Reactions of Other Glial Cells to Injury

Slide 1 · Reactions of Other Glial

Cells to Injury

Oligodendrocytes • Ependyma • Disease-associated changes

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Locate oligodendrocytes and ependymal cells within CNS tissue.

Recognize injury patterns involving myelin, viral inclusions, and cytoplasmic protein deposits.

Explain ependymal disruption, subependymal gliosis, and granulations.

Distinguish these responses from astrocytic gliosis and microglial activation.

Slide 3 · Glial injury is cell-type specific

Astrocytes

GFAP-positive gliosis

Microglia

Phagocytosis / nodules

Oligodendrocytes

Myelin / injury / inclusions

Ependymal cells

Ventricular surface disruption

Oligodendrocytes are specialized myelinating cells.

Ependymal cells form the ventricular lining.

Astrocytes and microglia mount more conspicuous reactive responses.

Slide 4 · Anatomic map: Myelin versus ventricular lining

Ventricle

Ependyma

Subependymal tissue / astrocytic response

Schematic — not a histologic specimen

Oligodendrocytes act on CNS axons within neural tissue.

Ependymal cells interface with ventricular cerebrospinal fluid.

Location helps narrow the interpretation of an injury pattern.

Slide 5 · How glial injury becomes visible

Cell / site

Prominent pathology

Interpretation

Oligodendrocyte

Loss of myelin; Nuclear or cytoplasmic inclusions

Depends on disease mechanism

Ependyma

Lining disruption; Surface granulations

Damage and subependymal astrocytic response

Astrocyte

Cellular hypertrophy / hyperplasia

Gliosis: Common marker of CNS injury

Microglia

Phagocytes; Nodules; Neuronophagia

Clearance and response to injury

Slide 6 · Oligodendrocytes produce CNS myelin

Axon

Axon

Myelin sheath segments are discontinuous at nodes

Schematic — not a histologic specimen

Cell processes wrap axons to create myelin sheaths.

A single oligodendrocyte can support multiple internodes.

Its injury can disrupt conduction in several axons.

Slide 7 · One oligodendrocyte, many internodes

Axon

Axon

Axon

Oligodendrocyte

Several internodes on multiple axons

Schematic — not a histologic specimen

A single cell distributes processes to more than one axon.

Each process contributes to a discrete myelin internode.

Cell loss can therefore affect a network of myelinated segments.

Slide 8 · Oligodendrocytes differ from Schwann cells

CNS

PNS

One cell: Multiple internodes

One cell: One internode

Schematic — not a histologic specimen

CNS: One oligodendrocyte myelinates many internodes.

Peripheral nerve: One Schwann cell myelinates one internode.

Do not transfer peripheral-nerve regeneration rules directly to CNS tissue.

Slide 9 · Why myelin preservation matters

Myelin wraps an axon

Rapid impulse propagation

Efficient circuit function

When myelin is destroyed, electrical conduction becomes impaired even before the axon is lost.

Slide 10 · Patterns of oligodendroglial injury

Immune-mediated myelin injury

JC virus replication

Inherited myelin instability

Glial protein aggregation

Loss of cells or myelin is common in demyelinating disease.

Distinct inclusions identify some viral and degenerative processes.

Inherited defects can impair the generation or maintenance of myelin.

Slide 11 · Myelin loss does not initially require axon loss

Axon

Axon

Segmental loss of myelin

Myelin loss

Preserved axon

Schematic — not a histologic specimen

Acquired CNS demyelination chiefly injures myelin.

Axons may remain relatively preserved in an active lesion.

Secondary axonal degeneration contributes to lasting deficits.

Slide 12 · Acquired and inherited white-matter injury differ

Feature

Acquired demyelination

Leukodystrophy

Principal process

Injury to existing myelin

Defective generation, turnover, or maintenance

Examples

Multiple sclerosis; PML

Krabbe; Metachromatic; Adrenoleukodystrophy

Pattern

Often multifocal / disease-specific

Frequently diffuse, symmetric and progressive

Slide 13 · Oligodendrocyte death is not a single disease

Distinct upstream insult

Oligodendrocyte dysfunction or loss

Myelin disruption

Cell loss is a shared reaction. The causal process must be established from lesion context.

Slide 14 · An active demyelinating lesion

Macrophage-rich active margin

Schematic — not a histologic specimen

Loss of myelin can coexist with relative axonal preservation.

Macrophages remove myelin breakdown products.

Inflammatory cells and active lesion borders help establish activity.

Slide 15 · Chronic lesions may lose oligodendrocytes

Oligodendrocyte reduction and dense gliosis

Schematic — not a histologic specimen

Inactive MS plaques contain fewer oligodendrocyte nuclei.

Residual myelin is sparse or absent.

Reactive astrocytic gliosis becomes prominent.

Slide 16 · Remyelination is possible but limited

Axon

Axon

Thin / incomplete myelin

Partial myelin regeneration

Schematic — not a histologic specimen

Shadow plaques contain thinner-than-normal sheaths.

This morphology suggests partial remyelination.

Much of the axonal substrate in established plaques remains unmyelinated.

Slide 17 · Why old plaques differ from active plaques

Active demyelination

Falling inflammatory activity

Gliosis ± partial remyelination

A lesion can change its cellular composition over time; Sample location and disease stage matter.

Slide 18 · Multiple sclerosis illustrates immune injury

Multiple sclerosis is an acquired autoimmune demyelinating disorder.

In active plaques, macrophages and lymphocytes accompany myelin destruction.

In inactive plaques, oligodendrocyte depletion and gliosis predominate.

It demonstrates myelin injury with evolving secondary axonal damage.

Slide 19 · Macrophage-rich activity has a location

Macrophage-rich active margin

Schematic — not a histologic specimen

Foamy macrophages characterize active myelin breakdown.

Perivascular lymphocytes may be evident.

The border of an active lesion may be more informative than its old center.

Slide 20 · Chronic plaques are not simply smaller active plaques

Oligodendrocyte reduction and dense gliosis

Schematic — not a histologic specimen

Inflammatory cells decline in inactive lesions.

Oligodendrocytes and axons can be reduced.

A dense glial response remains when active inflammation fades.

Slide 21 · Three MS plaque states

Active

Inactive

Shadow plaque

Myelin breakdown with macrophages

Little myelin; Gliosis; Fewer oligodendrocytes

Abnormally thin myelin sheaths

Inflammation can be conspicuous

Inflammatory cells mostly absent

Evidence of incomplete repair

Slide 22 · PML is a viral oligodendroglial injury

JC polyomavirus reactivation

Preferential oligodendrocyte infection

Demyelinating white-matter lesions

The distinctive viral cellular target explains why demyelination is a central lesion in PML.

Slide 23 · PML usually requires impaired immunity

Most PML develops in immunosuppressed individuals.

Primary JC virus exposure is usually asymptomatic.

Disease is linked to viral reactivation rather than ordinary primary infection.

Pathologic interpretation must integrate host immune status.

Slide 24 · PML lesions preferentially involve white matter

Axon

Axon

Segmental loss of myelin

Myelin loss

Preserved axon

Schematic — not a histologic specimen

Lesions form irregular, ill-defined areas of white-matter destruction.

Patches may merge into larger confluent regions.

Clinical abnormalities correspond to involved neural pathways.

Slide 25 · Enlarged oligodendroglial nuclei in PML

Viral inclusion

Enlarged nucleus

Schematic — not a histologic specimen

Oligodendrocyte nuclei become enlarged.

Glassy amphophilic viral inclusions occupy the nucleus.

Inclusion-bearing cells are classically found near lesion edges.

Slide 26 · PML has an edge-to-center gradient

Edge: Infected oligodendrocytes

Demyelinating lesion

Center: Lipid-laden macrophages

Different regions of one PML lesion can display different diagnostic clues.

Slide 27 · Astrocytes also change in PML

PML can contain bizarre enlarged astrocytes.

These may show irregular, hyperchromatic nuclei.

They coexist with reactive astrocytes and infected oligodendrocytes.

The distinctive oligodendroglial viral inclusion remains important for attribution.

Slide 28 · PML versus multiple sclerosis

Feature

PML

Multiple sclerosis

Central mechanism

JC viral infection of oligodendrocytes

Immune-mediated myelin injury

Distinctive clue

Enlarged oligodendroglial nuclei with viral inclusions

Plaques with stage-specific macrophages, inflammation and gliosis

Context

Typically immunosuppression

Immune-mediated disease with characteristic clinical course

Slide 29 · MSA demonstrates proteinopathy in glia

Cytoplasmic α-synuclein

Nucleus lacks the hallmark inclusion

Schematic — not a histologic specimen

Multiple system atrophy (MSA) has oligodendroglial inclusions.

They are cytoplasmic and composed primarily of α-synuclein.

This is different from the intranuclear viral inclusion of PML.

Slide 30 · The MSA inclusion lies in the cytoplasm

Cytoplasmic α-synuclein

Nucleus lacks the hallmark inclusion

Schematic — not a histologic specimen

A glial cytoplasmic inclusion is the characteristic lesion.

The cell is an oligodendrocyte rather than a neuron.

Compartment and inclusion composition direct disease recognition.

Slide 31 · MSA affects several neural systems

System

Corresponding clinical pattern

Striatonigral circuit

Parkinsonism

Olivopontocerebellar circuit

Ataxia

Central autonomic pathways

Autonomic dysfunction, including orthostatic hypotension

Slide 32 · Origin of α-synuclein in oligodendrocytes is uncertain

α-Synuclein is ordinarily associated with neuronal synaptic vesicles.

Its accumulation in MSA oligodendrocytes is puzzling.

Acquisition of aggregates from injured neurons has been proposed.

This proposed origin should not be presented as proven.

Slide 33 · The glial inclusion is meaningful in MSA

Oligodendroglial α-synuclein

Glial dysfunction / vulnerability

White-matter and neuronal degeneration

Associations; The exact initiating sequence and protein origin remain uncertain.

Slide 34 · PML and MSA: Inclusion compartment is decisive

PML

INTRANUCLEAR viral inclusion

MSA

CYTOPLASMIC α-synuclein

Schematic — not a histologic specimen

PML: Viral material is present in enlarged nuclei.

MSA: α-synuclein accumulates in oligodendroglial cytoplasm.

Both affect oligodendrocytes but reflect different mechanisms.

Slide 35 · Leukodystrophies are disorders of myelin biology

Inherited defects alter myelin formation, turnover, or maintenance.

Presentation often involves progressive dysfunction at young ages.

Diffuse symmetric white-matter abnormalities are a common pattern.

Not every white-matter disorder is acquired demyelination.

Slide 36 · Disease mechanism helps classify myelin injury

Category

Illustrative example

Primary insult

Immune-mediated

Multiple sclerosis

Autoimmune injury to myelin

Infectious

PML

JC viral oligodendroglial infection

Protein aggregation

MSA

Oligodendroglial α-synuclein inclusions

Inherited metabolic / myelin

Leukodystrophies

Defects of myelin metabolism or maintenance

Slide 37 · Krabbe disease injures oligodendrocytes

Inherited enzyme deficiency

Toxic galactosylsphingosine buildup

Oligodendrocyte and astrocyte injury

Myelin loss accompanies cell loss; The metabolic precursor lies upstream of the glial lesion.

Slide 38 · Globoid macrophages are a clue in Krabbe disease

Krabbe disease causes loss of myelin and oligodendrocytes.

Neurons and axons are relatively spared early in the process.

Engorged macrophages form characteristic globoid cells.

The macrophage reaction accompanies oligodendroglial injury.

Slide 39 · Metachromatic leukodystrophy: Stored sulfatides

Arylsulfatase A deficiency

Sulfatide accumulation

White-matter demyelination / dysmyelination

Metachromatic inclusions occur in macrophages; Glial injury and gliosis accompany the myelin defect.

Slide 40 · Adrenoleukodystrophy: A transport defect

ABCD1 dysfunction

Impaired very-long-chain fatty acid catabolism

Progressive CNS white-matter injury

Inflammation and gliosis may accompany the white-matter myelin loss.

Slide 41 · Four mechanisms, one vulnerable cell system

Immune-mediated myelin injury

JC virus replication

Inherited myelin instability

Glial protein aggregation

Immune, infectious, metabolic and degenerative mechanisms differ.

All can affect oligodendrocyte function or associated myelin.

An accurate diagnosis requires the disease-specific clue.

Slide 42 · Ependymal cells line the ventricular system

Ventricular CSF space

Subependymal tissue

Schematic — not a histologic specimen

Ependymal cells are ciliated columnar epithelial cells.

They form a cellular layer at the ventricular surface.

Their response differs from the parenchymal astrocytic reaction.

Slide 43 · Cilia distinguish normal ependymal architecture

Ventricular CSF space

Subependymal tissue

Schematic — not a histologic specimen

The ventricular interface is lined by columnar cells.

Cilia extend toward the ventricular lumen.

The layer can be disrupted by inflammation or marked ventricular dilation.

Slide 44 · Ependyma has no stereotyped injury response

No specific ependymal reaction pattern.

A damaged lining often reflects the underlying insult rather than a unique ependymal morphology.

Subependymal astrocytes provide a conspicuous secondary response.

Slide 45 · Inflammation may disrupt the ependymal lining

Ventricular CSF space

Subependymal tissue

Focal loss of ependymal lining

Schematic — not a histologic specimen

Inflammatory injury can interrupt the ventricular surface epithelium.

Loss of lining cells exposes the subjacent tissue.

Associated subependymal astrocytosis may distort the surface.

Slide 46 · Ventricular dilation is another route to disruption

Marked ventricular dilation

Ependymal lining disruption

Subependymal astrocytic proliferation

The resulting ventricular surface may become irregular rather than remain smoothly lined.

Slide 47 · Subependymal astrocytes account for granulations

Ventricular CSF space

Subependymal tissue

Proliferating subependymal astrocytes

Schematic — not a histologic specimen

The ependymal lining becomes interrupted.

Subependymal astrocytes proliferate beneath injured areas.

Small irregularities appear on the ventricular surface.

Slide 48 · Ependymal granulations are a reactive surface change

Ventricular CSF space

Subependymal tissue

Proliferating subependymal astrocytes

Schematic — not a histologic specimen

The term describes small ventricular surface irregularities.

Both prior lining disruption and astrocytic response contribute.

This reaction should not be conflated with an ependymal neoplasm.

Slide 49 · Ependymal granulation has two cellular components

Loss of normal ependymal cells

Proliferation of subependymal astrocytes

Ventricular surface irregularity

The reactive component is predominantly astrocytic, not hyperplasia of injured ependymal cells.

Slide 50 · CMV can directly injure the ependyma

Ventricular CSF space

Subependymal tissue

CMV inclusion-bearing cell

Schematic — not a histologic specimen

Cytomegalovirus (CMV) is an infectious cause of ependymal injury.

Viral inclusions may occur within ependymal cells.

Potentially extensive lining damage.

Slide 51 · CMV has a subependymal predilection

Ventricle

Ependyma

Subependymal tissue / astrocytic response

Schematic — not a histologic specimen

The source describes localization of CMV injury to subependymal regions.

Affected cells may contain recognizable viral inclusions.

Distribution along the ventricular interface can guide tissue sampling.

Slide 52 · Congenital CMV produces periventricular injury

CMV infection in utero may cause periventricular necrosis.

Severe cerebral injury can follow.

Later microcephaly and periventricular calcifications are described.

This disease context illustrates the vulnerability of the ventricular region.

Slide 53 · CMV also affects immunosuppressed adults

CMV is an opportunistic pathogen in immunosuppression.

The CNS may develop subacute encephalitis.

Subependymal involvement and viral inclusion-bearing cells are characteristic clues.

Slide 54 · Two common contexts of ependymal damage

Setting

Primary injury

Observed consequence

Inflammation / dilation

Lining disruption

Surface granulations with subependymal astrocytes

CMV infection

Viral injury to ependymal cells

Inclusion-bearing cells and ependymal damage

Slide 55 · The cell’s location shapes injury interpretation

Ventricle

Ependyma

Subependymal tissue / astrocytic response

Schematic — not a histologic specimen

Ventricular surface injury points toward ependymal involvement.

Subependymal astrocytosis is a secondary local response.

Myelin loss deeper in tissue points toward oligodendroglial disease.

Slide 56 · Astrocytes contrast with other glial cells

Reactive astrocytes undergo hypertrophy and hyperplasia (gliosis).

GFAP expression highlights their cytoplasmic processes.

Gliosis is a nonspecific but important indicator of CNS injury.

Oligodendrocytes and ependymal cells usually show less prominent generalized responses.

Slide 57 · Microglia contrast with other glial cells

Microglia act as resident CNS phagocytic cells.

After injury they can proliferate and form microglial nodules.

Neuronophagia describes clustering around dying neurons.

Recruitment of blood-derived macrophages may accompany inflammation.

Slide 58 · Different glial cells collaborate in one lesion

Component

Possible role in the same focus

Oligodendrocyte

Myelin production; May be target of damage

Macrophages / microglia

Clear debris and respond to tissue injury

Astrocyte

Reactive gliosis and cellular support

Ependymal cell

Ventricular lining; Damaged in local surface insults

Slide 59 · Case: Focal white-matter decline in immunosuppression

Teaching vignette: An immunosuppressed patient develops progressive focal neurologic deficits. White matter shows enlarged oligodendrocyte nuclei with amphophilic inclusions.

What cellular lesion best explains the pattern?

PML: JC-virus–associated oligodendroglial infection and demyelination.

Slide 60 · Case: Cytoplasmic inclusions with autonomic failure

Teaching vignette: Progressive parkinsonism and ataxia coexist with autonomic dysfunction. Tissue shows oligodendrocyte cytoplasmic α-synuclein inclusions.

Which glial proteinopathy is illustrated?

Multiple system atrophy, a glial α-synucleinopathy.

Slide 61 · Case: An irregular ventricular surface

Teaching vignette: After marked ventricular enlargement, an irregular ventricular surface is observed where the ependymal lining is interrupted.

Which cell population explains the reactive granulations?

Proliferating subependymal astrocytes.

Slide 62 · Case: Viral inclusions at the ventricular interface

Teaching vignette: CNS infection in an immunosuppressed person involves the ventricular and subependymal zones. Ependymal cells contain viral inclusions.

Which infectious agent is highlighted?

Cytomegalovirus (CMV).

Slide 63 · Distinguish four characteristic patterns

Pattern

Most informative association

Intranuclear inclusion in oligodendrocyte

JC virus infection / PML

Cytoplasmic α-synuclein in oligodendrocyte

Multiple system atrophy

Ventricular granulation following lining loss

Subependymal astrocytic proliferation

Inclusion-bearing infected ependymal cell

Cytomegalovirus

Slide 64 · Interpret the cellular lesion before naming a disease

Identify affected cell

Locate injury compartment

Assess morphology and context

Example: Nuclear viral inclusion ≠ cytoplasmic protein inclusion ≠ reactive ventricular surface granulation.

Slide 65 · Major distinctions to retain

Oligodendrocytes support many CNS myelin internodes; Injury often produces myelin pathology.

PML and MSA provide different inclusion patterns in the same glial cell type.

Ependymal cells may be disrupted by inflammation, dilation, or CMV.

Ependymal granulations reflect subependymal astrocytic proliferation.

Slide 66 · Source and further reading

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th ed. (2026).

Chapter 28 — Cellular pathology of the CNS, p. 1130–1132.

Disease examples: multiple sclerosis, PML, multiple system atrophy, leukodystrophies and CMV infection.

Detailed section/page mappings and source provenance are recorded in speaker notes.