Innate Immunity: Breached Barriers and Inflammation Flashcards
Macroscopic signs of Inflamation
- Calor (heat)
- Rubor (redness)
- Tumor (swelling)
- Dolor (pain)
- Functio laesa (loss of function)
Five R’s of Inflamation
- Recognize
- Respond
- Recruit
- Remove
- Resolve
Sequence of events following an infection or tissue injury?
- Tissue-resident innate cells detect the presence of microbes or necrotic cells and are activated: Dendritic and Mast Cells
- Endothelial activation and vascular changes. Circulating proteins recognize microbes & trigger humoral cascades
- Elimination: Phagocytosis
- Resolve and Repair or chronic inflamation
Recognition (Stage 1) of Innate Immune Response
- Epithelial and tissue-resident immune cells detect the presence of foreign or abnormal tissue
- Recognition by Macrophages, Dendritic Cells, and Mast Cells
- Toll-like receptors (TLR) use adaptors and a kinase cascade to upregulate cytokines and chemokines
- Mast cells w/ pathogen recognizers trigger inflammation
Respond (Stage 2) of Innate Immune Response
Increase diameter of local vasculature leads to increased blood flow, decreased flow rate to the region including nutrients, plasma, and additional neutraphils.
This leads to loosening of tight junction between epithelium. Also an upregulation of adhesion molecule and chemokine expression that facilitated cellular micratio to site of infection or injury
What are these examples of?
- Vasoactive amines (Histamine)
- Eicosanoids (Prostaglandins & Leukotrienes)
- Complement
- Cytokines (IL-1, IL-6, TNFa)
- Chemokines (CXCL8, MCP-1, MIP-1a)
Soluble inflammatory mediators
released locally at site of inflamation
__________ is stored as pre-formed molecules in granules in mast cells
- Typically near blood vessels in tissues
- Also stored in circulating basophils and platelets
- First mediator to be released during inflammation
- Released by degranulation in response to various stimuli
Histamine and Serotonin is stored as pre-formed molecules in granules in mast cells
- Typically near blood vessels in tissues
- Also stored in circulating basophils and platelets
- First mediator to be released during inflammation
- Released by degranulation in response to various stimuli
__________ binds H1 receptors on microvascular endothelial cells. What does this lead to?
- Dilation of arterioles
- Inter-endothelial gaps
- Anti-histamine drugs are H1 receptor antagonists
Vasoactive peptides with similar effects to Histamine
Kinins
Prostaglandins & Leukotrienes are exmaples of__________?
Eicosanoids = Prostaglandins & Leukotrienes
What do Eicosanoids (Prostaglanin and Leukotrienes) bind to?
GPCR
How do NSAIDs such as aspirin and Steroids reduce inflammation?
They are COX-1 and Cox2 inhibitors prevent conversion of arachidonic acid, released from epithelium when damaged, from converting into prostaglandins
Activation and Function of Complement System of Innate Immunity
•Plasma proteins coat microbes to promote phagocytosis
can also neutralize microbe function
•Cascade activated on contact with bacteria
- Also activated by antibody complexes and lectins
- Miliions released in minutes
- Promotes inflammation
- Does not need cellular intermediate →Kill bacteria directly
How does Membrane Attack Complex (MAC) Function
Forms a pore in membrane that leads to lysis of microbe
What are Cytokines and role of each type
- Low-molecular weight cell-cell signaling proteins secreted by immune and non-hematopoietic stromal cells as part of the acute immune response. Regulate function of other cells
- Tumor necrosis factors (TNF family)
- Interleukins (IL): IL-1 to IL-38
- Interferons (IFN): Anti-viral defences, T cell activation
Paracrine versus Endocrine function of Cytokines
Paracrine: Upregulates NEarby Cell
Endocrine: Systemic effect, enters circulation and initiates a broader cascade
Recruitment (Stage 3) of Innate Immunity
Recruitment of Professional Phagocytes & Killers
- Chemotactic cytokines with the ability to induce directed chemotaxis in nearby responsive cells (Neutrophils)
- -released by bacteria or by leukocytes or endothelial cells at the site of infection/injury
- Inflammatory cell recruitment via Chemotaxis
- Promotes Actin Polymerization
Methods of Leukocyte Migration to Site of Injury
- MARGINATION
- ROLLING
- ADHESION
- TRANSMIGRATION
* chemokines produced at sites of inflammation, attach to proteoglycans within blood vessels. Blood flow slows at sites of inflammation, forces white blood cells to the margin of vessel. Here they interact with adhesion molecules by binding, releasing, and ‘rolling’ along vessel wall*
Removal (Stage 4) Innate Immunity
Phagocytes via phagocytosis engulf and kill pathogens
Macrophages and Neutraphils
Difference between Macrophages and Neutrophils
•Macrophages
- Large Leukocytes can produce recruitment molecules
- Earliest Immune response
- Tissue-resident
- Long-lived (months –years)
•Neutrophils (PMNs)
- Small Polymorphic Molecules
- Consist of the majority of White Blood cells
- Most stored in bone marrow awaiting release
- Short-lived (hours -days)
How do phagocytes recognize a microbe?
Phagocytes follow a chemokine gradient to infected tissue.
•Guided by tissue-derived chemokines. “smell” microbe and move towards it
Receptor-mediated polymerisation of myosin-actin as part of Innate imunity are essential for ___________ and ____________
Receptor-mediated polymerisation of myosin-actin essential for chemotaxis and phagocytosis
Antibody (fc) and Complement (c3b) Receptors
Mechanism of Phagocytosis
Oxidative versus Non-oxidative killing by Phagocytes
Oxidative killing
- Respiratory burst
- Microbicidal reactive oxygen species (ROS)
-OH, Singlet Oxygen, Hydrogen Peroxide H2O2
- Produced by superoxide-generating NADPH oxidase system
- Chronic granulomatous disease (CGD): the breakdown in oxidative system leads to chronic prolonged infections and granuloma formation
Non-oxidative Killing
•Cytotoxic molecules:
- Lysozyme
- Myeloperoxidase
- Cationic proteins
- Stored in granules
- Act on the contents of the phagosome
- Nitric Oxide (NO): Reactive nitrogen species (RNS)
Method of Extracellular Phagocytic Killing
NETosis (Neutrophil extracellular traps)
Natural Killer Cells role in innate immunity
Cytokines secreted from macrophages activate and facilitate the entry of NK cells into the tissue to reduce proliferation. The NK cells eliminate infected or stressed cells through various pathways including the normal cell-killing function and the release of cytokines.
- Large, granular innate lymphocytes
- Early source of cytokines and chemokines
- Critical to the early control of many viral infections prior to the development of an adaptive response
- IFNg activates macrophages to destroy phagocytosed microbes
- Can be stimulated directly with cytokines. No antigen required
Mechanisms of Natural Killer Cell-Mediated Killins
NK cell recognizes MHC1 on healthy cell and does not kill it
The infected cell has MHCI downregulated, does present activating receptor, the cell will be killed.
- direct lysis of infected cells
- death receptor ligation
- antibody-dependent cell-mediated cytotoxicity (ADCC)
- release of cytotoxic granules (perforin and granzyme B)
- production of antiviral cytokines: IFNg& TNFa
- production of chemokines
- activation of DCs that mediate T cell differentiation and trafficking
Risk of Natural Killer Cell
In individuals w/ dysfunctional NK cells, cytokine storm can lead to cascade of macrophage and neutrophil recruitment, failure to clear infection and acute respiratory disease
______________: Massive accumulation of neutrophils and killed bacteria that fill up cell walls of alveoli. Cellular debris, plasma, and mucous form purulent, green sputum clogging lungs
- Acute or Puralent (more severe) Bronchopneumonia
