Lyme Disease

Slide 1 · Lyme Disease

Etiology • immune pathogenesis • morphology • clinicopathologic correlation

A systemic Borrelia infection transmitted by Ixodes ticks

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Identify the Borrelia species, Ixodes vector, and reservoir context.

Explain the three clinical stages and their organ-system manifestations.

Trace innate immunity, antibody responses, and bacterial immune evasion.

Correlate skin, joint, vascular, and nervous-system pathology with diagnosis.

Slide 3 · Spirochetes: Organism-level context

Structural features

Slender, helical bacteria

Axial periplasmic flagella

Outer sheath around the protoplasm

Schematic bacterial outline — not a photomicrograph

Slide 4 · Borrelia species: Geographic associations

Organism

Association

B. Burgdorferi

Principal species in the United States

B. Afzelii

Additional cause in Europe and Asia

B. Garinii

Additional cause in Europe and Asia

Slide 5 · Reservoir → Ixodes tick → human

Reservoir hosts

Rodents; Birds for B. Garinii

Ixodes tick

Human infection

Bite-mediated transmission

Transmission schematic; The host associations follow Robbins.

Slide 6 · Endemic distribution is geographically clustered

Lyme disease is endemic in the United States, Europe, and Asia.

The northeastern United States and upper Midwest are emphasized.

The distribution of Lyme arthritis is described as expanding.

Geographic exposure informs the interpretation of compatible clinical findings.

Slide 7 · Epidemiologic figures require temporal context

Older reported-case estimate

30,000–40,000 US reports per year over several years

Textbook notes this may be only 10% of persons treated

Interpretive caution

These are historical figures quoted by Robbins.

They are not presented as a current surveillance estimate.

Slide 8 · Tick coinfections: A separate diagnostic consideration

In some endemic areas, B. Burgdorferi in up to 50% of ticks.

The same Ixodes ticks may harbor Ehrlichia spp. And Babesia spp.

Coinfection possibility should not be confused with a defining feature of Lyme disease.

Do not infer individual infection probability from the proportion of ticks infected.

Slide 9 · Three-stage natural history

Early localized

Multiplication and spread in the dermis

Early disseminated

Hematogenous spread; Multisystem disease

Late disseminated

Delayed arthritis and less common neurologic disease

Clinical stages are descriptive; Organ manifestations can overlap.

Slide 10 · Clinical stage versus dominant manifestations

Phase

Dominant teaching features

Early localized

Erythema migrans; Fever or lymphadenopathy

Early disseminated

Secondary rash; Carditis; Cranial neuropathy; Meningitis

Late disseminated

Large-joint arthritis; Occasional neuropathy or encephalitis

Slide 11 · Initial dermal infection explains early rash

Tick inoculation

Organisms enter at bite site

Dermal replication

Spirochetes multiply and spread locally

Inflammatory lesion

Expanding cutaneous erythema

Slide 12 · Erythema migrans: Expanding cutaneous lesion

Simplified morphology schematic — not a clinical photograph

Characteristic pattern

Expanding erythematous area

Central pallor may occur

Often appears at the tick-bite site

Slide 13 · Erythema migrans is a frequent early sign

Erythema migrans in approximately 80% of patients.

The lesion often expands and may have a paler central region.

Fever and lymphadenopathy can accompany the skin finding.

A ring-like appearance is typical but is not required by the source description.

Slide 14 · Local disease: Lesion and systemic symptoms

Dermal infection

Local erythema migrans

Inflammatory response

Fever may accompany the lesion

Regional response

Lymphadenopathy may be present

Interpret rash, systemic symptoms, and tick exposure together.

Slide 15 · Spontaneous fading does not define microbial eradication

Erythema migrans resolves in 4–12 weeks.

Visible improvement of the skin lesion is distinct from elimination of infection.

The natural history includes potential subsequent dissemination.

The stage sequence is a disease framework, not a patient-specific prediction.

Slide 16 · Early dissemination occurs through the bloodstream

Initial dermal infection

Local bacterial multiplication

Hematogenous spread

Organisms enter systemic circulation

Remote tissue involvement

Skin, musculoskeletal, cardiac and nervous system findings

Slide 17 · Skin findings: Localized versus disseminated

Early localized

Primary expanding erythema migrans

Initial bite-site lesion

Early disseminated

Secondary cutaneous lesions

May occur with systemic symptoms

Slide 18 · Early disseminated musculoskeletal symptoms

Migratory joint pain can accompany systemic spread.

Migratory muscle pain is also reported.

These complaints should be distinguished from later established chronic synovitis.

The site and persistence of symptoms help frame the stage.

Slide 19 · Cardiac involvement during dissemination

Hematogenous disease

Early disseminated infection

Cardiac manifestation

Arrhythmias may occur

Conduction involvement

Textbook emphasizes conduction-system disturbance

Slide 20 · Lyme carditis: Conduction disturbances

The cardiac Robbins section reports myocarditis in approximately 5% of patients.

Its principal clinical expression is a usually self-limited conduction-system disorder.

Some presentations may require temporary cardiac pacing.

This figure is a textbook estimate, not a verified current population rate.

Slide 21 · Neuroborreliosis: Meninges and cranial nerves

Disseminated infection

Nervous-system involvement

Meningeal inflammation

Aseptic meningitis

Cranial neuropathy

Facial nerve palsy may accompany meningitis

Slide 22 · Facial neuropathy may be unilateral or bilateral

Cranial nerve involvement in disseminated disease.

Peripheral nerve material specifies unilateral or bilateral facial nerve palsies.

Associated polyradiculoneuropathy is primarily axonal in the source.

Cranial neuropathy and meningeal involvement need not be mutually exclusive.

Slide 23 · Borrelial lymphocytoma: Uncommon regional manifestation

Clinical pattern

Associated with B. Afzelii in Europe

Blue-to-red swelling

Earlobe in children; Nipple in adults

Pathologic correlate

Lymphocytic infiltration of the lesion

Distinctive but uncommon manifestation

Not equivalent to erythema migrans

Slide 24 · Early dissemination is multisystem

System

Reported manifestation

Skin

Multiple / secondary cutaneous lesions

Musculoskeletal

Migratory arthralgia and myalgia

Heart

Arrhythmia or conduction disturbance

Nervous system

Meningitis and cranial neuropathy

Slide 25 · Late disseminated disease can emerge after months

Late manifestations may appear many months after the tick bite.

Chronic arthritis is a defining late complication.

Progression can damage cartilage in large joints.

Neurologic manifestations are less common but sometimes disabling.

Slide 26 · The dominant tissue-injury mechanism is inflammatory

B. Burgdorferi

No endotoxin or exotoxin-mediated injury described

Host response

Innate and adaptive immunity respond

Pathologic outcome

Inflammatory tissue damage

Slide 27 · Bacterial lipoproteins activate innate receptors

Borrelial lipoproteins

Microbial inflammatory signals

TLR1 / TLR2

Receptors on macrophages

Macrophage activation

Inflammatory mediators released

Slide 28 · Activated macrophages amplify inflammation

TLR signaling

Lipoprotein recognition

Proinflammatory cytokines

IL-6 and TNF

Tissue response

Recruitment and maintenance of inflammation

Slide 29 · Innate responses reduce burden without reliably clearing infection

Macrophages generate bactericidal reactive nitrogen intermediates.

The initial host response usually lowers microbial burden.

That the response often fails to eradicate the organism.

Persistence therefore coexists with an active inflammatory response.

Slide 30 · T-cell and cytokine responses drive lesions

Persistent antigenic stimulation

Borrelia-associated signals

T cells / cytokines

Sustained immune activation

Tissue manifestations

Skin and synovial inflammation

Slide 31 · Borrelia-specific humoral immunity develops later

Specific antibodies appear about 2–4 weeks after infection.

These antibodies can promote complement-mediated opsonophagocytic killing.

Humoral immunity limits infection but does not guarantee elimination.

The antibody timeline gives context to serology-based diagnosis.

Slide 32 · Complement-assisted bacterial clearance

Borrelia-specific Ig

Antibody binding to bacterial surface

Complement activity

Facilitates phagocytosis

Bacterial killing

Reduces microbial load

Slide 33 · Immune defense versus bacterial persistence

Host protection

Macrophage cytokine response

Reactive nitrogen intermediates

Complement-assisted killing

Bacterial escape

Changes in VlsE antigenic identity

Downregulation of surface protein C

Slide 34 · Outer surface protein C has stage-dependent expression

Outer surface protein C (OspC) is needed for establishing infection.

It is not required for persistence.

The organism can downregulate OspC as part of immune escape.

Loss of a previously targeted surface epitope can reduce antibody recognition.

Slide 35 · VlsE antigenic variation: Genetic architecture

Schematic: One promoter region and alternative VlsE sequence cassettes

Promoter

Single expressed position

Variant 1

Variant 2

Variant 3

…

Approximately 15 coding sequences; This figure shows only illustrative alternatives.

Slide 36 · Antigenic switching can outpace an antibody response

Antibody to VlsE form A

Immune pressure against a displayed variant

Altered VlsE expression

Another antigenic surface form emerges

Immune escape

Previously elicited antibodies recognize less effectively

Slide 37 · VlsE variation is a mechanism for microbial persistence

VlsE is an antigenic surface protein.

Alternative coding sequences can be expressed at a promoter-associated position.

The host may recognize one variant while another escapes.

This provides a source-supported explanation for persistent infection.

Slide 38 · Proposed immune cross-reactivity in chronic disease

Borrelial antigen exposure

Host generates reactive immune responses

Possible cross-reactivity

Response may recognize a self antigen

Persistent inflammatory arthritis

Hypothesis, not proven single mechanism

Robbins explicitly treats this autoimmune explanation as a proposal.

Slide 39 · Skin biopsy: Edema and chronic inflammation

Microscopic findings

Dermal edema

Lymphocytic infiltrates

Plasma cells in the infiltrate

Original native schematic of dermis — not histology

Slide 40 · Dermal findings correlate with the expanding rash

Edema is a recorded pathologic component of Lyme skin lesions.

Inflammatory cells include lymphocytes and plasma cells.

This source description is not a substitute for an authentic skin photomicrograph.

The rash is an inflammatory tissue response to local infection.

Slide 41 · Synovial hypertrophy: Architecture of early arthritis

Villous synovial projections

Early Lyme synovitis

Villous hypertrophy

Synovial lining-cell hyperplasia

Subsynovial inflammatory cells

Schematic architecture — not an H&E section

Slide 42 · Villous hypertrophy enlarges the inflamed synovium

The early synovium can form prominent villous projections.

The synoviocyte lining becomes hyperplastic.

The tissue architecture can resemble early rheumatoid arthritis.

Microscopy must be interpreted with clinical and microbiologic context.

Slide 43 · Cellular infiltrates in Lyme synovitis

Abundant lymphocytes are present in the subsynovium.

Plasma cells accompany the chronic inflammatory infiltrate.

Chapter 26 additionally emphasizes mononuclear cells, especially CD4⁺ T cells.

Fibrin deposition may be seen in infected synovium.

Slide 44 · Onion-skin arteriolar change: Original schematic

Concentric arteriolar wall thickening

Pathology interpretation

Arteritis with onion-skin–like change

Chapter 26 describes obliterative endarteritis

Morphologic overlap with lesions described in lupus

Slide 45 · Arteritis is a distinctive morphologic clue

Onion-skin–like arteriolar lesions in Lyme arthritis.

Chapter 26 describes concentric arteriolar thickening as obliterative endarteritis.

Similar patterns occur in other inflammatory diseases.

The vessel change is suggestive in context, not independently specific.

Slide 46 · Lyme synovitis and rheumatoid arthritis: Overlap

Lyme arthritis

Villous hypertrophy and lining hyperplasia

Lymphoplasmacytic / CD4⁺ inflammation

May show onion-skin arteriolitis

Rheumatoid arthritis

Also produces chronic proliferative synovitis

Can show villous synovial hypertrophy

Morphologic overlap limits specificity

Slide 47 · Late joint damage emerges from chronic synovitis

Persistent joint inflammation

Proliferative synovitis

Injury to articular tissues

Inflammatory joint damage

Advanced outcome

Cartilage erosion in large joints

Slide 48 · Lyme arthritis: Characteristic large-joint distribution

Pattern

Textbook description

Most frequently involved

Knees

Other common joints

Shoulders, elbows, ankles

Initial attacks

Often one or two joints at a time

Course

Weeks to months; May recur elsewhere

Slide 49 · Lyme arthritis can migrate and recur

Initial arthritic episodes can last weeks to months.

Only one or two large joints may be involved simultaneously.

Subsequent episodes can occur in different joints.

Joint pain in early dissemination is not identical to advanced synovial damage.

Slide 50 · Treatment-era context changes the arthritis burden

Without timely treatment

Migratory arthritis in up to 80% of untreated individuals.

The figure describes the classic natural history.

Earlier treatment in practice

The same source reports arthritis in less than 10% of infections in the treatment era.

These are source-specific estimates.

Slide 51 · Serology is the main diagnostic method

Serologic testing as the principal diagnostic approach.

Interpret serologic evidence in the clinical and exposure context.

The source documents antibody generation after approximately 2–4 weeks.

A serologic result is not an anatomical map of active organisms.

Slide 52 · Serology and PCR answer different questions

Method

Detects / role

Limitation from source

Serology

Host anti-Borrelia antibodies

Does not localize organisms in a tissue

PCR of tissue

Borrelial DNA in sampled material

Depends on sampling of infected tissue

Synovial PCR

Borrelial DNA in joint fluid

May be negative in postinfectious arthritis

Slide 53 · PCR in Lyme arthritis: Contextual interpretation

Chapter 26 reports detectable Borrelia DNA in synovial fluid in about 70% of patients with Lyme arthritis.

This is a textbook figure, not a current assay performance specification.

PCR positivity demonstrates detectable target DNA in the sampled specimen.

Robbins still describes serology as the usual basis of diagnosis.

Slide 54 · Persistent arthritis: Infection versus postinfectious process

Active Lyme arthritis

Arthritis in Borrelia infection

Synovial PCR may detect organismal DNA

Antibiotic therapy is usually effective

Postinfectious arthritis

Uncommon persistence after antibiotic treatment

Organism frequently undetectable by PCR

Immune-mediated mechanism proposed

Slide 55 · Postinfectious Lyme arthritis is not proof of persistence

A minority have persistent joint inflammation after therapy.

In many such patients Borrelia is not detected, even by synovial PCR.

Cross-reactive immune injury as one possible explanation.

Persistent symptoms and detectable viable spirochetes must not be assumed equivalent.

Slide 56 · Treatment outcome as reported

Chapter 26 reports approximately 90% cure with antibiotics active against Borrelia.

Treatment often prevents the development of late arthritis.

Postinfectious inflammatory manifestations may require a separate conceptual framework.

This pathology lecture does not specify drug regimens or treatment durations.

Slide 57 · Lyme meningitis: A lymphoplasmacytic CSF response

CSF: Elevated cells (schematic only)

Reported CSF features

Hypercellularity

Lymphoplasmacytic infiltrate

Antispirochete IgG may be present

Slide 58 · Neurologic disease spans several compartments

Aseptic meningitis is a recognized nervous-system presentation.

Facial nerve palsy and polyneuropathy can occur.

Encephalopathy is noted in the central nervous system chapter.

Disease severity ranges from mild to disabling.

Slide 59 · Peripheral neuroborreliosis: Axonal neuropathy

Disseminated or late infection

Neurologic symptoms

Peripheral nerve involvement

Polyradiculoneuropathy or facial neuropathy

Pathologic pattern

Primarily axonal

Slide 60 · Autopsy evidence is rare and limited

The CNS chapter emphasizes that autopsy cases are unusual.

Reported findings include focal microglial-cell proliferation.

Scattered extracellular organisms have been described.

These findings should not be represented as routine biopsy criteria.

Slide 61 · Compartment-level clinicopathologic comparison

Site

Dominant manifestation

Pathology / correlate

Skin

Erythema migrans

Dermal edema; Lymphocytes and plasma cells

Synovium

Chronic large-joint arthritis

Lining hyperplasia; Arteritis; Fibrin

CSF / meninges

Meningitis

Lymphoplasmacytic cellular response

Heart

Conduction disturbance

Carditis / myocarditis

Peripheral nerves

Facial palsy / radiculoneuropathy

Predominantly axonal pattern

Slide 62 · Case application: An expanding rash

Hypothetical teaching case

A person living in an endemic region notices an enlarging erythematous lesion after a possible tick exposure. Fever and regional lymph-node enlargement are also present.

Which phase is most compatible with these findings?

Slide 63 · Case reasoning: Early localized infection

The expanding primary skin lesion supports erythema migrans.

Fever and lymphadenopathy are compatible accompanying signs.

The stage reflects local dermal multiplication and spread.

Do not equate fading of the rash with assured organism elimination.

Slide 64 · Case application: Episodic large-joint swelling

Hypothetical teaching case

A patient with a prior compatible tick-associated illness has recurrent episodes of knee swelling months later. Synovial inflammation is present; The clinician is evaluating for Lyme arthritis.

Which tissue features and tests are most informative?

Slide 65 · Case reasoning: Chronic inflammatory synovitis

Expect villous hypertrophy, lining-cell hyperplasia and mononuclear infiltrates.

An onion-skin arteriolar lesion is a distinctive associated feature.

Serology is the usual diagnostic method; Synovial PCR can provide additional evidence.

Persistent symptoms after antibiotics do not alone prove continued infection.

Slide 66 · Case application: Meningeal and facial involvement

Hypothetical teaching case

A patient develops lymphocytic meningitis together with unilateral facial weakness during an illness compatible with disseminated Lyme disease.

Explain the likely organ distribution and stage.

Slide 67 · Case reasoning: Neuroborreliosis

The clinical combination supports early disseminated neurologic involvement.

Meningeal inflammation and cranial neuropathy are both.

Lyme CSF may be hypercellular and contain antispirochete IgG.

The peripheral neuropathy described is mainly axonal.

Slide 68 · Integrated sequence: Infection → host injury → late effects

Tick-transmitted spirochete

Early dermal replication

Immune and hematogenous events

TLR1/TLR2 signaling; Variable antigen expression

Clinicopathologic disease

Multisystem inflammation; Possible late arthritis

Slide 69 · Mechanistic synthesis: Three essential distinctions

Question

Evidence-supported answer

How does tissue injury occur?

Mainly host inflammation; Not Borrelial endotoxin or exotoxin

How may bacteria persist?

OspC downregulation and VlsE antigenic variation

Why may arthritis persist after therapy?

A cross-reactive autoimmune mechanism is proposed, not proven

Slide 70 · Lyme disease: Five defensible conclusions

Ixodes-transmitted Borrelia infection can involve skin, heart, joints and nervous system.

The three-stage model links local dermal disease to dissemination and late sequelae.

Innate and adaptive immunity drive both protection and inflammatory tissue injury.

Antigenic variation helps explain persistent infection despite antibodies.

Lyme synovitis may mimic rheumatoid arthritis; Combine pathology and clinical testing.

Slide 71 · Sources and scope

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

Chapter 8

Lyme Disease, pp. 344–345; Spirochete Infections, p. 341

Chapter 26

Lyme Arthritis, pp. 1093–1094

Chapter 28

Neuroborreliosis, p. 1150

Chapter 27

Peripheral nerve manifestations, p. 1112

Chapter 12

Lyme myocarditis, pp. 523–524