins, and cerebrospinal fluid from the subarachnoid space, and empty into the jugular vein.

Epitope spreading

This term is used to describe how a self-directed immune response induced by a single peptide (or epitope) could spread to include other peptides (or epitopes) not only on the same autoantigen (intramolecular spreading) but also on other self-molecules clustered in close vicinity within the target cell (intermolecular spreading).

Diapedesis

The migration of leukocytes across the endothelium, which occurs by leukocytes squeezing through the junctions between adjacent endothelial cells.

Cross-presentation

The initiation of a CD8+ T cell response to an antigen that is not present within antigen-presenting cells (APCs). This exogenous antigen must be taken up by APCs and then re-routed to the MHC class I pathway of antigen presentation.

Mucosa-associated invariant T cells

(MAIT cells). A type of CD8+ T cell that is enriched at mucosal sites and is characterized by the expression of a semi-invariant T cell receptor (a dimer of Vα7.2 in combination with Jα12, Jα20 or Jα33) and is restricted by the non-polymorphic, highly evolutionarily conserved MHC class Ib molecule, MR1.

Tertiary lymphoid structures

Organized lymphocytic aggregates that form in sites of chronic inflammation. Typically, B cell- and T cell-rich zones are segregated, and dendritic cells (DCs), germinal centres with follicular DC networks and specialized endothelial cells are present.

Super-enhancer

A cluster of regulatory elements within a genomic region, often particularly enriched in sites that bind transcriptional co-activators.

Immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome

(IPEX). A disease caused by mutations in FOXP3 (which encodes forkhead box P3) and characterized by refractory enteritis and, in some patients, autoimmune endocrinopathies, autoimmune diabetes and thyroiditis.

Exhaustion

Non-responsiveness of the immune system resulting from the deletion of specific thymocytes (central tolerance) and the deletion or functional inactivation of specific T cells in the periphery (peripheral tolerance) in the presence of large quantities of antigen.

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Dendrou, C., Fugger, L. & Friese, M. Immunopathology of multiple sclerosis. Nat Rev Immunol 15, 545–558 (2015). https://doi.org/10.1038/nri3871

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