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

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

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

Chain of reactions

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

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

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.

MAC

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

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

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)

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

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

Activation and functions of macrophages

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.

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.

Macrophage–lymphocyte interactions in chronic inflammation

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

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

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

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

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.

Caseating granuloma, TB.