1. Manar Hajeer, MD, FRCPath
Inflammation-5
Manar Hajeer, MD, FRCPath

2. Plasma derived mediators of acute inflammation
Complement system
Coagulation and Kinin systems

3. Complement system
Complement components are , C1 – C9, circulate in the blood in an inactive form
Cleaved enzymatically to active components
Each activated component cleaves another … enzymatic cascade

4. Chain of reactions

5. Stimulated by three ways:
1. Classical: antigen- antibody complexes fix C1.
2. Alternative: contact with bacterial polysaccharide or other cell wall component
3. Lectin- mannose pathway: plasma lectin binds mannose componenet in a microbe

6. All three pathways leads to formation C3 convertase that plays a central role in complement effects.
C3 convertase cleaves C3 to C3a and C3b.
C3b deposit on surface of microbe>>>binds C3 convertase and forms C5 convertase.
C5 convertase cleaves C5 to C5a and C5b.
Assembly of C6-C9>>>> membrane attack complex

7. Actions of complement
1. Vascular effects: vasodilatation and increase vascular permeability through anaphlatoxins: C3a and C5a.
2. Leukocyte activation, adhesion, and chemotaxis : C5a, and to lesser extent, C3a.
2. Phagocytosis by opsonization: C3b
3. MAC (membrane attack complex) C6-C9: create pores in wall of bacteria.

9. MAC

10. Coagulation and kinin systems
Some of the molecules activated during blood clotting are capable of triggering multiple aspects of the inflammatory response

13. Chronic inflammation
• Infiltration with mononuclear cells, including macrophages, lymphocytes, and plasma cells • Tissue destruction, largely induced by the products of the inflammatory cells • Repair, involving new vessel proliferation (angiogenesis) and fibrosis

14. Settings of chronic inflammation
Persistent infections by microbes that are difficult to eradicate (Mycobacterium tuberculosis, Treponema pallidum, viral, fungal).
Immune-mediated inflammatory diseases (autoimmune diseases and allergic reactions). rheumatoid arthritis, inflammatory bowel disease, and psoriasis, bronchial asthma
Prolonged exposure to potentially toxic agents (silica, cholesterol crystals)

15. Chronic Inflammatory Cells and Mediators
Macrophages.
Lymphocytes
Plasma cells
Eosinophils
Mast cells

16. Macrophages Dominant in chronic inflammation.
Migrate to site of acute inflammation after 24 to 48 hours.
Derived from blood monocytes.

17. Activation and functions of macrophages

18. Lymphocytes and Plasma Cells
The activation of T and B lymphocytes is part of the adaptive immune response.
In infections and immunologic diseases.
In tissues, B lymphocytes develop into plasma cells, which secrete antibodies.
CD4+ T lymphocytes are activated to secrete cytokines.

19. CD4 T helper cell types
TH1 cells produce the cytokine IFN-γ, which activates macrophages in the classical pathway.
TH2 cells secrete IL-4, IL-5, and IL-13, which recruit and activate eosinophils and are responsible for the alternative pathway of macrophage activation.

20. Macrophage–lymphocyte interactions in chronic inflammation

21. Eosinophils
Important in parasitic infections and IgE mediated allergies.
Eotaxin: special chemotactic factor.
Major basic protein toxic to parasites and causes epithelial cell necrosis.

23. Mast cells
Important in allergic reactions, including anaphylactic shock.
Release histamine and AA metabolites.

24. Granulomatous Inflammation
Distinctive pattern of chronic inflammation
Aggregates of activated macrophages with scattered lymphocytes
“Wall off”
Not always lead to eradication of the causal agent

25. Granulomatous Inflammation
Persistent T-cell responses to certain microbes (such as Mycobacteriu tuberculosis, T. pallidum, leprosy or fungi)
In some immune mediated inflammatory diseases, notably Crohn disease (inflammatory bowel disease)
Disease of unknown etiology called sarcoidosis.
In response to relatively inert foreign bodies

26. Granulomas Caseous necrosis:
Activated macrophages have pink cytoplasm (epitheliod cells).
Surrounded by a collar of lymphocytes.
Rim of fibroblasts in old ones.
Frequently, multinucleate giant cells
Caseous necrosis:
Central area of necrosis
Hypoxia and FR injury.
Granular, cheesy appearance grossly.
Eosinophilic , amorphous, structureless, granular debris, with complete loss of cellular details on H&E.

27. Caseating granuloma, TB.