Pathology
Lecture 4 Granulomatous Inflammation
1) Define granuloma conceptually and histologically. A granuloma is a focus of chronic inflammation consisting of a microscopic aggregate of macrophages that are transformed into epithelium-like cells (epithelioid cells/histiocytes) surrounded by a collar of mononuclear leukocytes, principally lymphocytes and occasionally plasma cells. Note: epithelioid cells are essential to identification of a granuloma.
Monocytes from the blood form macrophages, epithelioid cells, and multinucleate giant cells that comprise the granulomas. Also found are lymphocytes (helper T, suppressor T and B), plasma cells, neutrophils, eosinophils and fibroblasts.
2) List the common causative agents of granuloma formation. Infectious agents including: mycobacteria (e.g. tuberculosis), bacteria (e.g. cat-scratch fever, syphilis, Chlamydia), fungi, and parasites. Foreign materials and soluble antigens can also cause granuloma formation.
3) Diagram the dynamic cellular events and mediators in granuloma formation.
1. The antigen is captured by a macrophage, processed, and prepared for presentation. The macrophage secretes IL-1.
2. A naïve CD4+ T cell recognizes the antigen.
3. CD4 + T cell differentiate into TH1 cells under the influence of IL-12 from macrophages. TH1 cells undergo blast formation and proliferation and secrete cytokines:
a. Interferon-gamma (IFN-γ) activates macrophages.
b. Interleukin-2 (IL-2) causes proliferation of T cells.
c. Tumor Necrosis Factor–α (TNF-α) increases blood flow to the area, promotes attachment of lymphocytes and monocytes, and secretes IL-8.
4) Discuss the possible sequelae of granulomas. Granulomas can undergo fibrosis, necrosis, or resolution. In Fibrosis, alveolar macrophages produce fibronectin to recruit fibroblasts and aid in their attachment and proliferation. Alveolar macrophage-derived growth factor (AMDGF) also aids in proliferation and collagen production. Platelet derived growth factor (PDGF), insulin-like growth factor (IGF) and IL-1 also participate in fibrosis. In Necrosis, tuberculous and fungal granulomas are caseous resulting from immune complexes while coagulative necrosis may be due to hypoxia. Resolution may leave no structural alteration although some fibrosis is usually seen.
5) Compare and contrast granulomatous with nongranulomatous inflammation.
Granulomatous / NongranulomatousNodular collections of epithelioid cells surrounded by lymphocytes. / Infiltration of mononuclear cells macrophages, lymphocytes, and plasma cells.
Formation of epithelioid and giant cells / Proliferation of fibroblasts and new vessels
Can form caseous necrosis or coagulative necrosis / Involves scarring and alteration of tissue architecture
Mediated by interaction of CD4+ lymphocytes and macrophages to release cytokines (interferon γ) / Mediated by monocyte-macrophages interaction with lymphocytes
6) Give a brief summary of sarcoidosis as a clinicopathologic disease. Sarcoidosis is primarily a pulmonary disease composed of epithelioid cells with some giant cells, surrounded by lymphocytes. These may remit spontaneously or become fibrotic due to chronic illness resulting in functional impairment or death.