Sjogren Syndrome

Slide 1 · Sjögren syndrome

Glandular autoimmunity • morphology • clinical consequences

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Connect glandular immune injury to sicca symptoms and microscopic change.

Recognize the cellular infiltrate, gland destruction, and B-cell evolution.

Interpret autoantibodies and extraglandular disease without overclaiming specificity.

Explain why chronic glandular inflammation raises lymphoma concern.

Slide 3 · A disease of exocrine-gland injury

A chronic autoimmune inflammatory disease preferentially affects lacrimal and salivary glands.

Loss of functioning secretory tissue produces keratoconjunctivitis sicca and xerostomia.

The same inflammatory process can extend beyond the principal glands.

Lacrimal gland

↓ Tears

Ocular surface injury

Salivary glands

↓ Saliva

Slide 4 · The sicca phenotype links two organ systems

Lacrimal system

Reduced tear production

Ocular surface dryness

Keratoconjunctivitis sicca

Salivary system

Reduced salivary secretion

Oral surface dryness

Xerostomia

Slide 5 · Exocrine targets extend beyond tears and saliva

The lacrimal and salivary glands are the dominant sites of inflammation.

Other potentially affected secretory surfaces include respiratory, gastrointestinal, and vaginal mucosa.

Systemic manifestations are distinct from local dryness, although both belong to the disease spectrum.

Lacrimal / salivary

Airway / GI / vagina

Systemic manifestations

Slide 6 · Primary and associated presentations

Primary Sjögren syndrome

Occurs as an isolated disorder

Gland-centered autoimmune manifestations

Historically described as the “sicca syndrome”

Associated (secondary) form

Occurs alongside another autoimmune disease

May coexist with its systemic findings

Classification depends on the clinical context

Slide 7 · Autoimmune diseases reported in association

Rheumatoid arthritis is the most frequently associated condition in the Robbins description.

Other associations include systemic lupus erythematosus, systemic sclerosis, myositis, vasculitis, and mixed connective tissue disease.

Autoimmune thyroiditis also belongs to the reported overlap spectrum.

Sjögren syndrome

RA

SLE

Thyroiditis

Systemic sclerosis

Slide 8 · Patient context and presentation

Greatest frequency in women aged approximately 50–60 years.

Presentations may emphasize ocular symptoms, oral symptoms, gland enlargement, or extraglandular findings.

Clinical pattern and immune markers should be interpreted together rather than in isolation.

Lacrimal gland

↓ Tears

Ocular surface injury

Salivary glands

↓ Saliva

Slide 9 · Why self-tolerance matters

Normal self-tolerance

Escape of autoreactive lymphocytes

Persistent tissue antigen exposure

Chronic autoimmune inflammation

Context’ autoimmune-tolerance framework; Not a uniquely proven Sjögren pathway.

Slide 10 · Central tolerance: First safeguard

Self-reactive immature lymphocytes are normally controlled in generative lymphoid organs.

Deletion by apoptosis limits persistence of strongly self-reactive clones.

B-cell receptor editing can replace an autoreactive antigen receptor.

Immature lymphocytes

Deletion / receptor editing

Autoreactivity constrained

Slide 11 · Peripheral tolerance: Secondary safeguard

Regulatory T cells suppress inappropriate activation of mature lymphocytes.

Inhibitory signaling through CTLA-4 and PD-1 restrains responses.

Anergy and apoptosis further reduce responses to self antigens.

Mature lymphocytes

Regulatory / inhibitory signals

Response restrained

Slide 12 · Genetic predisposition is plausible, not deterministic

Sjögren syndrome has weak reported associations with certain HLA alleles.

The causal significance of these associations remains uncertain.

Susceptibility fits the broader autoimmune framework, but no single causal genotype is established here.

Observed immune activation

Unknown initiating antigen

Uncertain cytokine hierarchy

Slide 13 · A viral trigger is a hypothesis

Local salivary-gland infection could injure epithelial cells and expose self antigens.

Autoreactive lymphocytes that escaped tolerance might respond to those antigens.

Robbins does not establish a specific virus as the causal agent.

Proposed viral injury

Release of local self antigens

Autoreactive response

Slide 14 · How tissue injury could initiate autoimmunity

Proposed infection / gland injury

Release of tissue self antigens

Response by self-reactive CD4⁺ and B cells

Inflammation and gland damage

Proposed mechanism; Initial trigger and target antigens remain unresolved.

Slide 15 · Viral associations are not causal proof

Sjögren-like presentations have been described with HTLV, HIV, and hepatitis C virus infections.

The relationship of these infections to the autoimmune disease remains obscure.

Phenotypic similarity must not be treated as evidence that one infection causes all Sjögren syndrome.

Observed immune activation

Unknown initiating antigen

Uncertain cytokine hierarchy

Slide 16 · Mechanistic boundaries

Supported disease features

Aberrant T-cell and B-cell activation

Glandular immune infiltration

Progressive destruction and fibrosis

Not yet established

Initiating autoantigens

Necessary cytokine or T-helper subsets

A unique infectious cause

Slide 17 · Cellular composition of the infiltrate

Activated CD4⁺ helper T cells predominate in involved glands.

B lymphocytes and plasma cells also contribute to the infiltrate.

The mixture explains why both cellular injury and circulating autoantibodies are prominent.

CD4⁺ T cell

B lymphocyte

Plasma cell

Mixed immune-cell infiltrate

Slide 18 · The gland is the site of the immune reaction

Inflammatory cells accumulate in relation to glandular ducts and blood vessels.

Prolonged tissue inflammation progressively compromises gland architecture.

Secretory failure is therefore an anatomic consequence of immune injury.

Salivary gland — schematic

Secretory acini

Duct / immune infiltrate

Original conceptual schematic; Not a histologic specimen

Slide 19 · Activated CD4⁺ T cells are prominent

A CD4⁺-rich infiltrate is a central morphologic observation.

The specific self antigens recognized by participating T cells remain unknown.

The roles of proposed cytokines or precise T-cell subsets are not resolved by the source.

CD4⁺ T cell

B lymphocyte

Plasma cell

Mixed immune-cell infiltrate

Slide 20 · B cells participate from early inflammation

Early salivary-gland infiltrates contain a mixture of polyclonal T and B cells.

B-cell stimulation contributes to a broad autoantibody repertoire.

Persistence of this response creates a setting for clonal B-cell selection.

Initially mixed infiltrate

Potential dominant B-cell clone

Slide 21 · Plasma cells connect tissue and serology

Plasma cells are present within inflammatory gland infiltrates.

Humoral autoimmunity can be detected through RF, ANA, and anti-Ro/anti-La assays.

A positive antibody result is a marker of immune activity, not direct proof of its pathogenic role.

CD4⁺ T cell

B lymphocyte

Plasma cell

Mixed immune-cell infiltrate

Slide 22 · Sustained inflammation impairs secretion

Lymphocytic infiltration

Ductal changes and acinar injury

Fibrosis / parenchymal loss

Decreased tears and saliva

Anatomic sequence integrating Robbins’ morphology with its clinical consequences.

Slide 23 · Rheumatoid factor is frequent but nonspecific

Approximately 75% of patients have rheumatoid factor.

Rheumatoid factor reacts with self IgG.

Its detection does not imply that the patient also has rheumatoid arthritis.

RF

IgG-reactive autoantibody

ANA

Broad nuclear reactivity

Ro / La

Ribonucleoprotein antigens

Slide 24 · Antinuclear antibodies are common

ANA positivity is reported in roughly 50–80% by immunofluorescence assay.

ANA is a broad serologic finding shared by several autoimmune diseases.

A positive ANA alone cannot establish Sjögren syndrome.

RF

IgG-reactive autoantibody

ANA

Broad nuclear reactivity

Ro / La

Ribonucleoprotein antigens

Slide 25 · Anti-SS-A/Ro and anti-SS-B/La

SS-A (Ro) and SS-B (La) are ribonucleoprotein-associated autoantigens.

Antibodies targeting these antigens are important serologic markers in the Robbins account.

Detection varies by assay; The text describes positivity in as many as 90% using sensitive techniques.

RF

IgG-reactive autoantibody

ANA

Broad nuclear reactivity

Ro / La

Ribonucleoprotein antigens

Slide 26 · Serologic specificity has limits

What positive Ro/La supports

An autoimmune sicca context

A disease-associated humoral response

Useful supportive serology

What it does not prove

Exclusive specificity for Sjögren syndrome

That glandular injury is antibody-mediated

A complete diagnosis without clinical context

Slide 27 · Interpret serologic results as a pattern

Marker

Robbins frequency

Interpretive caution

Rheumatoid factor

About 75%

Not synonymous with rheumatoid arthritis

ANA (IFA)

50–80%

Broad autoimmune marker

Ro/La antibodies

Up to 90% by sensitive methods

May occur in SLE

Slide 28 · Earliest salivary-gland lesion

The earliest described finding is periductal and perivascular lymphocytic infiltration.

An initially localized infiltrate precedes widespread architectural loss.

The spatial distribution is important because it links inflammation to ducts and vessels.

Salivary gland — schematic

Secretory acini

Duct / immune infiltrate

Original conceptual schematic; Not a histologic specimen

Slide 29 · Periductal and perivascular are different landmarks

Periductal

Immune cells collect around ducts

Duct epithelium may subsequently proliferate

Obstruction may follow epithelial hyperplasia

Perivascular

Immune cells collect near vessels

Occurs early in involved glands

A second landmark of localized inflammation

Slide 30 · Inflammatory infiltrates may become extensive

With progression, lymphocytes occupy increasing portions of glandular parenchyma.

The expansion occurs alongside loss of normal acinar organization.

The density of lymphocytes can eventually resemble a lymphoid neoplasm.

Salivary gland — schematic

Secretory acini

Duct / immune infiltrate

Original conceptual schematic; Not a histologic specimen

Slide 31 · Lymphoid follicles may form

Lymphoid follicles, sometimes with germinal centers, may appear in affected glands.

This represents organized lymphoid tissue within a chronically inflamed organ.

Follicle formation underscores persistent B-cell activity but is not itself a lymphoma diagnosis.

Salivary gland — schematic

Secretory acini

Duct / immune infiltrate

Original conceptual schematic; Not a histologic specimen

Slide 32 · Ductal epithelial hyperplasia

The epithelial lining of salivary ducts may become hyperplastic.

Luminal narrowing or obstruction can result from this proliferation.

Secretory dysfunction therefore reflects both parenchymal damage and altered ductal architecture.

Ductal hyperplasia — schematic

Thickened epithelium

Lumen

Original conceptual schematic; Not a histologic specimen

Slide 33 · Duct obstruction amplifies gland dysfunction

Duct epithelial hyperplasia

Reduction of duct lumen

Impaired movement of secretion

Greater oral dryness

Mechanistic consequence of the ductal changes.

Slide 34 · Acinar atrophy marks loss of secretory capacity

Secretory acini atrophy as inflammatory injury progresses.

Fewer functioning acini reduce the capacity to produce tears or saliva.

Structural loss explains why established dryness may be persistent.

Salivary gland — schematic

Secretory acini

Duct / immune infiltrate

Original conceptual schematic; Not a histologic specimen

Slide 35 · Fibrosis and hyalinization follow injury

Later glands show fibrosis and hyalinization.

Replacement of functioning tissue by scar further limits secretion.

Fibrotic remodeling is a consequence of sustained tissue injury, not the initiating lesion.

Salivary gland — schematic

Secretory acini

Duct / immune infiltrate

Original conceptual schematic; Not a histologic specimen

Slide 36 · Late parenchyma may be replaced by fat

Advanced disease may show atrophy with fatty replacement of glandular tissue.

Loss of acini, fibrosis, and fat collectively reflect chronic tissue remodeling.

This appearance is part of the later morphologic spectrum rather than a defining early change.

Salivary gland — schematic

Secretory acini

Duct / immune infiltrate

Original conceptual schematic; Not a histologic specimen

Slide 37 · Histologic progression at a glance

Early

Periductal / perivascular lymphocytes

Established

Dense infiltration; Follicles; Duct hyperplasia

Late

Acinar atrophy; Fibrosis; Fatty replacement

Slide 38 · Lymphoid-rich tissue is not automatically lymphoma

Dense reactive lymphoid infiltrates may resemble lymphoid neoplasia.

Early lesions can contain mixed polyclonal T and B lymphocytes.

A dominant expanding B-cell clone raises concern for true marginal zone lymphoma.

Initially mixed infiltrate

Potential dominant B-cell clone

Slide 39 · Reduced tears injure the ocular surface

Lacrimal gland destruction

Reduced tear film

Dry corneal epithelium

Inflammation, erosion, ulceration

The cornea is injured secondarily to impaired lacrimal secretion.

Slide 40 · Ocular symptoms follow keratoconjunctivitis sicca

Burning and itching reflect irritation of the dry ocular surface.

Blurred vision may accompany corneal epithelial damage.

Thick secretions may accumulate in the conjunctival sac.

Reduced tear film

Corneal epithelial drying

Irritation / epithelial damage

Slide 41 · Corneal injury can progress beyond discomfort

Reduced lubrication contributes to epithelial drying and inflammation.

Erosions and even ulceration are described in the source.

Clinical concern extends from symptoms to structural ocular-surface injury.

Reduced tear film

Corneal epithelial drying

Irritation / epithelial damage

Slide 42 · Salivary loss injures the oral mucosa

Salivary-gland inflammation

Xerostomia

Oral mucosal drying / atrophy

Fissures, inflammation, ulceration

The mucosal lesions are a downstream effect of reduced salivary protection.

Slide 43 · Xerostomia alters everyday function

Swallowing solid foods may become difficult.

Patients may report diminished taste.

Dry buccal mucosa and oral cracks or fissures are characteristic consequences.

Reduced saliva

Dry oral mucosa

Swallowing / taste changes

Slide 44 · Parotid enlargement is an important clue

Parotid enlargement in about one-half of patients.

Inflammatory gland enlargement can coexist with declining secretion.

The later emergence of a dominant B-cell clone changes the interpretation of a persistent gland mass.

Parotid inflammation

Gland enlargement

Secretion may still decline

Slide 45 · Other exocrine surfaces can be affected

Exocrine site

Possible consequence

Source-supported context

Nasal mucosa

Dryness; Crusting

Ulceration or septal perforation can occur

Airway mucosa

Dryness / airway symptoms

Recurrent bronchitis, pneumonitis

Gastrointestinal / vaginal

Additional mucosal dryness

Other exocrine glands may be involved

Slide 46 · Nasal dryness can damage local tissue

Dryness and crusting of the nose may lead to erosive mucosal damage.

Epistaxis is among the reported symptoms.

Severe local disease may cause ulceration or nasal septal perforation.

Dry nasal mucosa

Crusting / bleeding

Ulceration / perforation

Slide 47 · Respiratory presentations have more than one mechanism

Airway/exocrine involvement

Dry respiratory mucosa

Recurrent bronchitis

Pneumonitis

Extraglandular involvement

Diffuse pulmonary fibrosis

Part of systemic disease

Separate from isolated mucosal dryness

Slide 48 · Extraglandular disease affects a substantial minority

Manifestations outside the principal glands in approximately one-third of patients.

Examples include synovitis, diffuse pulmonary fibrosis, and peripheral neuropathy.

Systemic findings are described as more frequent with high anti-SS-A titers.

Lacrimal / salivary

Airway / GI / vagina

Systemic manifestations

Slide 49 · Synovitis belongs to the systemic spectrum

Inflammatory joint involvement may accompany ocular and oral dryness.

Synovitis can arise as an extraglandular Sjögren manifestation.

Coexisting rheumatoid arthritis must remain a separate diagnostic consideration.

Sicca phenotype

Systemic synovitis

Assess RA overlap

Slide 50 · Pulmonary fibrosis indicates systemic extension

Diffuse pulmonary fibrosis is included among extraglandular manifestations.

It should not be conflated with bronchitis arising from exocrine-airway dryness.

The distinction matters when interpreting respiratory disease in a patient with sicca symptoms.

Mucosal dryness

Pneumonitis / bronchitis

Separate systemic fibrosis

Slide 51 · Peripheral neuropathy is another systemic clue

Peripheral nerve involvement appears in the Robbins extraglandular list.

Neurologic complaints cannot be explained solely by tear or saliva deficiency.

Their presence should prompt consideration of multisystem autoimmune disease.

Glandular phenotype

Extraglandular disease

Peripheral neuropathy

Slide 52 · Renal involvement favors the tubulointerstitium

Renal tubular acidosis, uricosuria, and phosphaturia are described tubular abnormalities.

The reported association is tubulointerstitial nephritis.

Robbins specifically distinguishes this pattern from the glomerular lesions typical of lupus.

Tubulointerstitial inflammation

Tubular dysfunction

Glomeruli usually spared

Slide 53 · Tubular injury is distinct from glomerular injury

Sjögren pattern

Tubular functional defects

Associated interstitial nephritis

Glomerular lesions extremely rare

Contrast with SLE

Immune-complex glomerular injury prominent

Glomerular disease is a key source feature

Different major pathologic compartment

Slide 54 · Coexisting autoimmunity modifies the phenotype

More than one-half of patients in the Robbins account have another autoimmune disorder.

They may exhibit both sicca findings and manifestations of the accompanying condition.

Do not attribute every joint, skin, or renal abnormality automatically to Sjögren syndrome.

Sjögren syndrome

RA

SLE

Thyroiditis

Systemic sclerosis

Slide 55 · Persistent B-cell stimulation is a lymphoma risk

Early infiltrates are mixed and polyclonal.

Continued stimulation may favor expansion of a dominant B-cell clone.

Marginal zone lymphoma is a characteristic malignancy arising in this setting.

Initially mixed infiltrate

Potential dominant B-cell clone

Slide 56 · From chronic inflammation to dominant clone

Polyclonal immune infiltrate

Longstanding B-cell stimulation

Selective clonal growth advantage

Marginal zone lymphoma may emerge

Somatic mutations as a presumptive mechanism for clonal advantage.

Slide 57 · The magnitude of lymphoma risk

Lymphoma development in approximately 5% of patients.

Its reported incidence is about 40-fold higher than normal.

These textbook estimates underscore surveillance relevance; They are not individualized predictions.

Polyclonal infiltrate

Dominant B-cell clone

Marginal zone lymphoma

Slide 58 · Reactive infiltrate versus lymphoma: Diagnostic reasoning

Feature

Inflammatory disease

Concern for lymphoma

Population

Early mixed, polyclonal T and B cells

Dominant B-cell clone

Architecture

Inflammatory lymphoid aggregates / follicles

Evolving clonal lymphoid expansion

Interpretation

Chronic autoimmunity

Separate neoplastic event

Slide 59 · Clinicopathologic integration

Immune activation within glands

Ductal / acinar tissue injury

Ocular and oral sicca phenotype

Extraglandular features ± B-cell evolution

Final clinical phenotype depends on gland damage, systemic involvement, and any associated autoimmunity.

Slide 60 · Case: Sicca symptoms and parotid swelling

Clinical vignette

A woman in her late fifties reports persistent burning eyes, difficulty swallowing dry foods, and painless enlargement of a parotid gland.

Reason through the case

Which two gland systems are principally affected?

Which histologic distribution would support the expected autoimmune process?

Why can swelling coexist with poor secretion?

Slide 61 · Case interpretation: Connect structure to function

Lacrimal and salivary immune injury unifies eye and mouth symptoms.

Periductal/perivascular lymphocytes, later duct changes, and acinar atrophy fit the source morphology.

Gland enlargement reflects inflammation; It does not demonstrate normal gland function.

Lacrimal gland

↓ Tears

Ocular surface injury

Salivary glands

↓ Saliva

Slide 62 · Case: Anti-Ro positive with overlapping disease

Clinical vignette

A patient has xerostomia, positive ANA and anti-SS-A, and manifestations that also suggest systemic lupus erythematosus.

Reason through the case

Does anti-SS-A positivity alone prove Sjögren syndrome?

What diagnosis must remain in the differential?

Why does the clinical context matter?

Slide 63 · Case interpretation: Avoid serologic overreach

Anti-SS-A supports an autoimmune disease but is not fully specific to Sjögren syndrome.

Robbins documents Ro/La antibodies in a subset of patients with SLE.

Interpret antibody results alongside sicca findings and the features of associated disease.

RF

IgG-reactive autoantibody

ANA

Broad nuclear reactivity

Ro / La

Ribonucleoprotein antigens

Slide 64 · Case: Tubular dysfunction with sicca symptoms

Clinical vignette

A patient with longstanding dry eyes and dry mouth develops a renal tubular acidification defect but no evidence of a glomerular syndrome.

Reason through the case

Which renal compartment is implicated in Sjögren syndrome?

What associated lesion does Robbins describe?

How does this differ from the classic lupus pattern?

Slide 65 · Case interpretation: Compartment is informative

Tubular dysfunction fits the reported Sjögren-associated tubulointerstitial process.

Tubulointerstitial nephritis is the source-associated renal lesion.

Clinically prominent glomerular injury would warrant consideration of other causes, including SLE.

Tubulointerstitial inflammation

Tubular dysfunction

Glomeruli usually spared

Slide 66 · Case: An enlarging salivary-gland mass

Clinical vignette

A patient with established Sjögren syndrome develops a persistent, progressively enlarged salivary gland with an unusually dense lymphoid infiltrate.

Reason through the case

Why is reactive inflammation not the only possibility?

Which B-cell neoplasm is especially relevant?

What cellular change signals escalation in concern?

Slide 67 · Case interpretation: Clonal evolution matters

Longstanding B-cell activation can select a dominant lymphocyte clone.

Marginal zone lymphoma is a recognized complication in the affected tissue.

A dense infiltrate alone is not sufficient to conclude that lymphoma is present.

Initially mixed infiltrate

Potential dominant B-cell clone

Slide 68 · Five concepts that organize the disease

Immune injury

Activated CD4⁺ T cells, B cells, plasma cells

Tissue response

Periductal infiltrates → acinar loss / fibrosis

Clinical effects

Sicca manifestations ± systemic disease

Slide 69 · Diagnostic and prognostic boundaries

Supported clinical / diagnostic clues

Dry eye and mouth syndrome

Glandular immune pathology

Ro/La and other autoimmune serology

What needs careful interpretation

Assays are not fully specific

Mechanism remains partly unresolved

B-cell clonality changes risk assessment

Slide 70 · Primary textbook reference

Robbins, Cotran & Kumar: Pathologic Basis of Disease

11th edition (2026) • Chapter 6: Diseases of the Immune System

Sjögren syndrome: pathogenesis, morphology, and clinical features

Additional context: Immunologic Tolerance and Autoimmunity; Table 6.10; tubulointerstitial nephritis discussion in Chapter 20.