1. Define inflammation. Describe endothelial and leucocyte derived adhesion molecules and their role in inflammation. 2. Describe differential diagnosis of granulomatous disease in detail. 3. Discuss complement system in health and disease. 4. Define and classify granuloma. Discuss wegener’s granulomatosis.

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leukocyte recruitment adhesion molecules rolling marginaton steps inflammation

This pathophysiology diagram illustrates the sequential stages of the leukocyte adhesion cascade within a blood vessel or high endothelial venule (HEV). The process is divided into four main phases: Tethering, Rolling, Arrest, and Extravasation. 1. Tethering: Mediated by L-selectin and P/E-selectins interacting with their respective ligands. Leukocyte integrins are in a closed conformation. 2. Rolling: Leukocyte shape elongates as it interacts with chemokines via GPCRs. This triggers 'inside-out signaling,' shifting integrins to an open conformation. 3. Arrest: Firm adhesion is achieved through high-affinity integrin binding (VLA-4, LFA-1, Mac-1) to endothelial ligands (MAdCAM-1, ICAM-1, VCAM-1). 4. Extravasation: The leukocyte exits into the tissue/lymph node via two pathways: Paracellular migration (between endothelial cells, involving CD31, JAM, and VE-Cadherin) or Transcellular migration (through the endothelial cell, involving F-actin). The diagram concludes with the leukocyte passing the basement membrane and pericytes, directed by chemotaxis. This visual is designed for advanced immunology and medical students to understand cellular recruitment during inflammation or immune surveillance.

A two-part medical pathophysiology diagram illustrating the link between metabolic dysfunction and systemic inflammation. Part A depicts the cascade where hyperglycemia and hyperlipidemia generate Damage-Associated Molecular Patterns (DAMPs). These molecules bind to Toll-like receptors (TLRs) on macrophages and dendritic cells, triggering the release of pro-inflammatory cytokines (TNFͱ, IL-1̢, IL-6). This lead to leukocyte migration into insulin-dependent tissues and systemic low-grade chronic inflammation. An inset showing the vascular compartment details the neutrophil recruitment process, highlighting decreased rolling (mediated by selectin) and increased adhesion (mediated by integrins and ICAMs). Part B focuses on the cellular impact of hyperglycemia, showing attenuated ICAM expression, decreased neutrophil degranulation, impaired Neutrophil Extracellular Trap (NET) formation, and decreased phagocytosis by neutrophils and macrophages. It also notes the transition of macrophages to the M2 phenotype at sites of infection. This diagram is designed for advanced medical education regarding the immunology of metabolic diseases like diabetes and obesity.

Educational panel illustrating in vivo leukocyte dynamics within human oral mucosa microvasculature under healthy and inflamed conditions, captured using oblique back-illumination microscopy (mOBM). Panels (a) and (c) depict healthy tissue with uniform mucosal appearance and leukocytes exhibiting normal circulation and rolling behavior (blue arrowheads). Panels (b) and (d) show inflamed tissue featuring a canker sore, characterized macroscopically by focal erythema and microscopically by slow-rolling (red arrowheads) and stationary, adherent leukocytes (black arrowheads) forming clusters along the endothelium. Quantitative analysis is provided in graphs (e-g): Panel (e) shows a significant reduction in mean leukocyte velocity in inflamed tissue (p < 0.0001); panel (f) distinguishes two subpopulations in inflammation—slow-rolling (Inflamed_Rs) and adherent (Inflamed_A); panel (g) tracks displacement over time, contrasting the continuous movement in healthy vessels against the 'stop-and-go' or near-zero displacement patterns in inflamed vessels. This content demonstrates the pathophysiological recruitment of leukocytes (tethering, rolling, and adhesion) during a localized inflammatory response.

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granuloma epithelioid cells Langhans giant cells tuberculosis histology

Histology of granulomatous mastitis on bright-field light microscopy. A dense inflammatory infiltrate forms granulomas centered on Langhans-type giant cells surrounded by epithelioid histiocytes, scattered lymphocytes, and occasional eosinophils. The image depicts a high-power view of the center of a granuloma within breast tissue biopsy; multinucleated giant cells with horseshoe-shaped nuclei are evident. The granulomatous architecture includes a peripheral rim of lymphocytes and histiocytes with minimal necrosis described. Staining by Hematoxylin and Eosin highlights basophilic nuclei and eosinophilic cytoplasm; pink collagenous stroma and adipose breast tissue may be visible in the background. Clinically, granulomatous mastitis can mimic infectious etiologies or neoplasia; the presence of Langhans giant cells strongly suggests a granulomatous process and warrants infectious workup for tuberculosis and fungal pathogens, as well as consideration of sarcoidosis or granulomatous reaction to foreign material. This image is diagnostic for granulomatous inflammation in breast tissue when correlated with clinical data and microbiologic studies; useful for education, differential diagnosis, and research on breast granulomatous disease. Additional educational value lies in distinguishing nonnecrotizing granulomas from caseating TB patterns, correlating histology with mammography and ultrasound, and guiding microbiologic testing and patient management in suspected granulomatous breast disease. The image supports teaching of granuloma biology and pathology.

Histology image obtained with brightfield light microscopy on a hematoxylin and eosin stained tissue section. The specimen shows granulomatous inflammation characterized by aggregates of epithelioid macrophages (histiocytes) with elongated, pale to eosinophilic cytoplasm. Multinucleated giant cells, occasionally Langhans-type with peripheral, radiating nuclei, are interspersed among the epithelioid cells. Surrounding lymphocytes and a sparse fibrous stroma delineate nodular granulomas. In some fields there are crystalline or granular pink to eosinophilic deposits within the cytoplasm of histiocytes, and there may be mild necrosis at the center of larger granulomas, though necrosis is not uniformly present across the slide. The pattern is compatible with a granulomatous infectious or inflammatory process, requiring clinical correlation and microbiologic assessment. Differential diagnoses include mycobacterial infection (tuberculosis), fungal granulomas (histoplasmosis, blastomycosis), sarcoidosis, and foreign-body granulomatous reactions. The image emphasizes a macrophage-dominant infiltrate with discrete nodular architecture, preserving basic tissue planes while revealing cellular detail such as nuclear atypia is not prominent. This histologic phenotype is critical for guiding targeted tests (AFB stain, fungal stains, PCR) and therapeutic decisions, and it serves as an educational reference for recognizing granuloma formation in biopsy specimens. Correlation with clinical history and imaging is essential for diagnosis.

Histopathology image showing a granulomatous lesion composed of epithelioid histiocytes with a surrounding rim of lymphocytes and occasional Langhans-type multinucleated giant cells. Within a giant cell, lamellar inclusions known as Schaumann bodies are evident as concentric rings of protein and mineral material; calcium oxalate crystals may also be present. Asteroid bodies may be seen as stellate inclusions, though they are not required for diagnosis. The granuloma is noncaseating, lacking central necrosis, which favors sarcoidosis over infectious granulomatous processes such as tuberculosis. The tissue architecture shows well-formed granulomas with distinct borders, often adjacent to blood vessels in this section. The image is stained with Hematoxylin and Eosin (H&E), highlighting eosinophilic granulomatous material and basophilic nuclei within giant cells. Clinically, the presence of Schaumann bodies and Langhans giant cells supports a granulomatous inflammatory syndrome but is not pathognomonic for sarcoidosis. Differential considerations include berylliosis, hypersensitivity pneumonitis, fungal or mycobacterial infections, and foreign body reactions. Correlation with chest imaging, serum ACE levels, and clinical features is essential for diagnosis. This slide serves an educational role in recognizing granulomatous histology, giant cell inclusions, and lamellar calcific bodies, informing diagnostic workflows and teaching pathology trainees about sarcoidosis-related granulomatous disease.

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Question 1: Inflammation - Definition & Adhesion Molecules

Definition of Inflammation

Inflammation is a response of vascularized living tissues to cell injury - a protective host response designed to eliminate the initial cause of cell injury, remove necrotic cells and damaged tissues, and initiate tissue repair. The response has both beneficial (clearing of pathogens) and harmful (tissue damage) consequences.

The main components are a vascular reaction and a cellular response, both activated by mediators derived from plasma proteins and various cells. The steps can be remembered as the Five R's:

Recognition of the injurious agent
Recruitment of leukocytes
Removal of the agent
Regulation (control) of the response
Repair (resolution)

Inflammation is classified as acute (rapid onset, neutrophil-dominant, short-lived) or chronic (prolonged, macrophage/lymphocyte-dominant, associated with tissue injury and repair).

Causes

Infections (bacterial, viral, fungal, parasitic), tissue necrosis, foreign bodies, trauma, and immune reactions (hypersensitivity).

Cardinal Signs (Celsus + Virchow)

Rubor (redness) - due to vasodilation
Calor (heat) - increased blood flow
Tumor (swelling) - edema from vascular leakage
Dolor (pain) - bradykinin, prostaglandins
Functio laesa (loss of function)

Leukocyte Recruitment: The Adhesion Cascade

Leukocyte recruitment from blood to tissue is a multistep process. As stasis develops, blood leukocytes accumulate along the endothelium of postcapillary venules - a process called margination, followed by pavementing. The sequence involves four stages: Rolling → Activation → Firm Adhesion → Transmigration (Diapedesis).

Leukocyte adhesion cascade - tethering, rolling, arrest and extravasation

A. Endothelial-Derived Adhesion Molecules

1. Selectins (Endothelial)

P-selectin (CD62P)

Stored in cytoplasmic Weibel-Palade bodies of endothelial cells (and platelets)
Rapidly redistributed to the luminal surface within minutes in response to histamine (from mast cells) and thrombin (during coagulation)
Mediates initial low-affinity "tethering" and rolling of leukocytes

E-selectin (CD62E)

Synthesized de novo and expressed on the endothelial surface within 1-2 hours in response to IL-1 and TNF (produced by tissue macrophages and DCs)
Also induced by microbial products such as LPS
Mediates rolling of granulocytes, monocytes, and some T cells

Both P- and E-selectin bind to sialyl Lewis X (a tetrasaccharide) displayed on leukocyte surface glycoproteins, particularly PSGL-1 (P-selectin glycoprotein ligand-1).

2. Ig Superfamily Molecules (Endothelial Ligands for Integrins)

ICAM-1 (CD54 - Intercellular Adhesion Molecule 1)

Expressed on cytokine-activated endothelial cells, lymphocytes, macrophages, fibroblasts, and epithelial cells
Ligand for leukocyte integrins LFA-1 (CD11a/CD18) and MAC-1 (CD11b/CD18)
Contains extracellular Ig domains - member of the Ig superfamily

ICAM-2

Expressed constitutively on endothelial cells
Also binds LFA-1

VCAM-1 (CD106 - Vascular Cell Adhesion Molecule 1)

Expressed on cytokine-activated endothelial cells in some tissues
Ligand for VLA-4 (α4β1, CD49d/CD29) on eosinophils, lymphocytes, and monocytes
Important in eosinophil recruitment in allergic inflammation

MAdCAM-1 (Mucosal Addressin Cell Adhesion Molecule 1)

Expressed on endothelial cells in intestinal mucosa
Ligand for integrin α4β7 on gut-homing lymphocytes

B. Leukocyte-Derived Adhesion Molecules

1. Selectin (Leukocyte)

L-selectin (CD62L)

Expressed constitutively on leukocytes (not on endothelial cells)
Binds to sialomucins on activated endothelial cells (e.g., GlyCAM-1, CD34, MAdCAM-1)
Recognizes sialyl 6-sulfo Lewis X on endothelial ligands
Expression is upregulated by IL-1, TNF, and other inflammatory cytokines

2. Integrins (Leukocyte)

Integrins are heterodimers (α and β chains) that integrate extracellular ligand binding with cytoskeletal signals for motility and phagocytosis.

Integrin	Also Known As	Chains	Endothelial Ligand	Function
LFA-1	CD11a/CD18, αLβ2	α and β2	ICAM-1, ICAM-2, ICAM-3	Firm adhesion; T cell-APC interaction
MAC-1	CD11b/CD18, αMβ2, CR3	α and β2	ICAM-1, iC3b	Firm adhesion; complement receptor; phagocytosis
VLA-4	CD49d/CD29, α4β1	α4 and β1	VCAM-1	Adhesion of lymphocytes, monocytes, eosinophils
α4β7	LPAM-1	α4 and β7	MAdCAM-1	Gut-homing lymphocytes
αEβ7	CD103	αE and β7	E-cadherin on epithelium	Mucosal T cells and DCs
CR4	CD11c/CD18, αXβ2	α and β2	iC3b, ICAM-1	Phagocytosis; mainly DCs

In resting leukocytes, integrins are in a low-affinity (closed) conformation. Chemokines and PAF (platelet-activating factor) trigger "inside-out signaling" via G protein-coupled receptors, shifting integrins to a high-affinity (open) conformation - this is the key activation step for firm adhesion.

3. Leukocyte Selectin Ligands

The principal selectin ligand on leukocytes is PSGL-1 (P-selectin glycoprotein ligand 1), post-translationally modified to display sialyl Lewis X, the carbohydrate moiety that binds P-selectin and E-selectin on the endothelium.

Steps of Leukocyte Recruitment (Summary)

Step	Molecules Involved
1. Margination & Rolling	E-selectin/P-selectin (endothelium) + PSGL-1/sialyl LewisX (leukocyte); L-selectin (leukocyte) + GlyCAM/CD34
2. Chemokine activation	Chemokines (IL-8/CXCL8, MCP-1, MIP-1) bind GPCR on leukocyte → inside-out signaling → integrin activation
3. Firm adhesion (Arrest)	LFA-1/MAC-1 (leukocyte) + ICAM-1/ICAM-2 (endothelium); VLA-4 + VCAM-1
4. Transmigration (Diapedesis)	CD31 (PECAM-1), JAM-A/B/C, CD99 (at endothelial junctions); F-actin for transcellular migration
5. Migration in tissue	Chemotaxis via C5a, LTB4, IL-8, bacterial products

Question 2: Differential Diagnosis of Granulomatous Disease

Granulomatous inflammation is characterized by collections of activated macrophages (epithelioid cells), often with lymphocytes and sometimes with necrosis. The key clinical challenge is identifying the cause, since granulomas arise from a limited but important set of conditions.

Categories of Granulomatous Disease

I. Infectious Causes

1. Tuberculosis (Mycobacterium tuberculosis)

Prototype of granulomatous disease - must always be excluded first
Caseating (necrotic) granulomas = "tubercles"
Foci of epithelioid macrophages rimmed by fibroblasts, lymphocytes, histiocytes, and occasional Langhans giant cells (nuclei arranged peripherally in horseshoe pattern)
Central amorphous, granular, eosinophilic debris (caseous necrosis)
Diagnosis: Acid-fast stain (Ziehl-Neelsen), culture (gold standard), PCR, tuberculin skin test, IGRA
Key feature: AFB visible in 60-70% of cases

2. Leprosy (Mycobacterium leprae)

Tuberculoid leprosy: Compact, well-formed noncaseating granulomas with few bacilli; nerve involvement
Lepromatous leprosy: Poorly formed granulomas, abundant AFB in macrophages ("foam cells" or Virchow cells), no central necrosis
Diagnosis: Slit-skin smear, biopsy, Fite-Faraco stain

3. Syphilis (Treponema pallidum)

Gumma: microscopic to grossly visible lesion; wall of histiocytes and plasma cells; central coagulative necrosis (cellular outlines preserved - unlike TB)
Tertiary stage manifestation; can affect liver, bone, CNS, cardiovascular system
Diagnosis: Serology (RPR, VDRL, FTA-ABS), darkfield microscopy, biopsy with silver stain

4. Fungal Infections

Histoplasmosis (Histoplasma capsulatum): Endemic (Ohio/Mississippi River valleys); intracellular yeast in macrophages; can cavitate; Gomori methenamine silver (GMS) stain
Coccidioidomycosis (Coccidioides immitis): Southwestern US; large spherules with endospores; can be caseating
Blastomycosis (Blastomyces dermatitidis): Broad-based budding yeast; mixed granulomatous + suppurative pattern
Cryptococcosis (Cryptococcus neoformans): Immunocompromised hosts; "soap bubble" lesions in brain; India ink stain, mucicarmine for capsule
Aspergillosis: Septate hyphae with acute-angle branching; granulomatous in immunocompetent, invasive in immunocompromised

5. Cat-Scratch Disease (Bartonella henselae)

Gram-negative bacillus
Rounded or stellate granuloma with central granular debris and recognizable neutrophils ("suppurative granuloma" or "stellate necrosis")
Giant cells uncommon
Diagnosis: Warthin-Starry silver stain, serology, PCR

6. Schistosomiasis (Parasitic)

Granulomas form around Schistosoma egg antigens
Associated with Th2 response and eosinophils (unlike typical Th1-mediated granulomas)
Can lead to portal hypertension (hepatic), bladder cancer risk

7. Leishmaniasis, Toxoplasmosis, Brucellaosis

All can cause granulomatous reactions
Brucellosis: small, poorly formed granulomas

II. Non-Infectious Inflammatory/Immune-Mediated

1. Sarcoidosis

Unknown etiology - possible abnormal immune response to an unidentified antigen
Noncaseating granulomas (no central necrosis) - this is pathognomonic when combined with clinical picture
Characteristic inclusions: Schaumann bodies (concentric calcific lamellated structures), asteroid bodies (stellate inclusions in giant cells)
Multisystem: Lungs (bilateral hilar lymphadenopathy + pulmonary infiltrates), skin, eyes, heart, nervous system
Diagnosis: Elevated serum ACE, hypercalcemia (macrophages produce 1-hydroxylase), Kveim test, biopsy
Key histology: Well-formed epithelioid granulomas, no organisms on special stains

2. Crohn's Disease

Immune reaction against intestinal bacteria/self-antigens
Occasional noncaseating granulomas in the bowel wall (only 30-40% of biopsies show granulomas)
Dense chronic inflammatory infiltrate; transmural inflammation; skip lesions
Distinguishes from ulcerative colitis (which has no granulomas)

3. Granulomatosis with Polyangiitis (Wegener's Granulomatosis) - see Question 4

4. Primary Biliary Cholangitis (PBC)

Florid duct lesion with granulomatous bile duct destruction
Anti-mitochondrial antibody (AMA) positive

5. Hypersensitivity Pneumonitis (Extrinsic Allergic Alveolitis)

Inhalation of organic antigens (bird proteins, fungal spores)
Poorly formed noncaseating granulomas in interstitium
Eosinophilia may be present; precipitating antibodies (IgG)

III. Foreign Body Reactions

Reaction to inert, non-immunogenic foreign materials
No T cell involvement; no specific immune response
Materials: talc (IV drug users), silica, suture material, prosthetic implant debris, beryllium (berylliosis), silicone
Epithelioid macrophages and giant cells apposed to foreign material
Foreign material often identifiable in giant cells, especially with polarized light (birefringent/refractile material)
Berylliosis: Indistinguishable from sarcoidosis histologically; occupational history is key

IV. Summary Comparison Table

Disease	Necrosis	Giant Cells	Special Features	Key Test
Tuberculosis	Caseous (central)	Langhans (present)	AFB, caseation	AFB stain, culture, PCR, IGRA
Sarcoidosis	None	Langhans/foreign body	Asteroid/Schaumann bodies	ACE, biopsy, CXR
Crohn's disease	None	May be present	Skip lesions, transmural	Colonoscopy + biopsy
Syphilis (gumma)	Coagulative	Absent	Plasma cells, treponemes	Serology
Cat-scratch disease	Stellate/suppurative	Uncommon	Neutrophils in center	Warthin-Starry stain, PCR
Foreign body	None	Foreign body type	Birefringent material	Polarized light microscopy
Histoplasmosis	± Caseous	Present	Intracellular yeast	GMS stain, culture, urine antigen
Wegener's (GPA)	Necrotizing	Present	Vasculitis, c-ANCA	ANCA (anti-PR3), biopsy
Hypersensitivity pneumonitis	None	Poorly formed	Eosinophils, IgG precipitins	Precipitating antibodies, BAL
Leprosy	None	Poorly defined	Foam cells	AFB stain (Fite), skin smear

Granuloma histology - Langhans giant cells and epithelioid histiocytes

Noncaseating granuloma with Schaumann bodies (sarcoidosis pattern)

Question 3: Complement System in Health and Disease

Overview

The complement system is a collection of more than 20 plasma proteins and membrane receptors that function in host defense against microbes and in pathologic inflammatory reactions. The proteins are present in inactive proforms and are activated in a sequential enzymatic cascade with tremendous amplification capacity. - Robbins, Cotran & Kumar Pathologic Basis of Disease

Activation Pathways

The critical step in all pathways is proteolytic cleavage of C3, the most abundant complement component.

1. Classical Pathway

Triggered by C1 binding to antibody (IgM or IgG) complexed with antigen
Requires antigen-antibody complexes - bridges adaptive and innate immunity
Sequence: C1 → C4 → C2 → C3 convertase (C4b2a) → C5 convertase (C4b2a3b)

2. Alternative Pathway

Triggered by microbial surface molecules (LPS/endotoxin, complex polysaccharides, cobra venom factor) in the absence of antibody - innate immunity
Spontaneous hydrolysis of C3 is amplified and stabilized on microbial surfaces
Sequence: C3 spontaneous hydrolysis → Factor B + Factor D + Properdin → C3 convertase (C3bBb)

3. Lectin Pathway

Plasma mannose-binding lectin (MBL) binds carbohydrates on microbial surfaces
Activates MASP-1 and MASP-2 (serine proteases homologous to C1r and C1s)
Subsequent steps mirror the classical pathway - no antibody required

Common Terminal Pathway

All three pathways converge to form C3 convertase → C5 convertase:

C3 convertase cleaves C3 → C3a (released) + C3b (deposited on cell surface)
C5 convertase cleaves C5 → C5a (released) + C5b (attached)
C5b + C6 + C7 + C8 + poly-C9 → Membrane Attack Complex (MAC)

Functions (Health)

1. Inflammation (Anaphylatoxins)

C5a, C3a, C4a stimulate histamine release from mast cells → vasodilation and increased vascular permeability
C5a is the most potent: strong chemotactic agent for neutrophils, monocytes, eosinophils, basophils
C5a also activates the lipoxygenase pathway in neutrophils/monocytes → further inflammatory mediators

2. Opsonization and Phagocytosis

C3b and iC3b (inactivated C3b) coat microbial surfaces (opsonization)
Recognized by CR1 (C3b receptor, CD35) and CR3/MAC-1 (iC3b receptor, CD11b/CD18) on neutrophils and macrophages
Dramatically enhances phagocytosis

3. Cell Lysis (MAC)

Deposition of MAC on thin-walled microbes (especially Neisseria species) creates membrane pores → osmotic lysis
Particularly important against gram-negative bacteria

4. Clearance of Immune Complexes

C3b facilitates solubilization of immune complexes and transport by erythrocytes (via CR1) to the liver and spleen for clearance
This prevents tissue deposition of immune complexes

Regulation of Complement

Tight control prevents excessive activation and damage to host tissues. Regulatory proteins are expressed on normal host cells to protect them.

Regulator	Mechanism	Disease if Deficient
C1 inhibitor (C1-INH)	Blocks C1 activation; also inhibits kallikrein and Factor XII	Hereditary Angioedema (HAE) - recurrent episodes of angioedema
DAF (CD55)	GPI-anchored; prevents C3 convertase formation	PNH (acquired loss of GPI anchor)
CD59 (Protectin)	GPI-anchored; inhibits MAC formation	PNH - lysis of RBCs and platelets
Factor H	Promotes cleavage of C3b; accelerates alternative pathway C3 convertase decay	Atypical HUS, age-related macular degeneration (Factor H polymorphisms)
Factor I	Cleaves C3b to iC3b (with Factor H as cofactor)	Recurrent infections
C4BP (C4b-binding protein)	Inhibits classical pathway C3 convertase	-

Complement in Disease

A. Deficiencies - Susceptibility to Infections

Component Deficient	Consequence
C3	Most severe - susceptibility to all encapsulated bacteria (pneumococcus, Haemophilus, meningococcus)
C5-C9 (terminal complement)	Susceptibility to Neisseria infections (meningococcemia, disseminated gonococcemia)
C1q, C2, C4 (classical pathway)	Susceptibility to infections PLUS lupus-like autoimmune disease (impaired immune complex clearance)
MBL	Mild immunodeficiency; recurrent upper respiratory infections in children
Properdin	X-linked; susceptibility to Neisseria meningitidis

B. Complement-Mediated Tissue Injury

The complement system is activated by antibodies or immune complexes deposited on host cells, causing major tissue injury in:

Systemic Lupus Erythematosus (SLE): Classical pathway activation by DNA-anti-DNA immune complexes → nephritis, vasculitis, serositis; C3, C4 levels are LOW (consumed)
Membranoproliferative Glomerulonephritis (MPGN): Low C3 due to alternative pathway activation
Rheumatoid Arthritis: Complement activation by IgG immune complexes in joints
Myasthenia Gravis and other antibody-mediated autoimmune diseases

C. Regulatory Protein Deficiencies - Excessive Activation

Paroxysmal Nocturnal Hemoglobinuria (PNH): Acquired somatic mutation in PIG-A gene → loss of GPI anchor → deficiency of both CD55 and CD59 → uncontrolled complement activation → intravascular hemolysis, thrombosis, cytopenias. Treatment: eculizumab (anti-C5 monoclonal antibody)
Hereditary Angioedema (HAE): Autosomal dominant deficiency of C1-INH → unopposed activation of contact system and complement → bradykinin overproduction → episodic non-pitting angioedema of skin, GI tract, airway (life-threatening laryngeal edema). C4 levels chronically low. Treatment: C1-INH concentrate, icatibant (bradykinin B2 receptor antagonist), lanadelumab
Atypical HUS (aHUS): Loss-of-function mutations in Factor H, Factor I, MCP (CD46) OR gain-of-function in C3 or Factor B → uncontrolled alternative pathway activation → endothelial damage in glomeruli → thrombotic microangiopathy. Treatment: eculizumab
Age-Related Macular Degeneration (AMD): Polymorphisms in Factor H (particularly Y402H variant) are the strongest genetic risk factor identified → complement deposition in Bruch's membrane → choroidal neovascularization

D. Complement Inhibitor Therapies

Drug	Target	Indication
Eculizumab	Anti-C5 (blocks C5 cleavage)	PNH, aHUS, NMOSD
Ravulizumab	Anti-C5 (long-acting)	PNH, aHUS
Avacopan	C5a receptor antagonist	ANCA vasculitis (GPA, MPA)
C1-INH concentrate	C1 INH replacement	HAE

Question 4: Granuloma - Definition, Classification & Wegener's Granulomatosis

Definition of Granuloma

A granuloma is a focal area of chronic granulomatous inflammation characterized by collections of activated macrophages (epithelioid cells), often with T lymphocytes, and sometimes associated with central necrosis. The name derives from the granular macroscopic appearance of these foci.

Granuloma formation is a cellular attempt to contain an offending agent that is difficult to eradicate
Involves strong activation of macrophages and T lymphocytes, which can also cause injury to normal tissue
Activated macrophages develop abundant cytoplasm resembling epithelial cells → called epithelioid cells
Some activated macrophages fuse → multinucleate giant cells
- Robbins, Cotran & Kumar Pathologic Basis of Disease

Classification of Granuloma

Type 1: Foreign Body Granuloma

Pathogenesis: Reaction to inert foreign bodies that are non-immunogenic - no T cell-mediated immune response
Forms around materials large enough to preclude phagocytosis (talc, suture material, silicone, mineral oil, keratin, calcium deposits)
Epithelioid cells and giant cells apposed to the surface of the foreign body
Foreign material often identified within the giant cells, especially visible with polarized light (refractile/birefringent)
No necrosis; giant cells are "foreign body type" with randomly scattered nuclei throughout cytoplasm

Type 2: Immune (T cell-mediated) Granuloma

Pathogenesis: Caused by agents that induce persistent T cell-mediated immune responses - the inciting agent cannot be eliminated
Th1 cells produce IFN-γ → activates macrophages
In some parasitic infections (schistosomiasis), Th2 response with eosinophils predominates
Includes: tuberculosis, fungal infections, sarcoidosis, Crohn's disease, berylliosis, hypersensitivity reactions

Histological Subtypes by Necrosis

Subtype	Feature	Diseases
Caseating	Central caseous (cheese-like) necrosis; amorphous, structureless, eosinophilic debris; complete loss of cell outlines	Tuberculosis, histoplasmosis, coccidioidomycosis
Non-caseating	No necrosis; well-formed epithelioid granulomas	Sarcoidosis, Crohn's, foreign body, berylliosis
Suppurative (stellate)	Central microabscess with neutrophils within the granuloma	Cat-scratch disease, LGV, Yersinia
Necrotizing vasculitic	Granulomatous inflammation with vasculitis and tissue necrosis	Wegener's (GPA), Churg-Strauss

Morphological Features of Granuloma on H&E

Epithelioid cells: Large macrophages with pink granular cytoplasm, indistinct cell borders, oval/elongated vesicular nuclei; resemble epithelium
Langhans Giant Cell: Multinucleated (40-50 µm); nuclei arranged in horseshoe or peripheral ring pattern; characteristic of TB but not specific
Foreign Body Giant Cell: Nuclei randomly scattered throughout cytoplasm; forms around foreign material
Touton Giant Cell: Wreath-like arrangement of nuclei around lipid; seen in xanthogranulomatous conditions
Collar of lymphocytes surrounds the epithelioid aggregate
Older granulomas have a rim of fibroblasts and connective tissue
Healing is accompanied by fibrosis (may be extensive)

Wegener's Granulomatosis (Granulomatosis with Polyangiitis - GPA)

Definition

Granulomatosis with polyangiitis (GPA), formerly called Wegener's granulomatosis, is a systemic necrotizing granulomatous vasculitis of small- and medium-sized vessels that classically involves a triad of:

Necrotizing granulomas of the upper respiratory tract (sinuses, nose, trachea)
Necrotizing granulomas of the lower respiratory tract (lungs)
Focal necrotizing glomerulonephritis

GPA is classified as an ANCA-associated vasculitis (AAV).

Epidemiology

Rare disease: incidence ~11.8 per million person-years (UK data)
Peak incidence: ages 55-69 years
Slight male predominance (M:F = 1.3:1)
Genetic risk factors: CTLA4, PTPN22, COL11A2, SERPINA1

Pathogenesis

~90% of patients have ANCA (Anti-Neutrophil Cytoplasmic Antibodies)
Predominantly c-ANCA (cytoplasmic pattern by immunofluorescence), directed against PR3 (proteinase 3) in ~90% of GPA cases
p-ANCA (perinuclear, anti-MPO) in the remaining ~10%
Mechanism: ANCA-primed neutrophils are activated → release of PR3, ROS, and NETs (Neutrophil Extracellular Traps) → endothelial injury → necrotizing vasculitis
NETosis is increasingly recognized as a key mediator
An unidentified precipitating factor leads to initial ANCA production (possibly Staphylococcus aureus nasal carriage as a trigger)

Clinical Features

Upper Respiratory Tract (90% at presentation)

Severe sinusitis and rhinorrhea
Nasal mucosal ulcerations and epistaxis
Nodules in nose, larynx, trachea, bronchi
Saddle-nose deformity (destruction of nasal cartilage/bone from necrotizing granulomas)
Subglottic stenosis (hoarseness, stridor)
Oral involvement: necrotizing alveolar ridge, tongue ulcers, palatal perforation
"Strawberry gums" (hypertrophic gingivitis) - biopsy of this lesion may be diagnostic

Lower Respiratory Tract (71% have radiographic infiltrates)

Cough, dyspnea, chest pain
Pulmonary nodules that may cavitate
Pulmonary infiltrates, hemoptysis
Diffuse alveolar hemorrhage (life-threatening)

Renal Involvement (85% of patients)

Focal crescentic necrotizing glomerulonephritis
Hematuria, proteinuria, progressive AKI
Can be rapidly progressive (RPGN) → renal failure
Before cyclophosphamide therapy, renal failure was the most common cause of death

Cutaneous Findings (45%)

Palpable purpura (leukocytoclastic vasculitis)
Nodules along extensor surfaces of extremities (may ulcerate, can mimic rheumatoid nodules)
Petechiae, hemorrhagic pustules
Pyoderma gangrenosum-like ulcerations
Livedo reticularis (rare)

Other Systems

Eyes (58%): conjunctivitis, episcleritis, proptosis (orbital granuloma)
Joints (two thirds): arthralgia, arthritis
CNS (22%): cranial nerve palsies, peripheral neuropathy
Heart (12%): pericarditis, coronary vasculitis

Histopathology

Necrotizing granulomatous vasculitis - the hallmark
Palisaded granulomas with multinucleated giant cells and a central core of neutrophils and debris
Leukocytoclastic vasculitis (LCV) in skin biopsies
Renal biopsy: pauci-immune crescentic GN (little/no immune complex deposition on immunofluorescence - unlike lupus nephritis); crescents in ~90% of children with GPA

Diagnosis

Test	Finding
c-ANCA (anti-PR3)	Positive in ~90% of active generalized GPA (almost 100% in active disease)
p-ANCA (anti-MPO)	Positive in ~10% - associated with MPA
Chest X-ray/CT	Pulmonary nodules, cavities, infiltrates
Urinalysis	Hematuria, red cell casts (glomerulonephritis)
Biopsy (lung, URT, kidney, skin)	Necrotizing granulomatous vasculitis; pauci-immune crescentic GN
Nasal biopsy	Granulomatous inflammation (most accessible)

ELK Criteria (for diagnosis in children): 3 of 6 features - (1) renal involvement, (2) upper airway, (3) pulmonary involvement, (4) laryngo-tracheobronchial stenosis, (5) granulomatous inflammation on biopsy, (6) ANCA positive.

Limited vs. Generalized GPA

Limited GPA: Upper respiratory tract only, no renal involvement; better prognosis; may respond to methotrexate + prednisone alone; TMP-SMX may be used for maintenance
Generalized GPA: Multi-organ involvement including kidneys; requires aggressive immunosuppression

Treatment

Induction Phase

Cyclophosphamide (2 mg/kg/day oral or 500-750 mg/m² IV every 2-4 weeks) + Prednisone (1 mg/kg/day) - traditional standard
Rituximab (anti-CD20 monoclonal antibody) + high-dose glucocorticoids - FDA approved 2011; equivalent to cyclophosphamide for new patients; superior to cyclophosphamide for relapsing patients; preferred in PR3-ANCA positive disease
Avacopan (C5a receptor blocker) - emerging steroid-sparing agent added to either cyclophosphamide or rituximab
IV methylprednisolone boluses (3 days) before oral prednisone for severe disease
Plasma exchange (PLEX): For diffuse pulmonary hemorrhage and RPGN approaching dialysis

Maintenance Phase (after remission)

Methotrexate, azathioprine, leflunomide, MMF, or rituximab (instead of cyclophosphamide)
Treatment for at least 1 year
TMP-SMX long-term: reduces nasal S. aureus carriage → decreases relapse rate; useful for limited URT disease in remission

Refractory Disease

Plasma exchange, IVIG, anti-TNF therapy (infliximab), tacrolimus

Prognosis

Untreated GPA: Mean survival ~5 months; 90% mortality at 2 years
With cyclophosphamide + prednisone: Complete remission in up to 93% of patients, lasting average of 4 years
Major modern concern: treatment-related adverse effects (infection, hemorrhagic cystitis, malignancy from cyclophosphamide) now account for more deaths in year 1 than the vasculitis itself

Sources: Robbins, Cotran & Kumar Pathologic Basis of Disease (9780443264528); Robbins & Kumar Basic Pathology (9780323790185); Andrews' Diseases of the Skin (9780323547536); Cellular and Molecular Immunology (9780323757485); Brenner and Rector's The Kidney (9780323532655)

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