Granulomatous Diseases:

1. GranulomatousDiseases:

2. Granulomatous diseases • OBJECTIVES • DEFINITION • CAUSES • TYPES • PATHOGENESIS • GRANULOMATOUS DISEASES:TB,LEPROSY,LEISHMANIA,SCHISTOSOMIASIS,SARCOIDOSIS,ACTINOMYCOSIS.

3. Definition: • Granulomatous inflammation is a distinctive pattern of chronic inflammatory reaction. • It is a protective response to chronic infection or foreign material, preventing dissemination and restricting inflammation. • Some autoimmune diseases such as rheumatoid arthritis and Crohns disease are also associated with granulomas.

4. Cellular constituents of Granulomas

5. the predominant cell type is an activated macrophage with a modified epithelial-like (epithelioid) appearance Lymphocytes. Occasional plasma cells.

6. What Is A Granuloma?

7. Granulomatousinflammation • A granuloma is a microscopic aggregation of macrophages that are transformed into epithelium-like cells surrounded by a collar of mononuclear leukocytes, principally lymphocytes and occasionally plasma cells.

8. Granulomatousinflammation • Epithelioid cells fuse to form giant cells containing 20 or more nuclei. • The nuclei arranged either peripherally (Langhans-type giant cell) or • haphazardly (foreign body-type giant cell). • These giant cells can be found either at the periphery or the center of the granuloma.

9. Slide 3.41

11. Fibrous connective tissue often surrounds granulomas (remodeling of tissue) • Areas within the granuloma canundergo necrosis (prototype: caseous necrosis in tuberculosis). Necrosis can lead to calcification or liquefaction and formation ofa cavern if drained.

12. CAUSES OF GRANULOMATOUS DISEASES

13. Granulomatousinflammation Infectious causes: • Bacteria • Tuberculosis • Leprosy • Parasites • Schistosomiasis

14. Granulomatousinflammation • Fungi • Histoplasmosis • Blastomycosis • Metal/Dust • Berylliosis • Silicosis

15. Granulomatousinflammation • Foreign body Granulomas: • endogenous ( keratin, necrotic bone or adipose tissue uric acid crystals) • Exogenous (wood, silica, asbestos, silicone,suture…) • Specific chemicals: • Beryllium • Sarcoidosis (unknown cause)

16. Type of granulomas: • Foreign body granulomas – form when material such as talc, sutures, or other fibers are large enough to preclude phagocytosis by a single macrophage.

17. Immune granulomas - caused by insoluble particles that are capable of inducing a cell-mediated response. This type of immune response produces granulomas when the inciting agent is poorly soluble or particulate. Macrophages engulf the foreign material and process and present some of it to appropriate T lymphocytes, causing them to become activated, responding T cells produce cytokines, such as IL-2 which activates other T cells and IFN- which is important in transforming macrophages into epithelioid cells and multinucleate giant cells.

20. Foreign body aspiration Berrylliosis caseation

21. Mechanism Of granulomaformation

22. The classic example for the immune granuloma is that caused by the bacillus of tuberculosis. In this disease, the granuloma is referred to as a tubercle and is classically characterized by the presence of central caseous necrosis. Caseating necrosis is rare in other granulomatous diseases. • There are many atypical presentations that it is always necessary to identify the specific etiologic agent by: special stains for organisms (acid-fast stains for tubercle bacilli), culture methods (tuberculosis, fungal disease), and serologic studies (syphilis). In sarcoidosis, the etiologic agent is unknown.

23. Granuloma: bacilli are inhaled by droplets • Bacteria are phagocytosed by alveolar macrophages • After amassing substances that they cannot digest, macrophages lose their motility, accumulate at the site of injury and transform themselves into nodular collections; the Granuloma • A localized inflammatory response recruits more mononuclear cells • The granuloma consists of a kernel of infected macrophages surrounded by foamy macrophages and a ring of lymphocytes and a fibrous cuff (containment phase) • Containment usually fails when the immune status of the patient changes; the granuloma caseates, ruptures and spills into the airway

24. Caseous Necrosis Epithelioid Macrophage Langhans Giant Cell Lymphocytic Rim

26. GranulomatousInflammation • Pathology of Tuberculosis

27. Etiology and incidence

28. Characteristics Of MYCOBACTERIA • 2-10micrometer in length. • Struntrually gram positive but also containslarge amount of lipids in the cell wall:making them acid fast. • No toxins • No spores • Obligate Aerobic • Elicit granulomatous inflammation.

29. M. tuberculosis hominis & M. bovis • M. avium, M.intracellulare in AIDS - Atypical TB

30. Pathology of • Infects one third of world population..! • 3 million deaths due to TB every year • Under privileged population - • Crowding, Poverty, malnutrition, economic burden. • Since 1985 incidence is increasing in west • AIDS, Diabetes, Immunosuppressed patients, Diabetes, Drug resistance.

31. Tuberculosis • Tuberculosis is a chronic communicable disease in which the lungs are the prime target,although any organ may be infected.

32. TUBERCULOSIS • Primary TB • SecondaryTB • Progressive pulmonary TB • Miliary TB

33. Tuberculosis • PATHOGENESIS • The course of tuberculosis depends on age and immune competence AND total burden of the organisms • Tuberculous Infection: refers to growth of the organism in a person,whether there is symptomatic disease or not. • Active Tuberculosis; refers to infection manifested by tissue destruction-----symptomatic disease.

34. PRIMARY TUBERCULOSIS • Primary tuberculosis is the form of disease that develops in a previously unexposed and unsensitized person. • Tuberculosis is a type of delayed tissue hypersensitivity to the tuberculous bacillus which elicit a cell-mediated immune response which will resists the growth and spread of the mycobacterium. • This hypersensitivity reaction produces the pathologic feature of tuberculosis in immunocompetent individuals, i.e. granulomas, caseation, cavity formation.

35. PRIMARY TUBERCULOSIS The sequence of events which occur after inhalation of infectious agent in a previously unexposed immunocompetent individual are: The mycobacterium will gain access to the alveolar macrophage through receptors. * Once the organisms are inside the cytoplasm of the macrophage it will inhibit the microbicidal response of the macrophage (ineffective phagolysosome).

36. PRIMARY TUBERCULOSIS Multiplication of the organism inside the alveolar macrophage processing& presentation of the antigen on the surface A clone of sensitized T-cells proliferate, produce gamma INT. Activation of the macrophages(augmenting their capacity to kill mycobacteria)

37. PRIMARY TUBERCULOSIS • The lytic enzymes of the activated macrophages if released, also damaged host tissues. • This activation of macrophages and destruction of mycobacteria comprises the cell mediated immunity.

38. M. tuberculosis enters macrophages • Once inside the macrophage, M. tuberculosis replicates within the phagosome by blocking fusion of the phagosome and lysosome. • Thus the earliest stage of primary tuberculosis (<3 weeks) in the nonsensitized individual is characterized by proliferation of bacteria in the pulmonary alveolar macrophages and airspaces, with resulting bacteremia and seeding of multiple sites.

39. About 3 weeks after infection, a TH1 response against M. tuberculosis is mounted that activates macrophages to become bactericidal. • TH1 cells are stimulated by mycobacterial antigens drained to the lymph node.

40. About 3 weeks after infection, a TH1 response against M. tuberculosis is mounted that activates macrophages to become bactericidal. • TH1 cells are stimulated by mycobacterial antigens drained to the lymph node.

41. Mature TH1 cells, both in lymph nodes and in the lung, produce IFN-γ. • IFN-γ is the critical mediator which drives macrophages to become competent to contain the M. tuberculosis infection. • IFN-γ stimulates formation of the phagolysosome in infected macrophages, exposing the bacteria to an inhospitable acidic environment.

42. IFN-γ also stimulates expression of inducible nitric oxide synthase (iNOS), which produces nitric oxide (NO). NO helps in the destruction of several mycobacterial constituents, from cell wall to DNA.

43. In addition to stimulating macrophages to kill mycobacteria, the TH1 response orchestrates the formation of granulomas and caseous necrosis. • Activated macrophages, stimulated by IFN-γ, produce TNF, which recruits monocytes. • These monocytes differentiate into the "epithelioid histiocytes" that characterize the granulomatous response

46. PRIMARY TUBERCULOSIS • In immunocompromised persons granulomas are poorly formed or not formed at all and the infection progress at the primary site in the lung ,lymph nodes or in multiple sites---------progressive primary tuberculosis.

47. PRIMARY TUBERCULOSIS • Is characterized by: • Ghon Focus ----- lung lesion of primary TB,involves upper segments of the lower lobes or lower seg.of the upper lobe. • Ghon complex----- combination of a peripheral ghon focus and involved mediastinal or hilar lymphnode. • Microscopically the classic lesion of TB is a caseous granuloma

49. Caseating granulomas

50. Clinical and pathologic implications of primary tuberculosis 1] Development of resistance to the infection. 2] The foci of scarring may harbor viable bacilli for life and act as a nidus for reactivation. 3] The disease may develop into progressive primary tuberculosis in immunocompro- mised patients such as AIDS patients, elderly, and malnourished children.