Multiple Sclerosis, Part 1: Pathophysiology

Sections

Basic Immunology
Adaptive Immune System
Innate Immune System
Multiple Sclerosis: Acute Pathophysiology
References

pathophysiology and pharmacology of multiple sclerosis

Here, we'll learn about the pathophysiology and pharmacology of multiple sclerosis.

Overview

Clinical Correlation: Multiple Sclerosis

• Start a table.
• Denote that multiple sclerosis is broadly considered a demyelinating disorder wherein inflammatory events (for still unknown reasons) trigger a demyelinating process that ultimately evolves into chronic inflammation and neurodegeneration of both gray and white matter.

Basic Immunology

Basic Immunology Overview

Let's start with a review of some essential immunology – this will provide the vocabulary we need to learn about MS.

• To begin, indicate that we separate the immune system into innate and adaptive divisions:

Adaptive immunity (aka acquired immunity)

• Adaptive immunity (aka acquired immunity) derives from lymphoid precursor cells.
  • It produces a targeted defense to microbial invaders (ie, an antigen-specific response) via an expansion and differentiation of lymphocytes, which secrete cytokines and antibodies.

Innate immunity (aka native immunity)

• Innate immunity (aka native immunity) derives from myeloid precursor cells.
  • It is the first line of defense for the prevention of infection and elimination of microbials.
  • The innate immune system includes epithelial barriers, other barrier tissues, along with the mononuclear phagocytic and granulocytic cells we address here.

• Both of these functional divisions derive from hematopoietic stem cells in the bone marrow. Hematopoietic stem cells generate all of the formed elements in the blood.

Adaptive Immune System

We'll begin with the adaptive immune system.

Lymphocyte Histology

• On histology, the lymphocytes possess a large nucleus and agranular cytoplasm (they are all agranuloctyes).
  • Note that agranulocytes can contain granules (as we'll see with natural killer cells) just not to the density observed in standard granulocytes.

B-cells

• First, draw a B cell. B cells generate humoral immunity via antibody production and they present antigens to T cells.

T-cells

• Next, draw a T cell. T cells generate cell-mediated immunity via cytokines and direct cell-cell interactions.
  • They have a wide variety of responsibilities and, notably, T-cells express an antibody-shaped antigen-binding T-cell Receptor (TCR).

Natural killer (NK) cells

• Now, draw a natural killer (NK) cell. Indicate that NK cells act both as part of the innate and adaptive immune systems.
  • Their innate functions include perforin and granzyme release to kill infected cells and inflammatory cytokine release.
  • NK cells comprise a significant amount of cytoplasmic granules, but the density of this granule population is sparse enough that NK cells are still considered agranulocytes.
  • Their adaptive immune functions include their antigen specificity, ability for clonal proliferation, and their immunologic memory, which parallels that of T and B cells.
  • Natural killer cells (NK cells) also mediate an important function of antibody-dependent cellular cytotoxicity (ADCC).

Pharmacologic Correlation: Rituximab

• We address pharmacotherapeutics at the end but we'll indicate a few notable mechanisms of action of various drugs along the way. So let's pause to note that rituximab, which is a monoclonal antibody that binds CD20 and is used in immune modulation (especially in neuromyelitis optica (NMO), exerts its effects via modulation of NK cells and ADCC.

Innate Immune System

Next, let's address the innate immune cell line, which derives from myeloid cells.

• We'll divide this cell-line into the mononuclear phagocytes (the mononuclear phagocytic system) and the granulocytes, and we'll include the other non-immune related myeloid cell blood products.

mononuclear phagocytes (mononuclear phagocytic system)

Monocytes

• First, draw a monocyte. Show that it has a horseshoe-shaped nucleus.
  • Monocytes act as effector cells within the blood are the precursors for macrophages and dendritic cells.

Macrophages

• Next, draw a macrophage with an uneven surface to emphasize its phagocytic function.
  • Macrophages contain an oval to bean shaped nucleus and their pale cytoplasm becomes foamy, if activated: we can think of them like a sponge that builds-up soap suds when put into action.
  • Monocytes differentiate into various forms of macrophages in the tissues: for instance, they become microglia within the brain; alveolar macrophages in the lungs; and Kupffer cells in the liver.

Macrophage Functions

• Macrophages function in three main roles:

1. Phagocytosis – they engulf and digest debris and foreign agents (microorganisms);
2. Antigen-presentation – they serve as antigen-presenting cells (although, as we'll show in a moment, this is primarily the job of dendritic cells);
3. Cytokine release for repair or for induction of inflammation.

"Sea of Macrophages"

• Macrophages are a key finding in demyelination. Their propensity to flourish in states of demyelination has led to the histopathologic descriptor, "sea of macrophages".

Dendritic cells

• Now, draw a dendritic cell with octopus-like tentacles; they are antigen-presenting cells and have (only relatively recently) been shown to be the major antigen-presenting cell line.
  • Show that they serve as a bridge to the adaptive immune system.
  • They display the ingested particles to lymphocytes (especially within the lymph nodes and spleen) to trigger the adaptive immune response.

granulocytes

• Now, let's address the granulocytes.

Neutrophils

• First, draw a neutrophil. Neutrophils possess a multilobed nucleus and a heavily granulated cytoplasm. They, notably, comprise surface receptors geared for microbial phagocytosis and killing.
  • Note that the term left-shift is commonly used to describe an increase in immature neutrophil precursors, particularly neutrophil band cells, "bands" (typically in response to active infection).

Eosinophils

• Next, draw an eosinophil. Eosinophils are bilobed and heavily granulated; they are phagocytic, like neutrophils, but their signature feature is their toxic, antiparasitic basic proteins.

Basophils and Mast Cells

• Now, draw a representative non-phagocytic granulocyte to encompass both basophils and mast cells, which are functionally related and bear a common progenitor.
  • These granulocytes are notably involved in inflammatory and allergic (type 1 hypersensitivity) responses.

non-immune related myeloid cells

• Lastly, for completeness, let's include the non-immune related myeloid cells, since any drug that suppresses or modulates stem cells or myeloid progenitor cells will not only affect immune cells but can also affect the production of these additional blood cells, as well.

Erythrocytes

• Include the erythrocytes, which are the hemoglobin-containing, oxygen-carrying red blood cells.

Platelets

• And the platelets (derived from megakaryocytes), which are activated in the setting of blood vessel breakage and undergo a conformational transformation (they become spiky and sticky) in order to clump together and plug up the hole.

Multiple Sclerosis: Acute Pathophysiology

Demyelination

With that as a background, now let's address the basic acute pathophysiology of MS.

• To begin, outline a brain.
• Next, draw a neuron and then draw an oligodendrocyte wrapping myelin around the axon.
• Since MS is a demyelinating disorder, show that much of the myelin appears chewed up and broken down.
  • MS plaques or lesions refer to areas of active demyelination.
• Lastly, draw a pair of arterial vessels rising upward toward the brain and establish the blood-brain barrier, which serves to separate the brain, immunologically, from the rest of the body.
  • Thus, inflammatory mediators from the periphery must break-down the blood-brain barrier in order to attack the CNS.

Adaptive Immunity in MS

• Let's start with the adaptive immunity; show that it originates within the bone marrow.
• Draw a lymph node and show a B-cell circulate through the blood and enter the lymph node.
  • Note that although we focus our attention, here, on lymphocyte collection within lymph nodes, lymphocytes populate both lymphoid tissues (eg, lymph nodes, thymus, and spleen) and non-lymphoid tissues.
• Next, draw a thymus under a chest cage and show that T-cells emerge from the bone marrow and pass into the thymus where they mature (hence "T"-cell for "T"hymus).
• Show mature T-cells exit the thymus as CD4+ and CD8+ T-cells, and show them collect within the lymph node, along with the B-cells.
  • CD4+ T-cells are cytokine-producing; they subdivide into regulatory T cells (Treg cells) and conventional T helper cells (Th cells): Th1, Th2, Th17.
  • CD8+ T-cells trigger cell-death (apoptosis) of pathogenic cells: eg, viral-infected cells, foreign tissues, and tumor cells.
• Indicate that this maturation occurs during childhood; thus, past adolescence, the thymus no longer serves to form T-cells.
  • This is why thymectomy can be performed in adult myasthenia gravis patients without wiping-out the T-cell population.

Innate Immunity in MS

• Now, let's turn our attention to innate immunity; show that it originates from the bone marrow.
• Draw some muscle tissue.
• Show a monocyte enter the blood stream and differentiate into a macrophage in the muscle.
  • Remember that monocytes act within the blood whereas macrophages differentiate and act within body tissues.
• Now, draw a microglial cell: the resident macrophage of the CNS.
• Then, show a monocyte differentiate into a dendritic cell.
• Indicate that the dendritic cell presents antigen – in this case an autoreactive peptide – to the T-cells.
  • This autoreactive antigen presentation triggers production of autoreactive T-cells and the activation of autoreactive B-cells.
  • Normally, T regulatory cells would destroy these autoreactive cells but in the setting of poor regulatory function (eg, from reduced regulatory T-cell function), these autoreactive cells can flourish.

Molecular Mimicry: Peripheral vs Central

• There are two leading schools of thought regarding the molecular mimicry that triggers the formation of autoreactive lymphocytes:

Peripheral Hypothesis

• The peripheral hypothesis is that peptides derived from infections, such as HSV, EBV, or influenza and trigger autoreactive T-cells towards myelin proteins, such as: myelin basic protein (MBP), proteolipid protein, and myelin oligodendrocyte glycoprotein (MOG).

Central Hypothesis

• The central hypothesis is that CNS auto-antigens pass into regional lymph nodes and induce a peripheral immune response, which triggers a CNS attack.

Key Immune-Mediators in MS

Now, let's consolidate the key immune-mediators in MS pathophysiology.

Adaptive Immune System

• Show that from the adaptive immune system: B-cells and T-cells are recruited into the CNS via break-down in the blood brain barrier. Note that in MS, CD8+ T-cells are more numerous than CD4+ T-cells.

Pharmacologic Correlations:

• Natalizumab (Tysabri) is a monoclonal antibody targeted to the alpha-4 integrin; blockade of this integrin reduces T-cell trafficking to the CNS via the blood-brain barrier.
• Fingolimod traps T-cells in lymph nodes. It is a pro-drug that is converts to a sphingosine-1-phosphate analog, which down-regulates sphingosine-1-phosphate receptors on leukocytes and the endothelium, which prevents T-cells from leaving lymph nodes. Consequently, patients demonstrate lymphopenia on serologic testing.
• Dimethyl fumarate preferentially acts on CD8+ T-cells, which, again, are more numerous than CD4+ T-cells in MS.
  PML
• Unfortunately, all three drugs (natalizumab, far and away, being the biggest offender) can lead to PML (progressive multifocal leukoencephalopathy), a potentially fatal illness.

Innate Immune System

Next, show that, from the innate immune system:

• From the periphery, monocytes and macrophages are recruited to the CNS.
• Within the CNS, microglia, are activated.

Pathogenesis

• These key cellular mediators exert their pathogenesis, namely, via: phagocytosis, cytokine emission, and antibody secretion:

Phagocytosis

• A selection of these cells especially the macrophages and microglia chew-up myelin proteins. - As mentioned earlier, on histopathology, there is such a large ream of macrophages that the appearance bears the name, "sea of macrophages".

Cytokines

• Show that these cells secrete numerous cytokines (cell signaling proteins), including various interleukins (eg, Il-10, IL-17A, and IL-23), interferons (eg, IFN-gamma), tumor necrosis factor (TNF-alpha, THF-beta), and chemokines (eg, CCR1 through CCR6).

Pharmacologic Correlation

• As we'll see, the first chronic immune-modulatory agents for MS were interferons (interferon-beta) – endogenous regulatory cytokines that have wide-spread effects on hundreds of gene types. In fact, their broad mechanism of action probably helps explain why their efficacy various so widely from patient to patient.

Antibodies

• Show that the B-cells mature into plasma cells, which, along with immature B-cells, secrete antibodies.

Pharmacologic Correlation

• Monoclonal antibodies, such as natalizumab and ocrelizumab, are used in MS immune modulation.

MS Histopathology

Some key histopathologic signatures of MS include:

• Myelin protein products. Demyelinating plaques comprise varying myelin protein products at different stages: early on, minor myelin proteins are observed, whereas later-on, hydrophobic major myelin proteins are identifiable.
• Perivascular and parenchymal inflammatory infiltrates.
• Blood-brain barrier breakdown, which is observable on MRI as gadolinium enhancing lesions.
• Reactive astrocytes: gemistocytic (plump), eosinophilic, and/or heavily mitotic.
• Variable oligodendrocyte pathology. In early, active demyelination, there is simply a loss of oligodendrocytes. If degenerated oligodendrocytes are found, their cell bodies (like the astrocytes) are swollen and they tend to have a pale, poorly defined nucleus.
• Shadow plaques. Oligodendrocytes are replaced during remyelination and the axons become covered with thin sheaths of myelin. Remyelinated lesions are called shadow plaques: due to the faint nature of their myelin compared to unaffected surrounding myelinated regions. We can remember that the remyelinated plaques are more faint when we consider that physiological stress can re-exacerbate old MS lesions, called Uhtoff phenomenon.

> Acute Immune Suppression

Immunesuppressant Agents

Now that we have a basic understanding of the acute inflammatory events that occur in an MS attack, let's address some key treatments for acute attacks of demyelination: they act via immune suppression.

Methylprednisolone

• Indicate that the foremost treatment is intravenous methylprednisolone (typically 1 gram per day for 5 days), followed by oral prednisone taper (often for 2 – 3 weeks).
  • Side effects of brief, high-dose steroids include: anaphylaxis, osteonecrosis/avascular necrosis, psychosis, severe mood alteration, insomnia, GI distress, and myalgias.

Prednisone

• Alternatively, oral prednisone, alone, (starting at 60 – 80 mg/day with a 2 – 3 week taper) is used in less severe attacks.
  • Importantly, however, attacks of optic neuritis should not be treated with oral prednisone alone (without a methylprednisolone burst), as this was shown to have deleterious effects in the "Optic Neuritis Treatment Trial."

ACTH (repository corticotropin injection)

• Lastly, include injectable ACTH (repository corticotropin injection). Repository corticotropin is a first-line treatment in infantile spasms and is used in MS, albeit far less commonly than meythlprednisolone or prednisone, mostly due to cost.
  • Repository corticotropin is generally thought to have similar effect to corticosteroids due to its steroidogenesis but may have additional downstream effects, as well.

Efficacy of Immunesuppressants

• It is important to note that not all MS attacks require treatment, as generally, it is believe that they hasten recovery but do not, necessarily, change the ultimate likelihood of recovery via remyelination. However, the landscape of MS treatment is changing quickly, as we address in part 2, and it's certainly possible that this mentality will change in time, as well.

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