Learning Objective
Explain the definition, histologic features, immunologic mechanisms, and clinical associations of granulomatous inflammation.
Granulomatous inflammation is a distinct pattern of chronic inflammation triggered by a persistent T-cell–mediated immune response to poorly degradable stimuli, including certain infections, immune-mediated diseases, and foreign materials.
Granulomas function to “wall off” resistant antigens that cannot be eliminated, leading to persistent inflammation, which may progress to fibrosis and organ damage.
Histologic Features
A granuloma consists of:
- A central collection of epithelioid cells (activated macrophages with abundant eosinophilic cytoplasm)
- Surrounding lymphocytes
- Multinucleated giant cells, formed by the fusion of activated macrophages
Types of Granulomas
Caseating granulomas
- Central necrosis present
- Typically associated with infectious etiologies
- Examples: Tuberculosis, fungal infections
Noncaseating granulomas
- No central necrosis
- Typically related to noninfectious etiologies
- Examples: Sarcoidosis, Crohn’s disease
Immunologic Mechanism
- Antigen-presenting cells (APCs) present antigen via MHC II to CD4⁺ T cells and secrete IL-12
- CD4⁺ T cells differentiate into Th1 cells
- Th1 cells secrete IFN-γ → macrophage activation
- Activated macrophages secrete cytokines (eg, TNF-α), promoting:
- Transformation into epithelioid cells
- Formation of multinucleated giant cells
- Maintenance of granuloma structure
Clinical Correlations
- TNF-α is essential for maintaining granuloma integrity
- Anti-TNF therapy can cause granuloma breakdown → disseminated infection
- Always screen for latent TB before initiating anti-TNF therapy
- Hypercalcemia
- Due to increased 1α-hydroxylase activity in activated macrophages
- Leads to increased active vitamin D
Etiologies of Granulomatous Inflammation
Infectious
Bacterial
- Mycobacterium tuberculosis (TB)
- Mycobacterium leprae (leprosy)
- Bartonella henselae (cat scratch disease; stellate necrotizing granulomas)
- Listeria monocytogenes (granulomatosis infantiseptica)
- Treponema pallidum (tertiary syphilis)
Fungal
- Endemic mycoses (eg, histoplasmosis)
Parasitic
- Schistosomiasis
Immunodeficiency
- Chronic granulomatous disease (catalase-positive organisms)
Noninfectious
Immune-mediated
-
- Sarcoidosis
- Crohn disease
- Primary biliary cholangitis
- Subacute (de Quervain) granulomatous thyroiditis
Vasculitis
-
- Granulomatosis with polyangiitis
- Eosinophilic granulomatosis with polyangiitis
- Giant cell (temporal) arteritis
- Takayasu arteritis
Foreign bodies / Environmental
-
- Berylliosis
- Talcosis
- Hypersensitivity pneumonitis
