Epstein Barr Virus

Slide 1 · Epstein–Barr Virus

Infectious mononucleosis, immune response, and oncogenic associations

Morphology • pathogenesis • clinicopathologic interpretation

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Distinguish lytic EBV infection, latent B-cell infection, and the host cytotoxic response.

Explain the blood, nodal, splenic, and hepatic changes in infectious mononucleosis.

Construct a source-based diagnostic approach and recognize major complications.

Connect deficient EBV immune control with selected EBV-associated malignancies.

Slide 3 · EBV causes two very different clinical problems

Primary infection may cause self-limited infectious mononucleosis.

Persistence in B lymphocytes establishes life-long latency.

Impaired cellular surveillance permits pathologic B-cell expansion.

EBV participates in the pathogenesis of selected lymphomas and carcinomas.

Acute reactive syndrome

Long-term persistence and tumors

Slide 4 · EBV belongs to the herpesvirus family

A human herpesvirus capable of latent infection following primary acquisition.

Infected B lymphocytes constitute a major reservoir.

The clinical phenotype reflects both viral gene expression and immune competence.

Primary acquisition

B-cell infection

Latent reservoir

Slide 5 · Age at first infection alters the presentation

Primary infection during childhood is often asymptomatic.

Recognizable infectious mononucleosis is prominent in late adolescence and young adulthood.

The clinical syndrome is related to development of the host immune response.

Childhood: Often silent

Later acquisition: Mononucleosis

Slide 6 · Saliva enables close-contact transmission

EBV is frequently acquired by close human contact involving saliva.

Tonsillar and oropharyngeal lymphoid tissue provides an early infection setting.

This route links the clinical sore throat with lymphoid immune activation.

Salivary exposure

Oropharynx / tonsil

B-cell infection

Slide 7 · EBV enters B cells through CD21

EBV surface glycoproteins bind the complement receptor CD21 on B cells.

Receptor binding explains the strong B-cell tropism emphasized.

The interaction initiates a program that may be lytic or latent.

EBV glycoproteins

B-cell CD21 receptor

Infected B cell

Slide 8 · Two infection programs: Lytic and latent

In a minority of B cells, productive infection makes new virions and ends in lysis.

In most infected B cells, EBV establishes latency rather than killing the cell.

These alternatives produce different consequences for persistence and spread.

Lytic → progeny virions

Latent → persistent B cell

Slide 9 · Latent EBV persists as an episome

During latency, the viral genome remains extrachromosomal.

The episome is compatible with host-cell survival and B-cell propagation.

Latency is not synonymous with absence of viral gene expression.

Viral genome

Extrachromosomal episome

Persisting B cell

Slide 10 · Latent proteins activate infected B cells

LMP1 and EBNA2 promote B-cell activation, survival, and proliferation.

This proliferation can initially be polyclonal rather than neoplastic.

Effective cytotoxic immunity subsequently restrains activated infected cells.

EBV latency genes

B-cell activation

Polyclonal expansion

CTL control

Slide 11 · LMP1 imitates CD40 signaling

LMP1 behaves as a constitutively active CD40-like signaling receptor.

The cell receives growth-survival signaling without a conventional helper-T-cell stimulus.

The resulting B-cell activation helps expand the infected compartment.

EBV LMP1

CD40-like signal

B-cell survival

Slide 12 · LMP1 engages pro-survival pathways

LMP1 activates NF-κB and JAK/STAT pathways.

It also favors survival by upregulating anti-apoptotic BCL2.

The combined effect is autonomous growth and reduced cell death.

LMP1

NF-κB / JAK–STAT

BCL2 / survival

Slide 13 · EBNA2 modifies host growth programs

EBNA2 is a viral nuclear protein that mimics constitutive Notch-related signaling.

Activation of host genes including cyclin D and SRC-family proto-oncogenes.

EBNA2 complements LMP1 in immortalizing infected B cells.

EBNA2

Host transcriptional activation

B-cell proliferation

Slide 14 · EBV must evade immune recognition to persist

EBV encodes functions that reduce antigen presentation and impair effector responses.

Cells strongly expressing immunogenic latency proteins are usually controlled.

A minority that downregulates antigenic polypeptides can persist indefinitely.

Antigenic viral proteins

CTL selection pressure

Low-expression reservoir

Slide 15 · Polyclonal B-cell activation generates antibodies

Expanding infected B cells secrete antibodies of multiple specificities.

Some bind sheep or horse erythrocytes: The heterophile antibodies.

The resulting polyclonal response is central to the traditional Monospot test.

Expanded B-cell pool

Polyclonal antibodies

Heterophile reaction

Slide 16 · B-cell activation can produce autoantibodies

Infected activated B cells may also produce antibodies against self-antigens.

Antiplatelet antibodies can cause transient immune-mediated thrombocytopenia.

This links an EBV infection mechanism to a hematologic complication.

B-cell activation

Antiplatelet antibody

Transient cytopenia

Slide 17 · Cytotoxic CD8 T cells dominate the response

Most circulating atypical lymphocytes are activated EBV-reactive CD8 T cells.

NK cells also contribute to the reactive mononuclear population.

These effector cells target infected B cells rather than representing EBV-infected tumor cells.

EBV-infected B cell

Reactive CD8 T cell

Slide 18 · Immunopathology explains symptom onset

Symptoms arise as the host cellular immune response intensifies.

Reactive T-cell proliferation is centered in lymphoid tissues.

The same response causes blood atypia, lymphadenopathy, and splenomegaly.

EBV-infected B cells

T-cell activation

Systemic mononucleosis

Slide 19 · Most hosts control EBV but do not eradicate latency

Humoral and cellular immunity curb viral shedding and B-cell expansion.

B cells expressing many immunogenic latency proteins are eliminated.

A small low-antigen-expressing B-cell reservoir survives long-term.

Immune expansion

Elimination of activated cells

Persistent reservoir

Slide 20 · EBV-specific antibody classes evolve

Early infection induces IgM responses against viral capsid antigens.

IgG to viral antigens appears later and may persist throughout life.

The timing and specificity of antibody responses inform diagnosis.

Early anti-VCA IgM

Later antiviral IgG

Long-term seropositivity

Slide 21 · Natural history depends on immune balance

Strong immune control may yield no overt illness or self-limited mononucleosis.

Persisting latent cells normally remain under cellular surveillance.

Loss of surveillance increases the possibility of EBV-driven B-cell proliferation.

Effective T-cell immunity

Impaired T-cell immunity

Slide 22 · Age and exposure patterns are not uniform

Early-childhood primary infection often causes little recognizable illness.

Symptomatic mononucleosis is relatively prominent with later primary infection.

Differences in age at acquisition across world settings.

Acquisition context

Typical presentation

Early-childhood infection

Frequently asymptomatic

Late adolescence / young adulthood

Classic infectious mononucleosis

Slide 23 · Infectious mononucleosis: Clinical core

Fever and sore throat accompany systemic lymphoid activation.

Generalized lymphadenopathy is a characteristic finding.

Splenomegaly and atypical lymphocytosis reinforce the diagnosis.

Fever / pharyngitis

Lymphadenopathy

Splenomegaly / atypia

Slide 24 · Tonsillar inflammation reflects lymphoid activation

Tonsillar and oropharyngeal lymphoid tissues show reactive changes.

Local swelling is concordant with sore throat and pharyngitis.

These changes are part of the systemic lymphoproliferative response.

Oropharyngeal symptoms

Reactive lymphoid expansion

Slide 25 · Distribution of enlarged lymph nodes

Nodes are generally discrete and enlarged at multiple sites.

Posterior cervical, axillary, and inguinal nodes are often involved.

The broad distribution can clinically raise concern for lymphoma.

Posterior cervical

Axillary / inguinal

Slide 26 · Atypical mononuclear cells are reactive

The hallmark atypical blood cells are predominantly CD8-positive T lymphocytes.

Their activation reflects an antiviral immune response.

The viral reservoir is mainly in B cells: Cell-of-infection and cell-of-response differ.

EBV-infected B cell

CD8 T-cell response

Atypical blood cell

Slide 27 · Atypical lymphocyte: Microscopic appearance

Abundant cytoplasm may contain clear vacuoles and azurophilic granules.

Nuclei may be oval, indented, or folded.

These features are suggestive in the appropriate clinical context, not exclusive to EBV.

Original cell schematic — not microscopy

Slide 28 · Peripheral blood: Characteristic pattern

An absolute lymphocytosis is typical of acute infectious mononucleosis.

The supplied Robbins passage describes lymphocytes exceeding 60% of WBCs.

Atypical forms may constitute a widely variable proportion of lymphocytes (5–80%).

Absolute lymphocytosis

Variable reactive atypia

Slide 29 · Do not confuse reactive atypia with malignancy

Marked lymphocyte enlargement and nuclear irregularity can look alarming.

Interpret peripheral blood with the full clinical syndrome and confirmatory testing.

Reactive EBV lymphocytes are not, by themselves, proof of a lymphoid cancer.

Observation

Meaning in context

Large atypical lymphocytes

Common reactive antiviral response

Generalized adenopathy

May be benign or malignant

Clinical + EBV serology

Supports etiologic interpretation

Slide 30 · Lymph nodes: Expansion of the paracortex

Paracortical T-cell activation is the most striking nodal microscopic feature.

Numerous immunoblasts may substantially distort the apparent architecture.

B-cell follicles may show a lesser degree of reactive hyperplasia.

Expanded paracortex

Schematic; Not an H&E section

Slide 31 · EBV-positive B cells are a minority in reactive nodes

A minor paracortical population of infected B cells expresses latency-associated proteins.

EBNA2 and LMP1 in these cells.

Most activated large cells in this setting reflect the broader T-cell response.

Broad T-cell expansion

Minor EBV-positive B-cell pool

Slide 32 · Reed–Sternberg-like cells are a pitfall

Some EBV-infected reactive B cells resemble Reed–Sternberg cells.

Morphologic resemblance alone does not establish Hodgkin lymphoma.

Clinical course, architecture, and appropriate pathology workup remain essential.

RS-like reactive B cell

Hodgkin lymphoma: Not inferred

Slide 33 · Florid EBV lymphadenitis may mimic lymphoma

Reactive T-cell proliferation can be sufficiently exuberant to simulate malignancy.

A single striking immunoblast or architectural abnormality is not definitive.

The distinction requires integrated clinicopathologic interpretation.

Potential trap

Safer interpretation

Exuberant paracortical expansion

Can be reactive during EBV

RS-like B cells

Not sufficient for Hodgkin diagnosis

Short mononucleosis syndrome

Provides essential clinical context

Slide 34 · Oropharyngeal lymphoid tissue parallels the nodes

The tonsils can display the same active lymphoid proliferation as lymph nodes.

This helps connect regional morphology with pharyngitis.

The source describes the process as predominantly reactive rather than destructive.

T-cell activation

Tonsillar expansion

Sore throat

Slide 35 · Splenomegaly is a major morphologic finding

The spleen is enlarged in most symptomatic cases.

Typical spleen weights of approximately 300–500 g.

The organ is often soft and fleshy with a hyperemic cut surface.

Enlarged, soft spleen

Hyperemic, fragile tissue

Slide 36 · Splenic pulp contains activated lymphocytes

White-pulp follicles and red-pulp sinusoids expand with activated T cells.

These changes resemble the reactive processes seen in lymph nodes.

Diffuse lymphoid activation accounts for increased spleen volume.

White pulp: Reactive lymphoid expansion

Red pulp: Sinusoidal T-cell expansion

Slide 37 · Why an enlarged spleen may rupture

Rapid enlargement can stretch a tense, fragile splenic capsule.

Rupture may occur after minor trauma and cause life-threatening hemorrhage.

This uncommon complication is a clinically important consequence of the pathology.

Rapid enlargement

Capsular tension

Rupture / hemorrhage

Slide 38 · The liver is frequently involved

Hepatomegaly is generally moderate rather than massive.

Atypical lymphocytes infiltrate portal areas and hepatic sinusoids.

Occasional isolated or focal hepatocellular necrosis may accompany the infiltrate.

Hepatocyte cords and sinusoidal lymphocytes

Slide 39 · EBV hepatitis may resemble other viral hepatitis

Portal and sinusoidal mononuclear infiltration can produce a hepatitis pattern.

Scattered parenchymal necrosis does not uniquely identify EBV.

Clinical findings and EBV-specific evidence are needed to resolve the cause.

Lymphocytic inflammation

Focal hepatocellular injury

Slide 40 · EBV can affect organs beyond lymphoid tissue

Occasional involvement of the CNS, lungs, and other organs.

Meningoencephalitis and pneumonitis are among possible manifestations.

These are less typical than lymphoid, hematologic, and hepatic changes.

Site

Manifestation in Robbins

Blood / lymphoid organs

Atypia, adenopathy, splenomegaly

Liver

Hepatitis / occasional jaundice

CNS or lung

Less common inflammation

Slide 41 · The diagnostic evidence forms a hierarchy

First, recognize characteristic atypical lymphocytosis in the clinical setting.

Next, a heterophile antibody test provides supporting evidence.

EBV antigen-specific antibodies provide more specific etiologic information.

Smear / lymphocytosis

Heterophile reaction

EBV-specific antibodies

Increasing etiologic specificity →

Slide 42 · Peripheral smear is an early clue, not final proof

Large reactive lymphocytes strongly suggest a mononucleosis syndrome.

This blood pattern arises from immune activation, not directly from virion production.

Combine morphology with clinical and serologic evidence.

Original cell schematic — not microscopy

Slide 43 · The heterophile test detects a polyclonal effect

EBV-activated B cells can produce antibodies reactive with animal erythrocytes.

The Monospot reaction interrogates these heterophile antibodies.

The reaction after blood morphology and before antigen-specific serology in specificity.

Activated B cells

Heterophile antibodies

Monospot reaction

Slide 44 · EBV-specific serology adds etiologic specificity

The supplied source identifies viral capsid, early, and nuclear antigens as targets.

Early anti-capsid IgM and later IgG reflect evolution of the host response.

Interpret results in relation to clinical timing, not as isolated labels.

Antigen / response

Textbook relevance

Viral capsid antigen (VCA)

Early IgM; later IgG

Early antigen

Part of EBV-specific diagnostic testing

Epstein–Barr nuclear antigen

Part of EBV-specific diagnostic testing

Slide 45 · Synthesize the diagnostic findings

Clinical context: Fever, sore throat, lymphadenopathy, and splenomegaly.

Blood: Absolute lymphocytosis with reactive atypical lymphocytes.

Laboratory: Heterophile reaction and, where needed, EBV-specific antibody pattern.

Compatible syndrome

Reactive hematology

Etiologic antibody support

Slide 46 · CMV may produce a similar mononucleosis syndrome

CMV can cause fever, atypical lymphocytosis, adenopathy, and hepatitis.

Symptom overlap means atypical lymphocytes alone cannot establish EBV.

The neighboring Robbins CMV section emphasizes serologic diagnosis.

Clinical feature

EBV mononucleosis

CMV mononucleosis

Fever / fatigue

Present

Present

Atypical lymphocytes

Present

Present

EBV-specific serology

Diagnostic evidence

Does not establish CMV

Slide 47 · Lymphoma and leukemia enter the differential

Fatigue, lymphadenopathy, and atypical circulating cells can prompt concern for malignancy.

EBV nodal immunoblasts may produce an alarming lymphoma-like appearance.

Avoid relying on one morphologic feature without clinical and diagnostic correlation.

Reactive EBV proliferation

Neoplastic proliferation

Slide 48 · Hepatitis and exanthems complicate recognition

Hepatic involvement may mimic hepatotropic viral disease.

A febrile rash can resemble other childhood viral exanthems.

The combination of lymphoid findings and EBV-specific laboratory support is useful.

Hepatitis-like syndrome

Febrile viral exanthem

Slide 49 · The expected course is usually self-limited

Most patients recover from mononucleosis within approximately 4–6 weeks.

Fatigue may continue after other signs have subsided.

The illness resolves even though latent EBV infection persists.

Symptomatic illness

Clinical resolution

Persistent latency

Slide 50 · Hepatic manifestations range in severity

Hepatosplenomegaly and biochemical or clinical hepatitis commonly occur.

Jaundice can accompany hepatic involvement.

In the supplied source, necrosis is generally scattered or focal.

Portal / sinusoidal T cells

Hepatocyte injury

Hepatitis ± jaundice

Slide 51 · Immune cytopenias are less common complications

Immune cytopenias among the less frequent consequences.

Polyclonal B-cell activation offers a mechanism for antiplatelet autoantibodies.

This differs mechanistically from cytopenia caused by direct marrow replacement.

Polyclonal antibodies

Immune cell destruction

Cytopenia

Slide 52 · EBV can trigger hemophagocytic lymphohistiocytosis

HLH is listed as a rare, serious complication of EBV infection.

The key concept is pathologic immune activation rather than routine viral cytopathy.

Suspected HLH requires separate diagnostic evaluation beyond a basic EBV test.

Routine reactive response

Severe dysregulated inflammation

Slide 53 · Extra-lymphoid complications broaden the differential

Abnormalities affecting the nervous system and lungs.

Kidney, marrow, eye, and cardiac complications are also described.

These manifestations are unusual and should not be mistaken for the typical course.

Complication spectrum

Clinical meaning

Meningoencephalitis

Neurologic involvement

Pneumonitis

Pulmonary involvement

Other organ dysfunction

Broader but less frequent disease

Slide 54 · X-linked lymphoproliferative disease: Inherited susceptibility

Defects in SH2D1A can cause ineffective control of EBV infection.

SH2D1A encodes SLAM-associated protein (SAP), an immune signaling adaptor.

The phenotype may become apparent only after a significant EBV infection.

SH2D1A mutation

SAP signaling defect

Poor EBV control

Slide 55 · SAP dysfunction impairs cellular immunity

SAP participates in activation pathways of T cells, NK cells, and B cells.

Reduced cytotoxic immune activation undermines elimination of infected B cells.

The related Robbins immunodeficiency chapter also links SAP to Tfh-cell function.

Defective SAP

T / NK dysfunction

Persistent EBV-expanded B cells

Slide 56 · Severe outcomes in X-linked lymphoproliferative disease

Acute EBV infection may become overwhelming and potentially fatal.

Some patients develop EBV-positive B-cell lymphoma.

Hypogammaglobulinemia can predispose to other infections.

Fulminant EBV disease

Lymphoma / antibody deficiency

Slide 57 · EBV oncogenesis is context-dependent

EBV-associated cancers include selected B-cell lymphomas and carcinomas.

Viral latency proteins may drive cell survival and proliferation.

Additional genetic, environmental, or immunologic factors often matter.

Viral persistence

Growth / survival effects

Additional cofactors

Neoplasia

Slide 58 · Malignant transformation is not inevitable

Most people infected with EBV do not develop an EBV-associated tumor.

Cytotoxic T-cell surveillance usually controls antigenic EBV-driven expansion.

Cancer development reflects interaction of immune context and other transforming events.

Common: Controlled latency

Rare: Malignant outgrowth

Slide 59 · Endemic Burkitt lymphoma has a strong EBV association

Latent EBV in more than 90% of endemic Burkitt lymphomas.

EBV is less common in morphologically similar nonendemic tumors.

Geographic and environmental cofactors affect the strength of the association.

Burkitt context

EBV detected in tumors

Endemic regions

>90% (Robbins)

Outside endemic regions

15–20% (Robbins)

Slide 60 · Burkitt oncogenesis requires cooperating events

EBV can sustain an expanded B-cell pool in which mutations can accumulate.

Dysregulation of MYC, usually by chromosomal translocation, is central.

The text emphasizes EBV as a facilitator rather than a sole direct cause of Burkitt lymphoma.

EBV-driven B-cell expansion

MYC translocation

Malignant clone

Slide 61 · Burkitt tumors restrict antigenic EBV proteins

Burkitt lymphoma cells generally lack the LMP1 and EBNA2 pattern of fully transformed B cells.

This contrasts with the antigenically broad latency program in early infected B cells.

Restricted viral antigen expression helps explain persistence despite immune pressure.

Early activated B cell: LMP1 / EBNA2

Burkitt cell: Restricted latency

Slide 62 · Immunosuppression favors EBV-positive B-cell tumors

Defective T-cell surveillance permits proliferation of EBV-infected B cells.

Such proliferations may begin polyclonally and progress to monoclonal neoplasia.

, these tumors often express LMP1 and EBNA2 and typically lack MYC translocations.

Reduced CTL surveillance

EBV-positive B-cell expansion

Potential clonal lymphoma

Slide 63 · Restoring T-cell surveillance may constrain proliferation

Some EBV-related B-cell proliferations arise during post-transplant immunosuppression.

Reduction of immunosuppressive drugs can permit control in some cases.

The essential concept is immune dependence; No treatment algorithm is inferred here.

Drug-related T-cell suppression

EBV B-cell expansion

Restored immunity → control

Slide 64 · Nasopharyngeal carcinoma has a strong EBV link

EBV genomes in nasopharyngeal carcinomas worldwide.

Clonal viral genomes within tumors support infection before clonal tumor expansion.

Geographic concentration points to contributions from additional cofactors.

Prior EBV infection

Clonal EBV-positive epithelium

Carcinoma + cofactors

Slide 65 · LMP1 affects epithelial tumor biology

LMP1 can activate NF-κB signaling in EBV-associated nasopharyngeal carcinoma.

Increased VEGF, FGF2, MMP9, and COX2 among potential downstream mediators.

Tumor immune-evasion pathways can limit an otherwise conspicuous T-cell infiltrate.

Epithelial-cell LMP1

NF-κB / downstream mediators

Tumor progression

Slide 66 · Other tumor associations remain important

EBV-associated Hodgkin lymphoma elsewhere in the text.

EBV-positive carcinomas may also occur in sites such as stomach or thymus.

Association does not mean that every example of a named tumor is EBV-driven.

Tumor category

Textbook association

Selected B-cell lymphomas

Variable EBV prevalence and latency

Nasopharyngeal carcinoma

Strong EBV association

Some other carcinomas / Hodgkin lymphoma

EBV-associated subsets

Slide 67 · Case 1: Acute infectious mononucleosis

A young adult has fever, sore throat, fatigue, and posterior cervical adenopathy.

Blood testing shows absolute lymphocytosis with large reactive cells.

Question: Which cell population explains the atypical circulating lymphocytes?

Slide 68 · Case 1: The atypical cells are activated T cells

Most conspicuous circulating atypical lymphocytes are CD8-positive reactive T cells.

They expand in response to EBV-infected B cells.

The diagnostic argument strengthens with heterophile and EBV-specific serology.

EBV-infected B lymphocyte

CD8 antiviral response

Reactive blood lymphocyte

Slide 69 · Case 2: Alarming lymph-node biopsy

An EBV-compatible febrile illness is accompanied by a rapidly enlarged node.

The biopsy shows paracortical immunoblasts and occasional RS-like cells.

Question: What error should be avoided before a lymphoma diagnosis is made?

Slide 70 · Case 2: Integrate morphology and clinical setting

Acute EBV lymphadenitis can closely resemble a lymphoma.

RS-like cells and a florid paracortex are not sufficient for malignancy.

Interpret architecture, clinical course, and confirmatory workup together.

Reactive EBV lymphadenitis

Malignancy: Requires independent proof

Slide 71 · One mechanism explains diverse manifestations

Infected B cells and their latent gene products initiate proliferation.

Activated CD8 T cells account for the characteristic blood and lymphoid morphology.

Immune control usually yields recovery; Immune failure increases severe infection and tumor risk.

EBV-infected B cell

Reactive CD8 immunity

Control vs dysregulation

Slide 72 · Selected textbook references

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

Infectious Diseases: Epstein–Barr virus, infectious mononucleosis, and tissue morphology.

Neoplasia: EBV-associated lymphomas and nasopharyngeal carcinoma.

Immune disorders: X-linked lymphoproliferative disease.