Granulomatous inflammation

Background

Granulomatous Inflammation is a form of chronic inflammation that arises when a stimulus cannot be eradicated by the acute inflammatory response.

It is characterised histologically by a collection of epithelioid macrophages (≥5), often with surrounding lymphocytes and sometimes fibroblasts. Epithelioid macrophages are activated/altered macrophages specialised for killing and phagocytosis; they may fuse to form multinucleated giant cells.

Pathogenesis

Initial trigger:

• Stimuli resistant to digestion/clearance (e.g. organisms with digestion-resistant capsules like Mycobacterium tuberculosis, or inert materials such as sutures, silica, glass).

Early response:

• A transient acute inflammatory response occurs.

Failure of clearance:

• If clearance ineffective, a chronic granulomatous response develops.

Mediators:

• IFN-γ: key initiator that activates macrophages, their transformation into epithelioid cells and ultimately granuloma formation. IFN-γ is absolutely essential for granuloma formation.
• IL-1: contributes to the inflammatory milieu, recruits immune cells, assisting in the initial formation of granulomas.
• IL-2: enlarges granulomas.
• TNF-α: maintains granulomas.
• Overall mechanism: Type IV hypersensitivity reaction, mediated by Th1 CD4+ T cells.

Causes
All share the feature of being resistant to resolution by acute inflammation.


Types:

• Caseating granulomas: central necrosis and 'cheese-like' e.g. TB, fungal infection.
• Non-caseating granulomas: no necrosis e.g. sarcoidosis, Crohn’s, foreign body.

Clinical relevance
Granulomas contain difficult-to-eradicate stimuli but may impair tissue/organ function (e.g. pulmonary fibrosis in TB or sarcoidosis). The Histological type (caseating vs non-caseating) provides diagnostic clues.