1. Definition, Mechanism and Causes of Granulomas
Dr. Mamlook Elmagraby

2. Objectives of the lecture:
Upon completion of this lecture, students should be able to:
Appreciate the high prevalence of granulomatous diseases in the Kingdom of Saudi Arabia with special emphasis on tuberculosis
Understands the mechanisms and causes of granuloma formation with special emphasis on interaction between T lymphocytes, macrophages and epithelioid histiocytes

3. Annual TB patient numbers and incidence rate/100,000 in Saudi Arabia (1991-2010)

4. Overview
Granulomatous inflammation is a specific pattern of chronic inflammation characterized by aggregates of activated macrophages that have an epithelioid appearance The lesion of granulomatous chronic inflammation is the “granuloma” The formation of a granuloma partition the offending agent and is therefore a useful defense mechanism Granuloma formation does NOT always lead to eradication of the causal agent (frequently resistant to killing or degradation) Granulomatous inflammation with subsequent fibrosis may be the major cause of organ dysfunction

5. The sequence in evolution of granuloma
Macrophages and monocytes engulf the antigen and try to destroy it But since the antigen is poorly degradable, these cells fail to digest and degrade the antigen Poorly digestible antigen is presented by macrophages to CD4+ lymphocytes CD4+ lymphocytes get activated and elaborate cytokines (interferon-γ)

6. The sequence in evolution of granuloma
Interferon-γ mediate the transformation of monocytes and macrophages to epithelioid cells and giant cells
Caseous necrosis is characteristic (Tuberculosis), resulting from the killing of mycobacteria-laden macrophages by:
T lymphocytes
possibly by cytokines or sensitized macrophages   
The presence of multinucleated giant cells derived from macrophages is also characteristic

7. Morphology
Epithelioid cells in granulomas have pink, granular cytoplasm with vague cell boundaries The aggregates of epithelioid macrophages are surrounded by a lymphocytes (mainly T cells) Older granulomas may have a border of fibroblasts and connective tissue Frequently, multinucleated giant cells are found in granulomas Giant cells consist of a large mass of cytoplasm and many nuclei

8. Granulomatous inflammation.
Note the absence of caseation in this granuloma taken from a lymph node from a patient with sarcoidosis.
The lesion consists of focal accumulations of altered macrophages referred to as epithelioid cells.

9. Giant cell in granulomatous inflammation.
Giant cells, derived from macrophages, are a frequent component of granulomatous inflammation.
This typical example with the nuclei arranged in the periphery in a horseshoe pattern is referred to as a Langhans giant cell.

10. Morphology
In granulomas associated with certain infectious organisms, a central zone of necrosis can be seen Microscopically, this necrotic material appears as amorphous, structureless, granular debris Healing of granulomas is accompanied by fibrosis

11. Causes Infectious agents Foreign bodies Unknown etiology (sarcoidosis)
Granulomatous inflammation is associated with a number of etiologic agents, including:
Infectious agents
Mycobacterium tuberculosis
Histoplasma capsulatum (many other fungi)
Treponema pallidum
Foreign bodies
Unknown etiology (sarcoidosis)