L3: Innate Immunity----Inflammation

Learning Objectives

• Appraise the importance of innate immunity

• Understand the process of inflammation

• Recognize the functions of inflammatory mediators

• Compare acute and chronic inflammation

Definitions

• innate immunity involves non-specific and broadly specific control

• Cells involved

  • Neutrophil & natural killer cell: primarily phagocytes bacteria and other pathogens

  • Macrophage

    • bridging innate and adaptive by activating T cells

    • phagocyte dead cells and bacteria

    • secrete cytokines

  • Dendritic cell

    • antigen presenting cells

    • secrete cytokines

    • bridging innate and adaptive by activating T cells

Process of Inflammation

Etiology

• Exogenous causes

  • physical injury: trauma, burn

  • chemical agents: toxic gases, acids…

  • biological agents: bacteria, viruses, parasites

• Endogenous causes

  • immune reactions (hypersensitivity)

  • circulaton disorders (thrombosis)

  • metabolic products deposals (uric acids)

Types

• metabolic syndrome

• arthritis

• alzheimer’s disease

• asthma

• ulcerative colitis and inflammatory Bowel disease

• colon, breasy and lung cancers

• eye disorders

• cardiovascular disease

• gingivitis

Process of Acute Inflammation

Stimuli

• Types

  • infarction

  • bacterial infection

  • toxin

  • trauma

• result: mast cell secrete histamine

Vascular Changes

• vasodilation → increase blood flow

Vascular permeability

• stimulated by cytokines

Leakage of exudate

• plasma fluid: fibrin and antibody → tissue edema

• lymphoctes and bacteria → lymphatic system → adaptive immunity

Movement of neutrophils

• margination: getting close to blood vessel wall

• rolling

  • binding of selectin ligand (on neutrophil) to E- or P-selectin (on endothelium)

  • binding of chemokine receptor (on neutrophil) to chemokine (IL-1 secreted by macrophage) presented by proteoglycan (on endothelium) → activate neutrophil

• adhesion: binding of β2 integrin (on neutrophil) to ICAM-1

Transmigration of neutrophils

• transmigrate from blood vessel to tissue

Chemotaxis

• cytokines produced by Langerhan cells and macrophage attract neutrophils to site of infection

Leukocytes activation

• initial: activating neutrophils → kill microbes by short-lived

• later stage: activating monocytes (multi-potential)

  • IFN-γ → stronger killing ability

  • IL-4 → macrophages: tissue repair and barrier immunity

  • IL-10 → clean up cell debris during resolution

Phagocytosis

• engulf pathogens or apoptotic cells

• form phagosome

• fuse with lysosome → phagolysosome

• digested by lysozyme and released as exocytic vesicles

Termination/ Resolution

• process

  • granulocytes secrete lipoxin → initiate termination

  • secrete resolvins and protectins (anti-inflammatory) → stop neutrophil recruitment

  • macrophage engilf apoptotic neutrophils → release TGF-β

  • decrease pro-inflammatory cytokines (leukotrienes) & increase anti-inflammatory cytokines (IL1 receptor antagonist)

  • increase IL-4 and IL-10

  • macrophage leaves and end of inflammation

• outcomes

  • resolution

    • inflammed tissue back to normal status

    • stop vasodilation, cytokine production and leukocyte infiltration

  • fibrosis

    • inflamed tissue is damaged and cannot regenerate

    • fibrous scarring by collagen → functional repair

  • pus/abscess formation

    • dead leukocytes and bacteria and debris from destroyed cells

  • chronic inflammation

    • due to persistant stimuli

    • dominating presence of macrophages: release ROS → tissue destruction

Inflammatory medirators

Histamine

• produced by mast cells and basophils

• increase permeability of blood capillaries via H1 receptors

• drug: histamine antagonist → block H1 receptor to treat allergy or runny nose

TNFa and IL-1

• produced by tissue macrophages, monocytes, mast cells and endothelial cells

• trigger fever

• induce IL-6 (stimulate acute-phase proteins) , IL-8 and IFN-γ (induce prostaglandins)

Prostaglandins

• eicosanoid inflammatory mediator

• induces vasodilation, capilary permeability, pain and fever

• PGE1 and PGE2 → inflammation & potentiate histamine’s effect

• production determined by arachidonic acid, COX1 and COX2

• related drug

  • NSAIDs: blck COX1 and COX2

  • corticosteroids: inhibit phospholipase A2 release

Leukotrienes

• eicosanoid inflammatory mediator

• produced by enzyme 5-lipoxygenase

• similar fucntion with PG

• induce chemotaxis and extra-vascularisation of neutrophils, eosinophils and monocytes

• related drug: leukotriene receptor antagonist → treat asthma

Platelet-activating factor

• induces platelet aggregation

• activate neutrophils

• strong chemoattractant of eosinophil

• → extra-vascularisation of plasma proteins → edema

Plasma mediators

Bradykinin

• produced by kinin system

• increase vascular permeability

• smooth muscle contraction

• inflammation

Plasmin

• activate fibrinolytic system: degrade fibrin

• fibrin undergo fibrinolysis → fibrinopeptide → increase vascular permeability and attract leukocytes

Thrombin

• produced by coagulation system

• convert soluble fibrinogen → insoluble fibrin

Complement proteins

• produced by complement system

• C3

  • C3a: induces histamine release by mast cell

  • C3b: opsonisation

• C5

  • C5a: induces histamine release by mast cell

  • C5b: strong chemoattractant

• MAC (membrane attack complex)

  • C5b + C6 + C7 + C8 + polymeric C9

  • insert into bacterial cell wall → lysis

Acute and Chronic Inflammation

Comparison

• inducing agent

  • acute

    • pathogen

    • injured tissues

    • allergens

  • chronic

    • non-degradable pathogens

    • persistant foreign body

    • autoinmmune response

• cells involved

  • acute

    • neutrophils

    • monocytes

    • macrophage

    • basophils

    • eosinophils

    • mast cells

  • chronic

    • monocytes

    • macrophage

    • lymphocytes

    • plasma cells

    • fibroblast

• process

  • acute

    • vacular changes

    • neutrophils recruitment

  • chronic

    • angiogenesis

    • mononuclear cell infiltration

• outcomes

  • acute

    • resolution

    • abcess formation

    • chronic inflammation

  • chronic

    • tissue destruction

    • fibrosis

    • necrosis

Sepsis Syndrome

• whole-body inflammation caused by infection

• symptoms

  • high fever

  • increased heart rate and breathing rate

• bacteria septicemia (sepsis syndrome by bacterial infection)

  • activate monocytes → TNFα and IL-1 release → inflammation

  • shock from loss of blood pressure due to vasodilation and leakge of fluid into tissue

  • enhanced coagulation

  • results: multi-organ failure and death