Bio 328 Immunology Leukocyte migration and inflammation

Innate or natural immunity.  Innate vs adaptive response  Passive Defenses  Mechanical properties boundaries  Chemical properties boundaries  Inflammatory response  Mobilization of active defenses  Initiation of innate responses  Effectors of the active, innate response  Soluble mediators  Cellular mediators

Acute Inflammatory Response 1.Mobilization of active defenses  Vasodilation  Vascular permeability  Recruitment of neutrophils 2.Localized vs systemic.

INVASION Tissue damage Pathogens Clotting System (Factor VII) Kinin/ Bradykinin (Hageman factor) Complement cascade Vasodilation Permeability Neutrophils Macrophages Dendritic cells PPRRs Basophils/ Mast cells Lipid mediators Cytokines Chemokines

Tissue damage exposes the blood protein Factor VII to Tissue Factor expressed on the basolateral surface of endothelial cells.

Kinin system

C3bB C3bBb

Bradykinin C3 and C5 C3a and C3b C5a and C5b Prekallikrein Kallikrein Kininogen Kallidin C3bB C3bBb Complement activation Active Hageman factor (XII) Plasmin

Plasminogen Activator inactive Plasminogen Activator active Kallikrein Thrombin Elastase Cathepsin Plasmin PlasminogenPlasmin C3 and C5 C3a and C3b C5a and C5b

C3 activation MBL (mannose, fucose) Ficolins (N-aceylglucosamine) C1q (LPS) CRP-phosphocholine) kallikrein Plasmin

Vasodilation and increased vascular permeability lead to fluid leakage (edema) and extravasation of neutrophils.

Cellular component of inflammatory response: a.Neutrophils: phagocytosis. b.(resident) Macrophages and Dendritic cells: augmentation of acute inflammatory response (and initiation of adaptive response). c.Mast cells: augmentation of inflammatory response.

Cyclooxygenase Lipoxygenase LeukotrienesProstaglandins

Inflammatory Response Local Response Epithelial cells Endothelial cells Macrophages/ Dendritic cells Systemic Response Liver Hypothalamus Bone Marrow

Endothelial cells Cytoskeleton E- and P-Selectin ICAM-1/2 Interleukin-8 MHC-1 Macrophages/ Dendritic cells IL-1, TNFa, IL-6 AA metabolites iNos, Cox2 Interleukin-8 Defensins MHC-I, MHC-II Vasodilation Vasopermeability Recruitment neutrophils

INVASION Tissue damage Pathogens Clotting System (Hageman Factor) Kinin/ Bradykinin Complement cascade Vasodilation Permeability Neutrophils Macrophages Dendritic cells PPRRs Basophils/ Mast cells Lipid mediators Cytokines Chemokines

C-reactive Protein: A Pentraxin

(Phosphocholine)

Ligand-bound CRP recruits and binds C1q and activates the classic pathway of complement, Ligand-bound CRP is recognized by the Fc  receptor and, thus, is an opsonin.

Resolve the Inflammatory response: 1.LPS tolerance: short form of MyD88, protein phosphatases, sTNF  R and sIL- 1R, IL-1Ra. 2.IL-10 and TGF  3.Decay-Activating Factor. 4.Arachidonic acid metabolites (Charles Serhan).

Chronic inflammation: persistent infections, autoimmunity, tissue damage, obesity. Macrophages and TH1 INF  and TNF  (cachectin) Fibrosis and granuloma

Chronic Inflammation: accumulation and continuous activation of macrophages. Fibrosis: Scar tissue fibroblast proliferation collagen production Granuloma

William Coley ( ).

“Coley’s toxin”

Anti-inflammatory therapy: - Anti-adhesin therapy - Corticosteroids (prednisone, prednisolone, and methylprednisolone - NSAIDS (aspirine, Tylenol, ibuprofen, Naproxen)

Celebrex, Vioxx

CR3

Extra-vasation: cells squeeze between neighboring endothelial cells without interupting the integrity of the endothelium: 1.Homotypic binding of PECAM-1 of the leukocyte with PECAM-1 of the tight junction of the endothelial cells. 2.LFA-1 binds to JAM-1 of the junctional complex PECAM: Platelet Endothelial Cell Adhesion Molecule. JAM: Junctional cell Adhesion Molecule.

PSGL-1: P-selectin Glycoprotein Ligand-1

CCL21 CCl19 T cells CXCL12 CXCL13 B cells  L  2 LFA-1)  4  1 (VLA-1)

 4  Gut CCL25 binds CCR9 CCL17 CCL27 CCL1

The End