Noninfectious Vasculitis

Slide 1 · Noninfectious vasculitis

Immune mechanisms, vessel patterns and clinicopathologic interpretation

Large vessels

Medium vessels

Small vessels

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Classify noninfectious vasculitides by vessel caliber, distribution and immune-deposit pattern.

Explain how immune complexes, ANCAs, endothelial-directed antibodies and T cells damage vessels.

Connect vascular injury with ischemia, hemorrhage, thrombosis and aneurysmal change.

Distinguish major vasculitic patterns using morphology, tissue distribution and laboratory clues.

Slide 3 · Vasculitis is inflammation of the vessel wall

Inflammatory injury centered on vascular walls can compromise perfusion or disrupt vascular integrity.

Vascular beds of many organs can be involved.

Clinical manifestations depend on the caliber and location of affected vessels.

Systemic inflammation may coexist with local ischemic injury.

Slide 4 · The injured vascular bed determines the phenotype

Wall inflammation

Endothelium and media injured

Vascular consequence

Narrowing, rupture or thrombosis

Tissue consequence

Ischemia, infarction or hemorrhage

Clinical syndrome

Organ-specific deficit and systemic signs

Slide 5 · Systemic and organ-limited patterns

Systemic distribution

Multiple vascular territories become inflamed.

Fever, malaise, myalgia and arthralgia may accompany organ injury.

Manifestations may evolve as additional beds are involved.

Initially limited disease

One tissue or organ may dominate the presentation.

Local injury can precede recognition of a wider syndrome.

A limited presentation does not define a unique mechanism.

Slide 6 · Infectious versus noninfectious injury

Direct infectious arteritis

Microorganisms invade or directly damage the vessel wall.

Can accompany adjacent infection, bacteremia or infected emboli.

Antimicrobial/source management is a primary concern.

Noninfectious immune-mediated vasculitis

Immune attack drives wall inflammation without direct microbial invasion.

Infections may trigger immune complexes or immune cross-reactivity.

Immunosuppression may be appropriate after an infectious cause is assessed.

Slide 7 · Therapeutic implications of the distinction

Is direct microbial invasion plausible?

YES

NO / ALTERNATE

Investigate infectious source

Avoid assuming primary autoimmunity

Correlate immune patterns

Consider immune-mediated differential

An immune trigger after infection is not identical to direct infectious invasion.

Slide 8 · Noninfectious vasculitis is not one disease

The textbook recognizes more than 25 primary forms, with overlapping clinical and pathologic features.

Vessel caliber is a useful starting point, not an absolute boundary.

Tissue predilection, immunity and demographics add discriminatory information.

Exceptions and mixed patterns occur across the nomenclature.

Slide 9 · Four complementary classification axes

Vessel size

Large, medium or small

Distribution

Aorta, viscera, capillaries or organ-limited

Immune pattern

Deposits, ANCA-associated or cellular

Context

Granulomas, autoantibodies and demographic clues

Slide 10 · Vessel caliber provides an anatomical map

Large

Aorta; Major branches

Medium

Muscular organ arteries

Small

Arterioles; Capillaries; Venules

Slide 11 · Large-vessel category: Aorta and major branches

The aorta, great arch vessels and large limb arteries are preferentially affected.

Chronic inflammation often produces mural thickening and stenosis.

Giant cell arteritis and Takayasu arteritis are the major textbook examples.

Smaller arteries can also be affected: “large vessel” denotes predominance.

Slide 12 · Medium-vessel category: Muscular arteries

Medium-sized visceral arteries and their branches are the usual targets.

Wall necrosis may cause microaneurysms, thrombosis and organ ischemia.

Polyarteritis nodosa, Kawasaki disease and thromboangiitis obliterans illustrate distinct phenotypes.

An entity may also affect some smaller or larger arteries.

Slide 13 · Small-vessel category: Microcirculation

Small intraparenchymal arteries, arterioles, capillaries and venules predominate.

Glomerular and pulmonary capillary involvement can be clinically critical.

The amount and pattern of immunoglobulin deposition distinguish major groups.

Skin and kidney can provide accessible tissue manifestations.

Slide 14 · Classification overview

Predominant caliber

Representative entities

Discriminating emphasis

Large

Giant cell arteritis; Takayasu arteritis

Aorta and major branches; granulomatous patterns

Medium

PAN; Kawasaki; Buerger disease

Muscular artery ischemia or aneurysm

Small, ANCA-associated

MPA; GPA; EGPA

Pauci-immune necrotizing vasculitis

Small, immune deposits

IgA; cryoglobulinemic; anti-GBM patterns

Immunoglobulin/complement in tissues

Slide 15 · Classification has overlapping boundaries

Caliber predominance

Site + morphology

Immune mechanism

A diagnosis comes from the intersection, not a single label.

Slide 16 · What constitutes noninfectious pathogenesis?

Immune complexes

Antibody–antigen deposits activate inflammation

ANCA

Neutrophil-directed antibodies provoke effector injury

Anti-endothelial antibodies

Antibodies react with endothelial targets

Autoreactive T cells

Cell-mediated vascular inflammation and granulomas

Slide 17 · Immune complexes initiate vascular injury

Antigen + antibody

Complex formation or in situ binding

Vascular deposition

Immunoglobulin in vessel walls

Complement/Fc receptors

Leukocyte recruitment and activation

Wall destruction

Leakage, necrosis and thrombosis

Slide 18 · Where can pathogenic immune complexes originate?

Circulating complexes

An antigen–antibody complex forms in blood.

Complexes may lodge in susceptible vascular beds.

The initiating antigen is often not identified.

Local formation

Antibody may encounter antigen at the vessel.

Inflammatory effector mechanisms follow local recognition.

The two possibilities are often difficult to distinguish.

Slide 19 · Complement links deposits to neutrophil injury

Immunoglobulin deposition

Vascular immune reaction

Complement activation

Inflammatory mediator generation

Fc-receptor engagement

Neutrophils/macrophages stimulated

Wall injury

Permeability, necrosis and luminal thrombosis

Slide 20 · Immune complex morphology: The diagnostic signature

Inflamed small vessels may show immunoglobulin and complement deposition.

Direct immunofluorescence helps demonstrate deposited reactants.

Necrotizing injury may coexist with neutrophilic fragmentation.

Distribution and deposit composition must be interpreted with clinical context.

Slide 21 · Kidney involvement reflects capillary injury

Glomerular capillary deposits

Immune complexes or direct antibodies

Capillary inflammation

Wall permeability and injury

Glomerular dysfunction

Hematuria, proteinuria

Severe injury

Necrosis with loss of filtration

Slide 22 · Drug-associated immune complex vasculitis

Some drugs act as haptens after binding serum proteins.

Antibody formation can generate circulating immune complexes.

Skin manifestations are common, but severity varies.

A careful drug-exposure history can identify a potentially reversible trigger.

Slide 23 · Infection may trigger a noninfectious mechanism

Microbial antigen

Antibody response to infection

Immune complex formation

Circulating antigen–antibody complexes

Vascular deposition

Inflammation without direct vessel invasion

Organ injury

Immune-mediated vasculitic syndrome

Slide 24 · Hepatitis B provides an immune-complex example

In a subset of polyarteritis nodosa, hepatitis B surface antigen–antibody complexes contribute to vascular disease.

The link is immune-complex-mediated, not simply direct invasion of arterial walls.

The association does not explain all PAN cases.

Mechanistic context helps avoid misclassifying every infection-associated vasculitis.

Slide 25 · Vasculitis associated with systemic autoimmunity

Systemic lupus erythematosus

DNA/anti-DNA immune complexes may contribute.

Vascular lesions can occur in small and medium vessels.

Other autoantibodies can participate in injury.

Rheumatoid arthritis

Vasculitis typically occurs with severe long-standing disease.

Small- or medium-vessel involvement may predominate.

Immune complexes and cellular mechanisms may both contribute.

Slide 26 · IgA and cryoglobulinemic processes

IgA vasculitis

Abnormally glycosylated IgA participates in immune complexes.

Small vessels and glomeruli are characteristic sites.

Deposits provide an immune-pathologic clue.

Cryoglobulinemic vasculitis

Cryoglobulin immunoglobulins precipitate below body temperature.

Immunoglobulin deposition damages small vessels.

Systemic and renal injury may accompany skin disease.

Slide 27 · Anti-GBM injury: Binding rather than complexes

Immune-complex pattern

Preformed or locally assembled antigen–antibody complexes.

Deposits trigger complement and leukocyte activation.

Patterns depend on antigen and lesion location.

Anti-GBM pattern

Autoantibodies directly bind basement-membrane components.

Glomerular and pulmonary capillaries are major targets.

Antibody deposition is a direct-binding mechanism.

Slide 28 · Why deposit mechanisms cannot be conflated

Immune complexes and direct basement-membrane autoantibodies both recruit inflammation, but antigen recognition differs.

Mechanism informs the expected tissue deposit pattern.

Similar clinical pulmonary–renal manifestations can arise by different routes.

Morphology, immunopathology and serology should be integrated.

Slide 29 · ANCA-associated vasculitis is usually pauci-immune

Autoantibodies recognize neutrophil antigens; Extensive antibody deposits in vascular lesions are usually absent.

Major specificities are proteinase 3 (PR3) and myeloperoxidase (MPO).

Neutrophil activation produces oxidants, enzymes and endothelial injury.

Small-vessel necrotizing lesions are typical.

Slide 30 · PR3-ANCA and MPO-ANCA

Antibody specificity

Target

Common textbook association

PR3-ANCA

Proteinase 3; neutrophil primary granules

Granulomatosis with polyangiitis

MPO-ANCA

Myeloperoxidase; leukocyte granules

Microscopic polyangiitis; eosinophilic GPA

Slide 31 · Antigen specificity supersedes staining shorthand

Historical terminology

C-ANCA: Cytoplasmic staining pattern.

P-ANCA: Perinuclear staining pattern.

Pattern names refer to assay appearance.

Preferred mechanistic terminology

PR3-ANCA identifies the antigenic target.

MPO-ANCA identifies the antigenic target.

Specificity gives a clearer disease association.

Slide 32 · How ANCAs activate neutrophils

Primed neutrophil

PR3/MPO accessible on surface

ANCA engagement

Autoantibody binds antigen

Effector activation

Oxidants and proteases released

Endothelial injury

Necrotizing microvascular inflammation

Slide 33 · Why ANCA lesions contain few immune deposits

Autoantibody targets a cell

PR3/MPO within or on leukocytes

Leukocytes attack endothelium

Reactive oxygen species + enzymes

Necrotizing vessel wall

Few retained immunoglobulin complexes

Pauci-immune pattern

Descriptive immunopathologic label

Slide 34 · ANCA is mechanistic and diagnostically useful

PR3-ANCA and MPO-ANCA support recognition of characteristic vasculitic syndromes.

A serologic result does not replace organ distribution or tissue morphology.

The source associates ANCA titer changes with activity and relapse.

Interpret the antigen specificity alongside the clinical phenotype.

Slide 35 · Microscopic polyangiitis: Small-vessel archetype

Necrotizing vasculitis affects capillaries, arterioles and venules.

Glomerulonephritis and pulmonary capillaritis are prominent potential manifestations.

MPO-ANCA is commonly associated.

Granulomatous inflammation is absent in the described pattern.

Slide 36 · Granulomatosis with polyangiitis

Necrotizing granulomatous inflammation affects the respiratory tract.

Necrotizing vasculitis involves small to medium vessels.

Focal necrotizing glomerulonephritis may occur.

PR3-ANCA is characteristic in the source description.

Slide 37 · Eosinophilic granulomatosis with polyangiitis

Asthma, allergic rhinitis and tissue eosinophilia define the broader phenotype.

Necrotizing vasculitis occurs with eosinophilic and granulomatous inflammation.

MPO-ANCA occurs in a subset, particularly with renal involvement.

Cardiac injury can arise from eosinophilic infiltration.

Slide 38 · Granulomas imply organized cellular immunity

T-cell–dominated response

Antigen-directed immune activation

Cytokines and macrophages

Sustained vessel-wall recruitment

Granulomatous inflammation

Epithelioid macrophages ± giant cells

Remodeling and injury

Media destruction and intimal expansion

Slide 39 · Anti-endothelial antibody mechanisms

Endothelial antigen

Antibody binds vessel lining

Immune activation

Inflammatory cells and mediators

Mural inflammation

Endothelial/smooth-muscle injury

Vascular complication

Luminal stenosis or aneurysm

Slide 40 · Kawasaki disease illustrates endothelial injury

A childhood febrile mucocutaneous syndrome can involve coronary arteries.

Immune activation with antibodies to endothelium and smooth muscle is implicated.

Arteritis can damage the coronary wall and allow aneurysm formation.

The cardiac consequence reflects location, not only the degree of inflammation.

Slide 41 · T-cell immunity contributes to large-vessel disease

Giant cell arteritis is associated with a T-cell–mediated wall response.

IFN-γ and IL-17 are noted among inflammatory mediators.

Macrophage-rich inflammation can disrupt the internal elastic membrane.

Healing may produce concentric intimal thickening and ischemia.

Slide 42 · No single pathway explains every vasculitis

Autoantibodies

Cellular immunity

Vessel-specific context

The same clinical syndrome may involve more than one effector mechanism.

Slide 43 · Wall inflammation produces four major lesions

Stenosis

Intimal thickening or luminal narrowing

Thrombosis

Luminal occlusion on an injured surface

Aneurysm

Loss of mural structural support

Hemorrhage

Rupture or small-vessel leakage

Slide 44 · Vascular cross-section: Normal versus stenotic

Reference architecture

Inflammatory narrowing

Inflammation + intimal proliferation → reduced luminal flow

Original native PowerPoint schematic — not a histologic specimen.

Slide 45 · Necrotizing arteritis compromises the media

Reference architecture

Destructive arteritis

Transmural injury disrupts normal layers of the wall

Original native PowerPoint schematic — not a histologic specimen.

Slide 46 · An inflamed wall can thrombose

Reference architecture

Superimposed thrombus

Endothelial injury promotes flow-limiting thrombus

Original native PowerPoint schematic — not a histologic specimen.

Slide 47 · Wall destruction may lead to aneurysm

Reference architecture

Aneurysmal dilation

Loss of wall integrity permits pathological dilation

Original native PowerPoint schematic — not a histologic specimen.

Slide 48 · Healing can cause persistent luminal loss

Active mural inflammation

Cells, injury and necrosis

Repair response

Fibrosis and intimal proliferation

Wall remodeling

Thickened intima and scarred media

Fixed flow limitation

Chronic ischemic symptoms

Slide 49 · Lesions are frequently segmental and patchy

Active and unaffected segments may alternate along an artery.

A biopsy can miss pathologic involvement in a clinically affected vessel.

Older scars and active inflammation can coexist across different arterial segments.

Sampling must be interpreted in light of the distribution and differential diagnosis.

Slide 50 · Fibrinoid necrosis indicates severe vascular injury

Necrotizing arteritis may show intensely eosinophilic wall material on H&E.

It accompanies destructive inflammation and loss of normal mural architecture.

Luminal thrombosis and downstream tissue ischemia may accompany the lesion.

This morphology is not specific to one named vasculitic syndrome.

Slide 51 · Leukocytoclasis is a morphologic pattern

Fragmentation of infiltrating neutrophils produces nuclear debris.

Postcapillary venules are a common site of leukocytoclastic injury.

The pattern may occur in both immune-complex and ANCA-associated disease.

It should not be used as a stand-alone etiologic diagnosis.

Slide 52 · Cutaneous purpura reflects microvascular damage

Inflamed dermal microvessels

Venular wall injury

Barrier dysfunction

Erythrocyte extravasation

Palpable purpura

Cutaneous inflammatory lesion

Diagnostic inference

Assess systemic context and tissue deposits

Slide 53 · A pulmonary–renal pattern has mechanistic breadth

Pulmonary capillary injury

Capillaritis may produce alveolar hemorrhage.

Airway symptoms can reflect inflammatory injury.

The lung pattern is not unique to ANCA disease.

Glomerular capillary injury

Necrotizing lesions may yield hematuria and impaired function.

Crescents can appear after severe capillary injury.

Deposits versus pauci-immune staining refine the mechanism.

Slide 54 · Distribution is a diagnostic clue, not proof

Finding

Plausible vessel context

Interpretive caution

Pulse asymmetry or limb ischemia

Major branch arteries

Consider other causes of arterial stenosis

Visceral ischemia or aneurysms

Muscular medium arteries

Several vasculitides may affect the same site

Purpura + glomerulonephritis

Dermal/renal small vessels

Deposit analysis distinguishes mechanisms

Pulmonary–renal injury

Capillary beds

ANCA and anti-GBM patterns differ

Slide 55 · Named syndromes: Large-vessel contrasts

Entity

Characteristic emphasis

Important caveat

Giant cell arteritis

Older patients; head arteries ± aorta

Granulomas may be patchy or absent

Takayasu arteritis

Aorta and arch branch stenosis

Histology can overlap giant cell arteritis

Slide 56 · Named syndromes: Medium-vessel contrasts

Entity

Characteristic emphasis

Vascular consequence

Polyarteritis nodosa

Muscular arterial necrosis; pulmonary arteries spared

Ischemia, infarction, microaneurysms

Kawasaki disease

Febrile childhood syndrome; coronary arteritis

Coronary aneurysm/thrombosis

Buerger disease

Distal thrombosing arteritis; tobacco association

Extremity ischemia and gangrene

Slide 57 · Named syndromes: Small-vessel contrasts

Entity

Defining context

Immune pattern

Microscopic polyangiitis

Necrotizing capillaritis; no granulomas

Usually MPO-ANCA; pauci-immune

Granulomatosis with polyangiitis

Respiratory granulomas + renal disease

Often PR3-ANCA; pauci-immune

Eosinophilic GPA

Asthma + eosinophils ± granulomas

MPO-ANCA in a subset

IgA/cryoglobulinemic vasculitis

Deposit-associated microvascular injury

Immunoglobulin/complement deposits

Slide 58 · Why organ involvement helps separate categories

Artery size

Pulse loss or visceral ischemia can localize injury to large/medium vessels.

Organ pattern

Skin, kidney and lung disease suggest small-vessel participation.

Immune deposits

Deposits versus pauci-immune lesions further narrows mechanisms.

Slide 59 · A mechanism-led diagnostic approach

Does evidence indicate vessel-wall inflammation?

YES

NO / ALTERNATE

Map vessel size + affected organs

Assess deposits, ANCA and granulomas

Evaluate nonvasculitic mimics

Reassess tissue and clinical evidence

Before immune suppression, consider direct infectious arteritis and infection-triggered immune disease.

Slide 60 · Tissue evaluation and immunopathology complement each other

Routine morphology

Locate the lesion within the vessel wall.

Assess fibrinoid necrosis, granulomas and leukocytoclasis.

Recognize thrombosis, aneurysm or healed scar.

Immune evaluation

Ask whether immunoglobulin/complement deposits are present.

Relate PR3/MPO specificity to the clinical phenotype.

Consider direct anti-GBM antibody binding.

Slide 61 · A negative sample is not always exclusionary

Skip lesions and variable vessel involvement impose an important limitation on biopsy interpretation.

An adequately sampled artery can still miss a focal lesion.

Destructive, healed and uninvolved regions may coexist.

Clinical and tissue findings should be reconciled rather than treated in isolation.

Slide 62 · Teaching case: Headache and visual symptoms

An older adult develops new temporal headache, scalp tenderness, constitutional symptoms and abrupt visual disturbance.

Which vessel category and mechanism are most relevant?

Head/ophthalmic arterial territory

High consequence of ischemia

Possible discontinuous wall inflammation

Illustrative teaching vignette — no patient data.

Slide 63 · Case analysis: Ischemia in large-vessel arteritis

Consider giant cell arteritis, with T-cell/macrophage-mediated arterial inflammation.

An inflamed arterial wall may thicken and narrow the lumen.

Ophthalmic arterial involvement can cause permanent visual loss.

A negative arterial biopsy does not absolutely exclude patchy disease.

Slide 64 · Teaching case: Purpura with hematuria

A patient has palpable purpura, microscopic hematuria and a history of a recent medication exposure.

Which vessel compartment and immune pathway merit evaluation?

Dermal postcapillary venules

Renal microvasculature

Possible medication-derived immune complexes

Illustrative teaching vignette — no patient data.

Slide 65 · Case analysis: Deposit-associated small-vessel injury

Assess small-vessel vasculitis and consider an immune-complex mechanism.

Neutrophilic wall injury can produce purpura.

Glomerular capillary injury explains hematuria.

Tissue immunoglobulin/complement deposits help distinguish this from pauci-immune patterns.

Slide 66 · Teaching case: Lung and kidney injury

Pulmonary hemorrhage accompanies new glomerular abnormalities and constitutional symptoms.

Which different immune mechanisms can converge on this phenotype?

Pulmonary capillary disruption

Glomerular inflammation

Potentially similar clinical manifestations

Illustrative teaching vignette — no patient data.

Slide 67 · Case analysis: The pulmonary–renal differential

Distinguish ANCA-associated pauci-immune disease from anti-GBM antibody injury and immune-complex disease.

PR3/MPO testing informs the ANCA-associated pathway.

Direct anti-GBM antibodies target basement membranes.

Immunopathology separates mechanisms that share target organs.

Slide 68 · Three questions that organize vasculitis

Where?

Which vessel sizes and vascular beds are involved?

How?

Do deposits, ANCAs, anti-endothelial antibodies or T cells predominate?

What happens?

Stenosis, thrombosis, aneurysm, hemorrhage or healed fibrosis?

Slide 69 · Core concepts to retain

Noninfectious vasculitides are classified by predominant caliber, anatomy and immune findings.

Immune complexes, ANCAs, anti-endothelial antibodies and T cells are major mechanisms.

Overlap and exceptions prevent diagnosis from caliber or one serologic marker alone.

The vascular lesion determines the resulting ischemic, hemorrhagic or systemic syndrome.

Slide 70 · Source and teaching boundaries

*Robbins, Cotran & Kumar: Pathologic Basis of Disease*, 11th edition (2026), Chapter 11, Blood Vessels.

Primary section: “Noninfectious Vasculitis,” printed p. 464; neighboring vasculitis sections, printed pp. 463–470.

Classification derived from the textbook table adapted from the 2012 Chapel Hill Consensus nomenclature.

All vascular and immune illustrations in this presentation are original native PowerPoint schematics; no histologic specimen images are reproduced.