STEPTRACKERGENERAL PRINCIPLES | PATHOLOGY + IMMUNOLOGY | HIGH-YIELD REVIEW

Chronic & Granulomatous Inflammation

Weeks to years of lymphocytes, plasma cells and macrophages — destroying and repairing tissue at the same time.

FOCUS ON
The granuloma pathway: macrophage → IL-12 → Th1 → IFN-γ → epithelioid histiocytes, held together by TNF. Caseating granulomas mean infection (TB, fungi) until proven otherwise. Noncaseating granulomas carry a separate list of causes. Anti-TNF drugs reactivate TB.
ELEMENT
WHAT IT IS
KEY SIGNALS
CLINICAL LINK
Chronic inflammation
definition
Lymphocytes, plasma cells and macrophages; ongoing injury plus repair (fibrosis, angiogenesis).
Causes: persistent microbes, autoimmunity, prolonged toxins (silica), unresolved acute inflammation
Hepatitis C, RA, silicosis, chronic osteomyelitis
Macrophages
two modes
M1 (classically activated): kill microbes with NO and ROS. M2 (alternatively activated): repair and fibrosis.
M1 ← IFN-γ · M2 ← IL-4, IL-13 → TGF-β
Long-standing M2 signaling → scarring
CD4⁺ T-cell subsets
direct the response
Th1 activates macrophages; Th2 drives IgE and eosinophils; Th17 recruits neutrophils; Treg suppresses.
Th1: IFN-γ · Th2: IL-4, IL-5, IL-13 · Th17: IL-17 · Treg: IL-10, TGF-β
IL-12/IFN-γ receptor defects → disseminated mycobacteria
Granuloma
structure
Nodule of epithelioid histiocytes (macrophages with abundant pink cytoplasm) ± multinucleated giant cells, rimmed by lymphocytes.
Langhans giant cells: nuclei in a horseshoe at the edge
Foreign-body giant cells: nuclei scattered
Granuloma formation
the Th1 loop
Macrophage presents antigen on MHC II and secretes IL-12 → CD4 cell becomes Th1 → IFN-γ transforms macrophages.
TNF keeps the granuloma intact
Infliximab, adalimumab → TB reactivation; screen first
Caseating granuloma
central necrosis
Cheesy amorphous center of dead tissue.
Mycobacteria and dimorphic fungi
TB, histoplasmosis, coccidioidomycosis, blastomycosis
Noncaseating granuloma
no central necrosis
Tight nodules of epithelioid cells and giant cells.
Immune or foreign-material driven
Sarcoidosis, Crohn, berylliosis, foreign body, PBC, hypersensitivity pneumonitis, tuberculoid leprosy
Necrotizing (non-caseous)
special patterns
Stellate microabscesses or vessel-centered necrosis.
Mixed neutrophils + histiocytes
Cat-scratch disease (Bartonella), GPA

Mechanism — building a granuloma

Persistent antigenHard-to-kill microbe or material
→
MacrophageMHC II + IL-12
→
Th1 cellIFN-γ
→
Epithelioid histiocytesGiant cells form
→
TNFHolds the wall

Activated macrophages in granulomas express 1α-hydroxylase → excess calcitriol → hypercalcemia (sarcoid, TB, fungi).

Acute vs chronic

FEATURE
ACUTE
CHRONIC
Main cells
Neutrophils
Lymphocytes, plasma cells, macrophages
Onset
Minutes to hours
Weeks to years
Vessels
Dilation, leak, edema
Angiogenesis
Tissue
Little damage if brief
Destruction + fibrosis
Outcome
Resolution, abscess, or chronic
Scar; loss of function

How it's tested

COMMON CONFUSIONLanghans giant cells (peripheral horseshoe nuclei) suggest an immune granuloma; foreign-body giant cells (scattered nuclei) surround material like suture or talc.
THE TRAPA patient with Crohn or RA starts a "biologic" and then gets fever and an upper-lobe cavity. The cause is TNF blockade reactivating latent TB.
YOUR APPROACHCaseation points to TB or fungus — culture and stain. No caseation: look for hilar nodes (sarcoid), bowel disease (Crohn), beryllium exposure, foreign material.

If you see… think…

Lymphocytes, plasma cells and fibrosis in a biopsy → chronic inflammation
Caseating granuloma in the lung apex → tuberculosis
Bilateral hilar nodes + noncaseating granulomas + ↑ ACE → sarcoidosis
Transmural bowel inflammation with granulomas → Crohn disease
Aerospace or electronics worker, noncaseating lung granulomas → berylliosis
New TB after starting infliximab → loss of TNF holding granulomas
Granulomatous disease + high calcium → macrophage 1α-hydroxylase
Disseminated mycobacteria in a child → IL-12 / IFN-γ receptor defect
Tender axillary node after a kitten scratch, stellate abscesses → Bartonella henselae
Giant cells with scattered nuclei around suture → foreign-body granuloma