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Inflammation

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					                                   Inflammation
General Features
   a. Can be either local or systemic
   b. Local reaction 
          - heat, redness (increased blood flow due to vasodilation)
          - edema (leakage of fluid from the circulation into the tissues (increased
              vascular permeability)
          - pain (stimulation of the nerve endings by dradykinin)
          - pus (accumulation of dead phagocytes and bacteria)
   c. Effectors in Inflammation
          - complement
          - mast cell degranulation
          - coagulation
          - macrophages
   d. Net effect: diapedesis of leukocytes
   e. Changes
          - secretion of chemokines and cytokines
          - generation of inflammatory mediators
          - altered expression and/or enhanced affinity of adhesion molecules
          - increased vascular permeability
          - degradation of the basement membrane
          - extravasation of neutrophils, monocytes and lymphocytes
   f. innate and adaptive immunity involved

Vasodilation, Increased Vascular Permeability and Edema
   a. mast cell released histamine and bradykinin produce vasodilation

Mast cells
  a. mast cell activation or degranulation  histamine  vasodilation  increased
       blood flow
  b. histamines induces contraction of the endothelial cells  increased vascular
       permeability  edema
  c. binding of anaphylotoxins to mast cell receptors (CR-5a, CR-3a/4a) leads to mast
       cell degranulation
  d. kallikrein splits C5 into C5a and C5b
  e. mast cell can also be activated by binding of IgE to its FcR

Contact system: Source of bradykinin
   a. tissue damage activates coagulation pathway contact system
   b. factor XIIa: prekallikrein  kallikrein
   c. kallikrein: kininogen  bradykinin (vasodilator, increases vascular permeability)
   d. kallikrein: C5  C5a + C5b
Recruitment of Neutrophils and Monocytes to the Site of Inflammation

General Features
   a. neutrophils are the first leukocyte actively recruited to an inflammatory site
   b. Diapedesis of neutrophils and monocytes
          - leukocyte rolling on activated endothelium
          - expression of cytokine induced counter-molecules on the endothelium
          - enhancement of the adhesiveness of integrins present on leukocytes
          - firm adherence of leukocytes to vascular endothelium
          - squeezing in-between endothelial cells
          - degradation of basement membrane
          - migration of leukocytes into inflamed tissue
   c. Leukocyte rolling  selectins
   d. Leukcoyte firm adhesion  integrins

Leukocyte rolling: Selectins
   a. L-selectin, E-selectin, P-selectin
   b. L-selectin
          - naïve lymphocytes, monocytes, neutrophils
          - noninflammatory states
   c. E-selectin and P-selectin
          - postcapillary venules
          - inflammation
   d. mast cell derived histamine causes P selectin to appear on the surface
   e. E selectin expression is induced by cytokines derived from activated macs (TNF,
      IL-1)
   f. Leukocyte rolling prolongs the duration of time to which leukocytes are exposed
      to chemoattractancts and activators

Firm adhesion and stable conjugates: Integrins on leukocytes
   a. classified into families based on beta chain: 2 integrin family, 1 integrin family,
      7 integrin family

Role of cytokines and chemokines
   a. activated macs secrete:
           - cytokines: TNF, IL-1
           - chemokines: IL-8, MCP-1, MIP-1)
   b. TNF and IL-1 stimulate endothelial cells to express the adhesive molecules E-
       selectin and VCAM-1 and also secretion of IL-8 and MCP-1
   c. IL-8  increased adhesiveness of b2 integrins LFA-1 and Mac-1 and shedding of
       L-selectin, chemoattractant for neutrophils
   d. MCP-1 and RANTES  chemotactic for monocytes and lymphocytes
   e. In early phase of the inflammatory response C5a and PAF (produced by mast
       cells and activated endothelial cells) act as chemoattractants and activators of
       neutrophils
   f. TNF and IL-1 act systemically  vasodilation  low blood pressure  shock
         - also produce fever
   g. IL-6 releases CRP from hepatocytes

Basement membrane transmigration
   a. degradation of the basement membrane by metalloproteinases allows leukocytes
      to enter

Adaptive Immune Responses in Inflammation

General features
   a. T cells and B cells as effectors
   b. Memory cells activated at the site of infection (secondary immune response)

Recruitment of Th cells to the site of inflammation
   a. activated and memory lymphocytes express high concentrations of the integrins,
       LPAM and VLA-4

Transmigration of lymphocytes
   a. T cells secrete MMP-2 and MMP-9

Role of Type 1 cytokines at inflammatory sites
   a. Type 1 cytokines (IL-2, IFN, TNF) enhance inflammation
   b. IFN activates macs  increased phagocytosis
   c. CD40/CD40L interaction may be required for mac activation

Role of Type 2 cytokines at inflammatory sites
   a. Type 2 cytokines (IL-4, IL-10, TGF) decrease Th1 response
   b. Serve to control inflammation

Role of Innate and Adaptive Immunity in Inflammation
   a. innate immunity begins inflammation
           - complement activation
           - mast cell degranulation
           - macrophage activation
   b. tissue damage recruits nonimmune systems such as coagulation pathway
       producing bradykinin
   c. memory cells secrete cytokines (IFN) 
           - macs  monocytes
           - activate macs
   d. activated macrophages, mast cells and neutrophils secrete cytokines and
       inflammatory mediators
Clinical Relevance

Leukocyte adhesion deficiency, Type 1
          - deficiency in CD18 (2 integrin chain of LFA-1 and Mac-1)
          - no migration of lymphocytes, monocytes, and neutrophils to sites of
             inflammation
          - recurrent localized pustular infections
          - normal numbers of leukocytes and lymphocytes
          - treat with antibiotics or BMT in severe cases

Systemic inflammatory response syndrome (SIRS)
          - no apoptotic death of neutrophils thought to be mediated by IL-1

				
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posted:11/14/2011
language:English
pages:4