Immunology L8: Vasculitis

Question 1

Mechanisms

Answer 1

Immune complex deposition – Endogenous Ags
– Drug hypersensitivity
– Viral infection (e.g. HBsAg+Ab)

Anti-neutrophil cytoplasmic Abs

– (Myeloperoxidase) MPO-ANCA (p-ANCA)

– (Proteinase-3) PR3-ANCA (c-ANCA)

Anti-endothelial cell Abs

Question 2

Types of vasculitis

Answer 2

• Large: Giant cell, Takayasu
• Medium: PAN, Kawasaki
• Small: Wegener granulomatosis (pulmonary granulomatous polyangitis, Churg-Strauss, Microscopic polyangitis

Question 3

Giant Cell Arteritis

Answer 3

• Affects elastic-rich major arteries
  
  • – Temporal artery
  • – Ophthalmic artery
  • – Aorta
  • – Branches of carotid
  • – Heart and lungs

Sx

• Constitutional symptoms – Fever, fatigue, weight loss
• Severe headache and facial pain: Often unilateral and most intense along, temporal artery
• Visual disturbances: Diplopia & Blindness
• Most common form of vasculitis in the elderly in US (≥50 yrs required for Dx)
• ~50% of cases are associated with polymyalgia rheumatica: Syndrome of pain and muscle stiffness associated with inflammation in selected muscle groups, predominately in neck, shoulders, upper arms and pelvic girdle

Etiopath

• Activated DCs in vessel wall recruit T cells and MF to form granulomatous infiltrates
  
  • – IL-12/Th1/IFN-γ and IL-6/Th17/IL-17 axis
  • – Familial & ethnic clustering suggests a genetic susceptibility
• Intimal proliferation obstructs lumen.
• Proteolytic and elastolytic enzymes promote remodeling of affected arteries.

Histo

• Granulomatous inflammation with multi-nucleated giant cells centered on the internal elastic lamina, which is often disrupted
• OR mononuclear infiltrate w/o giant cells; may have fibrinoid necrosis
• Obliteration or thrombosis of the vascular lumen

Question 4

Takayasu arteritis aka pulseless disease

Answer 4

Classically affects the aortic arch; Also affects major aortic branches (~34%); or pulmonary a. (50%)

Sx

• Fatigue, weight loss, fever
• Vascular insufficiency
  
  • – Of upper extremities: Coldness, numbness, weak pulse but lateral symmetry of BP
  • – Of carotid: Postural dizziness, vision changes
  • – Of lower extremities: Claudication
• Affects those under 50 yrs

Etiopath

• Unclear; may involve
• – T cell-mediated (type IV) hyper-sensitivity
• – Genetic component: Increased prevalence in Japan and in HLA- DR4-positive individuals

Histology

• Granulomatous arteritis, involving primarily media and adventitia
• – Healing lesions may contain mostly lymphocytes
• Transmural fibrous thickening, with severe luminal narrowing
• – Grossly, aortic intima may be wrinkled and orifices of major branches narrowed.

Question 5

PAN

Answer 5

Sx

• Typically young - middle aged adults – M:F 2-3:1
• Constitutional symptoms: – Malaise, fever, weakness, weight loss
• Vascular lesions (± hypertension)
• Exacerbations and remissions: – Abdominal pain, melena, infarcts, glomerulonephritis, renal failure, death

Etiopath

• Still uncertain
• – 30% have chronic hepatitis B, with HBsAg-HBsAb complexes (Type III HS)
• – Not associated with ANCA
• A familial form of PAN recently identified to be associated with recessive mutations in the CECR1 gene that encodes adenosine deaminase-2.
• – Compromised endothelial integrity, endothelial cell activation, inflammation, and defective differentiation of M2 macrophages

Histo

• Transmural inflammation of vessels – Neutrophils, eosinophils, mononuclear inflammatory cells
• May have fibrinoid necrosis
• Lesions may be segmental, non- circumferential, and of varying age
  
  • – Can vary from necrosis to fibrosis
  • – Segmental fibrotic lesions form “nodules”

Complications

Question 6

Kawasaki Disease aka mucocutaneous lymph node syndrome

Answer 6

• Affects small and medium-sized arteries of skin, ocular and oral mucosa, coronary arteries
• Occurs in infancy and early childhood (80% < 4 yrs)

Sx

• Fever
• Conjunctivitis
• Erythematous, desquamative rash – Involves palms and soles
• Lymphadenopathy, – Generally a single cervical LN
• Coronary artery involvement – Arrhythmias, aneurysms, MI, heart failure

Etiopath

• Unclear; one possible scheme:
• – DTH (type IV HS) T cell response and cytokine production; Ag unknown; ? infectious agent
• – Stimulation of endothelial cells, which express activation antigens
• – Production of anti-endothelial Abs, leading to damage (type II HS)

Histo

• Arteritis similar to PAN, but with more severe inflammation of the intima
• May progress from smaller to larger vessels
• May result in myocarditis, valvulitis, or pericarditis in later stages

Rx

• Disease is usually self-limited.
• 20% of patients develop cardio-vascular sequelae. – Coronary artery aneurysms, MI, sudden death
• This can be decreased to 4% by treatment with i.v. Ig and aspirin

Question 7

Wegener’s Granulomatosis aka Pulmonary Granulomatous Polyangitis

Answer 7

Sx

Upper respiratory inflammation

• – Severe sinusitis
• – Bloody nasal discharge

Pulmonary symptoms

• – Cough
• – Hemoptysis
• – Shortness of breath

Renal manifestations
– Hematuria
– Rapidly progressive renal failure

May also involve other organs

– Eyes

– Skin
– Heart (less common)

Etiopath

• ? T-cell mediated (type IV) hypersensitivity to inhaled environmental or infectious agent
• Formation and deposition of immune complexes (type III HS)
• 95% of cases have PR3-ANCA that may activate neutrophils and cause tissue damage

Histo

• Necrotizing granulomas of upper respiratory tract (ears, nose, sinuses, throat)
• Necrotizing granulomatous vasculitis, especially in lungs
• Necrotizing glomerulonephritis, often with crescents

Question 8

Churg-Strauss Syndrome (CSS) aka allergic granulomatous angiitis

Answer 8

CSS affects small to medium-sized arteries and veins

Sx

• Necrotizing vasculitis that can involve lungs, spleen, GI tract, heart, kidneys
• Classically associated with asthma and allergic rhinitis
• Marked eosinophilia – Cardiomyopathy in 60%

Etiopath

• Uncertain; may involved hypersensitivity reaction to an exogenous antigen
• ~50% of cases have MPO-ANCA

Histo

• Granulomatous and/or necrotizing vasculitis
• Extravascular granulomas
• Large numbers of eosinophils

Question 9

Buerger’s Disease aka thromboangiitis obliterans

Answer 9

Affects medium and small arteries and veins, especially tibial and radial arteries

Etiopath

• Unclear, but may involve immune reactivity to or direct toxicity of tobacco derivatives
• Associated with HLA-A9 and B5 – High incidence in Israel, Japan, India

Histo

• Segmental acute and chronic arteritis
• Vascular thrombosis – Thrombus may contain necrosis surrounded by granulomatous inflammation
• Inflammation often spreads to adjacent nerves and veins

Question 10

Microscopic Polyangiitis

a.k.a leukocytoclastic vasculitis or hypersensitivity vasculitis

Answer 10

Sx

• Skin lesions
  
  • – Palpable purpura
  • – Macules, vesicles
  • – Necrosis, ulceration
• Vascular lesions in other organs – Lungs, brain, kidneys, GI
• Glomerulonephritis in 90%, infarcts

Causes

• Henoch-Schonlein purpura: only IgA deposits
  
  • Pt produce a galactose-deficient IgA1; this exposes an N-acetyl-galactosamine neoepitope that binds to a (?anti-microbial or viral) anti-glycan IgA1.
• Serum sickness
• Connective tissue diseases (SLE)
• Mixed cryoglobulinemia
• Chronic hepatitis B
• Lymphoproliferative disorders
• Reactions to drugs or pathogens

Etiopath

• Antibody response to exogenous or autoantigen (MPO-ANCA impt)
• Formation of immune complexes
• Deposition of immune complexes in vessels, esp. small venules
• Complement fixation (C5a=chemotactic)
• Infiltration by inflammatory cells (esp. PMNs) and tissue destruction

Histo

• Lesions tend to be the same age
• Infiltration of vessel walls by neutrophils (leukocytoclasis)
• Vessel wall necrosis
• Immune complex deposition
  
  • – IgA (Henoch-Schonlein purpura)
  • – Mixed (SLE)