Innate Immunity Inflammation Flashcards
Innate Immunity (1st line defense) -Physical Barriers
Epithelial Cells of the:
- Skin
- GI
- GU
- Respiratory system
Innate Immunity
- Includes Natural Barriers (physical, mechanical, biochemical)
- Inflammation
Innate Immunity (1st line defense) -Mechanical
Removes bacteria by:
- Coughing
- Sneezing
- Vomiting
- Flushing - urine
Innate Immunity (1st line defense) -Epithelial Cell-derived Chemicals
- Lysozyme
- enzyme attacks the cell walls of GRAM POSITIVE BACTERIA - Cathelicidin / Defensins
- Antimicrobial peptides that disrupts bacterial membranes and kills them
Innate Immunity (1st line defense) -Normal Flora
- Compete w/ pathogens for nutrition and prevent attachment to epithelium
- Helps w/ digestion / produces biotin and Vit K (clotting)
- Assits w/ absorption of Ca, Fe, Mg
Innate Immunity: 2nd Line Defense
-Inflammation
- Protective process
- May result from injury, infection
- Stimulates healing
- Prevent further damage and progressive deterioration
Inflammation
-Signs & symptoms
- Redness – decreased blood flow & increase RBC concentration to area
- Heat – pooling of blood
- Swelling – leakage of plasma proteins
- Pain - Bradykinin & prostaglandin’s
Inflammation Goals
- Limit and control the inflammatory process
- Prevent and limit infection and further damage
- Initiate adaptive immune response
- Initiate healing.
Inflammation:
-Development process
- Damage to Tissue
- Vasodilation
- Increased Vascular permeability
- WBC’s adherence to inner walls of vessels
Cathelicidin
- Cathelicidin is produced by epithelial cells of the skin, gut, Urinary tract, Respiratory tract
- Antimicrobial peptides that disrupt bacterial membranes and kills them
Cathelicidins
-Action
- Bacteria have cholesterol-free cell membranes into which cathelicidin can insert and disrupt the membrane, killing the bacteria
Epithelial Cell-Derived Chemicals
Alpha Defensin’s
- Often require activation by proteolytic enzymes
- Rich in the granules of neutrophils
- May contribute to the killing of bacteria by those cells.
Epithelial Cell-Derived Chemicals
Beta Defensins
- Synthesized in active forms
- Can kill bacteria the same way as cathelicidin
- Found in epithelial cells lining:
- respiratory, urinary, and intestinal tracts as well as skin - May help protect epithelial surfaces from infection with adenovirus & HIV
Epithelial Cell-Derived Chemicals
Collectin’s
- React w/ carbs on the surface of a wide array of pathogenic microorganisms and help cells of the INNATE immune system (MACROPHAGES) recognize and kill microorganisms
Epithelial Cell-Derived Chemicals
-Mannose-Binding lectin (MBL)
- Powerful activator of a plasma protein system (COMPLEMENT) resulting in damage to bacteria or increased recognition by macrophages
Normal Flora Benefits
- Digest Fatty acids, large polysaccharides, and other dietary substances
- Produce Biotin and Vitamin K
- Assist in absorption of ions, such as Ca, Fe, and Vitamin K
- Train the adaptive immune system by inducing growth of gut-associated lymphoid tissue (Where cells in the adaptive immune system reside)
Prolonged treatment with Broad-Spectrum Antibiotics
Can lead to:
- Candida albicans
- Clostridium difficile
Opportunistic Microorganisms
- Can cause disease if the individual’s defenses are compromised
- Psudomonas aeruginosa
Plasma Protein Systems
- Complement System
- Clotting System
- Kinin System
Compliment Cascade
-Overview
- Factors produced by compliment cascade are among the body’s MOST POTENT defenders against bacterial infection
Compliment Cascade
-Most Important function
- most important function of the complement cascade is:
- ACTIVATION OF C3 & C5 - Resulting in:
- Opsonins
- chemotactic factors
- anaphylatoxins
Compliment Cascade
-Opsins
- Coat the surface of bacteria and increase their susceptibility to being phagocytized (eaten) & killed by neutrophils and macrophages
Compliment Cascade
-Chemotactic Factors
- Diffuse from a site of inflammation and attract PHAGOCYTIC CELLS to that site
Compliment Cascade
-Anaphylatoxins
- Induce rapid degranulation of mast cells
- release of histamine that induces vasodilation and increased capillary permeability
Compliment Cascade
-Activation of complement components C5b through C9
- Membrane attack complex
2. Results in a complex that creates pores in outer membrane
Compliment Cascade
-Most potent products
- C3b (opsonin)
- C3a (anaphylatoxin)
- C5a (anaphylatoxin, chemotactic factor)
Pathways that control the Activation of Complement (3)
- Classical Pathway
- Lectin Pathway
- Alternative Pathway
Pathways that control the Activation of Complement (3)
-Classical Pathway
- Primarily activated by antibodies (proteins of the acquired immune system)
- Antibodies activate the 1st component of complement, C1.
- C1 leads to activation of other complement components leading to activation of C3 & C5
Antibodies of the Acquired immune response can use the complement system to kill bacteria and activate inflammation
Pathways that control the Activation of Complement (3)
-Alternative Pathway
- Activated by several substances found on the surface of infectious organisms (lipopolysaccharides, endotoxin)
- Uses Unique proteins (Factor B, D, and properdin) to form complex that activates C3
- C3 activation leads to C5 activation and convergence w/ the classical pathway
Can Directly activate complement system by infectious organisms w/out antibody presence ***
Pathways that control the Activation of Complement (3)
-Alternative Pathway (Activation Summary)
- Directly activate the complement system by presence of certain infectious organisms W/OUT ANTIBODY BEING PRESENT
Pathways that control the Activation of Complement (3)
-Lectin Pathway
- Similar to classical pathway but is INDEPENDENT OF ANTIBODY
- Activated by Mannose-binding lectin (MBL)
- MBL is similar to C1 and binds to bacterial polysaccharides containing the carbohydrate mannose
Pathways that control the Activation of Complement (3)
-Summary
Complement cascade can be activated by:
- Opsonization
- Anaphylatoxic activity – resulting in mast cell degranulation
- Leukocyte chemotaxis
- Cell lysis
Clotting System
-Purpose
- Plug damaged vessels and stop bleeding
- Trap microorganisms and prevent their spread
- Provide framework for future repair and healing
Clotting Cascade
-Activation by substances
Substances that are released by tissue injury and infection:
- Collagen
- Proteinases
- Kallikrein
- Plasmin
- Endotoxins (bacterial products)
Clotting Cascade
-Activation Pathways
- Tissue (Extrinsic) Pathway
2. Contact activation (Intrinsic) Pathway
Clotting System
-Tissue (Extrinsic) Pathway
- Activated when there is TISSUE INJURY and membrane-bound or soluble tissue factor (TF) (also called tissue thromboplastin), a substance released by damaged ENDOTHELIAL CELLS in blood vessels, REACTS w/ ACTIVATED FACTOR (VIIa)
Clotting System
-Tissue Factor (TF)
- A substance released by damaged endothelial cells in blood vessels
Clotting System
-Contact Activation (Intrinsic) Pathway
- Activated w/ abnormal vessel wall and Hageman factor (factor XII) contacts negatively charged SUB-ENDOTHELIAL substances
- Killikrein & Kininogen can also activate factor XII
- Clotting pathways converge at factor X
Kallikrein & Kininogen
- Can activate factor XII in the contact activation (intrinsic) pathway
Factor X
- Activation of factor X begins a common pathway leading to activation of fibrin that polymerizes to form a fibrin clot
Clotting Pathway
-Fibrinopeptides (FP’s)
- Activation of the clotting cascade produces fragments known as FP’s A & B that enhance the inflammatory response
- FP’s are released from fibrinogen when fibrin is produced
- Both Fibrinopeptides are CHEMOTACTIC for neutrophils and increase vascular permeability by enhancing effects of BRADYKININ.
Kinin Cascade
-Activation
- Both the clotting and Kinin systems can be initiated through activation of Hageman factor (factor XII) to factor XIIa.
Kinin Pathway
-Prekallikrein
- Another name for factor XIIa is prekallikrein because it
- enzymatically activates the 1st component of the kinin system, prekallikein.
- Final products of the kinin cascade is bradykinin
- produced from a larger precursor molecule, kininogen
Kinin Pathway
-Bradykinin
- Final product of the kinin cascade
- Produced from a larger precursor molecule, kininogen
- Causes dilation of blood vessels
- Acts w/ prostaglandins to induce pain
- Causes smooth muscle cell contraction
- Increases vascular permeability
Plasmin
- Degrade fibrin polymers in clots
- Can also activate the complement cascade through components C1, C3, & C5
- Can activate the kinin cascade by activating factor XII and producing prekallikrein activator
C1 inh
- Inhibits complement activation through C1 (Classical pathway )
- MASP-2 (lectin pathway), & C3b (alternative pathway)
Hereditary Angioedema
- A genetic defect in C1 inh results in hereditary angioedema, which is a self-limiting edema of cutaneous and mucosal layers resulting from:
- stress, illness, or relative minor or unapparent trauma
PRR’s
Pattern Recognition Receptors
- Recognize:
- Pathogen-associated molecular patterns PAMPs
- Damage-associated molecular patterns DAMPs
PAMP
Pathogen-associated molecular patterns
1. molecules that are expressed by infectious agents, either found on their surface or released as soluble molecules
DAMP
Damage-associated molecular patterns
1. Products of cellular damage
PRR’s
-Toll-like receptors
- Primarily recognize a large variety of PAMPs located on the microorganisms cell wall or surface
Complement Receptors
- found on many cells of the innate and acquired immune responses.
- Recognize molecules produced by activation of plasma protein systems.
Cytokines
- Variety of secretions that affect other cells to help with cooperation to produce effective protective responses.
- Can be either pro-inflammatory or anti-inflammatory.
- Usually diffuse over short distances
- Some effects of cytokines occur over long distances (FEVER)
Interleukins
- Majority of important cytokines are classified as interleukins or interferons
- Produced predominantly by macrophages and lymphocytes in response to stimulation of PRRs or by cytokines
Interleukins
-Effects
- Alteration of adhesion molecule expression on many types of cells
- Attraction of leukocytes to a site of inflammation (chemotaxis)
- Induction of proliferation and maturation of leukocytes in the bone marrow
- General enhancement or suppression of inflammation
Interleukin-1 (IL-1)
- Produced mainly by macrophages
- Activates monocytes, other macrophages, and lymphocytes
- Enhances both innate and acquired immunity
- Acts as a growth factor for many cells - Increases # of circulating neutrophils
- IL-1 is an endogenous pyrogen
IL-1 and Fever
- IL-1 is an endogenous pyrogen that reacts w/ receptors on cells of the hypothalamus and affects the body’s thermostat resulting in fever
IL-6
- Produced by macrophages, lymphocytes, fibroblasts, and other cells
- Directly induces hepatocytes to produce many of the proteins needed in inflammation
- Stimulates growth and differentiation of blood cells in the bone marrow and the growth of fibroblasts (required for wound healing)
3.
Tumor necrosis factor-alpha
- Secreted by macrophages & mast cells in response to stimulation of Toll-like Receptor (TLR)
- Pro-inflammatory effects on
- vascular endothelium and macrophages
Tumor Necrosis factor-alpha
-Systemic Effects
- Inducing fever
- Causing increased synthesis of inflammation-related serum proteins by liver
- Causing muscle wasting (cachexia)
- Very high levels of TNF-alpha can be lethal and are responsible for fatalities from SHOCK caused by gram-negative bacterial infection.
INterleukin-10
- Produced by lymphocytes
- Suppresses growth of lymphocytes and the production of pro-inflammatory cytokines by macrophages
- Down-regulation of both inflammatory and acquired immune responses
Transforming Growth Factors
- Produced by many types of cells in response to inflammation and induce cell division and differentiation of other cell types, such as immature blood cells
Interferons
- type of cytokine that protect against viral infections
- Principal interferons are:
- INF-alpha
- INF-Beta
- INF-Gamma
INF
-Action
- Macrophages and cells that become infected w/ viruses produce and secrete both INF-alpha and INF-beta.
INF-alpha & INF-beta
- Protect the surrounding cells from infection and limit the spread of the virus
INF-gamma
- Produced by lymphocytes;
- activates macrophages (increasing microbiocidal activity)
- resulting in increased capacity to kill infectious agent
Chemokines
- attract leukocytes to sites of inflammation
- Leukocyte Chemotaxis - Synthesized by macrophages and endothelial cells in response to pro-inflammatory cytokines
Mast Cells
- MOST IMPORTANT cellular activator of the inflammatory response
- Cellular bags of granules located in the loose connective tissues close to blood vessels
- skin, digestive lining, respiratory tract
Basophils
- Protect mucosal surfaces
- Release cell mediators that promote inflammatory response
- Much like mast cells
Leukotrienes
- Sulfur-containing lipids
- Produce histamine-like effects
- smooth muscle contraction
- increased vascular permeability - Important in later stages of inflammatory response (prolonged)
Prostaglandins
- Cause increased vascular permeability
- neutrophil chemotaxis
- Pain by direct effects on nerves - Long chain, unsaturated fatty acids
Prostaglandins E1 & E2
Cause increased vascular permeability and smooth muscle contraction
Histamine
- Causes rapid constriction of smooth muscle and dilation of post-capillary venules
- Increased vascular permeability
Mast Cells
-begin synthesis of..
- Leukotrienes
- Prostaglandins
- Platelet activating factor
Endothelial Cells
-Action
- Produce Nitric Oxide (NO) from arginine
- Produce prostacyclin from arachidonic acid
- Both NO and PGI2 maintain blood flow and pressure and inhibit platelet activation
- PGI2 and NO are synergistic
Platelets
-Activation
- Interact w/ components of coagulation cascade to STOP BLEEDING
- Degranulation, releasing biochemical mediators like serotonin, which has vascular effects like HISTAMINE
- Promote wound healing
Platelets
-definition
cytoplasmic fragments formed from megakaryocytic
Neutrophil
-Primary Role
- Removal of debris and dead cells in sterile lesions (burns)
- Destruction of bacteria in non-sterile lesions
- Predominant phagocytes in early inflammatory site
- Release macrophage chemotactic factors to attract macrophages to injury site
3 Systemic changes associated w/ acute inflammatory response
- Fever
- Leukocytosis (increase in level of circulating leukocytes
- Increased level of circulating plasma proteins
Pyrogens
- IL-1 is an endogenous pyrogen released from neutrophils and macrophages
- act directly on the hypothalamus
- area that controls the body’s thermostat
Left Shift
Leukocytosis-increased number of circulating WBC’s
- more immature forms of neutrophils are present in relatively greater than normal proportions
Repair Vs. Resolution
- Repair is when there is replacement of destroyed tissue with scar tissue
- Resolution is when there is regeneration of tissues close to normal tissues
Cells capable of complete Mitotic Regeneration?
- Epithelial cells
- Hepatic cells
- Bone marrow cells
Macrophages
- Engulf Cellular debris, present foreign proteins or antigens to lymphocytes
- Arrive 24 hrs or later after neutrophils
Monocytes
- Produced in the bone marrow
2. Enter the circulation and migrate to inflammatory site where they develop into macrophages
Neutrophils
- Move to areas of tissue damage
- 1st WBC to arrive at injury/infection site (early inflammation)
- Cells are short lived and become component of purulent exudate
Eosinophils
- Important in preventing parasitic infection
- Regulation of vascular mediators
- Limits inflammation
- Controls vascular effects - Mildly phagocytic
Lymphocyte
- Part of adaptive immune system
- Breaks up into T and B lymphocytes
- T lymphocytes turn into natural killer cells
Natural Killer Cells
- Recognize and eliminate cells infected w/ viruses
- Some function in eliminating cancer cells
- LINK between innate and adaptive immune system
Mast Cells
-Activation
- Physical & Chemical Injury
- Immunologic processes
- Toll-like receptors
Mast Cells
-Chemicals release in two ways…
- Degranulation and synthesis of lipid-derived chemical mediators
Mast Cell Degranulation
- Histamine
- Vasoactive amine causes temporary, rapid constriction of large blood vessels and dilation of post-capillary venules - Retraction of endothelial cells lining capilaries
- Increases vascular permeability
Histamine
-H1 receptor
- Pro-inflammatory
2. Present in the smooth muscle cells of the bronchi
Histamine
-H2 Receptor
- Anti-inflammatory
- Present on parietal cells of the stomach mucosa
- induces secretion of gastric acid
Purulent Exudate
- Pus: indicates a bacterial infection
- Cysts or abscesses
Leukocytosis
- Increased number of circulating leukocytes
2. Shift to the left
Healing
-Reconstructive Phase
- Fibroblast proliferation
- Collagen synthesis
- Epithelialization (sealing the wound)
- Contraction (shrinking the wound)
- Cellular differentiation
Healing
-Maturation phase
- Continuation of cellular differentiation
- Scar tissue formation
- Scar remodeling
Impaired Inflammation in Older adults leads to??
Chronic Illness
- Diabetes
- Cardiovascular
- Diabetes
Causes of Impaired Inflammation
- Chronic medication intake
Older Adults and Inflammation
- Impaired inflammation causes chronic disease
- Chronic med intake decreases inflammatory response
- Healing response is diminished because of skin’s loss of regenerative ability
- Infections are more common in older adults
Dysfunctional Wound Healing
-Reconstructive phase dysfunction
- Impaired collagen matrix assembly
- Keloid scar
- Hypertrophic scar - Impaired epithelialization
- Anti-inflammatory steroids, hypoxemia, nutritional deficits - Impaired contraction
- Contracture
Causes of Dehiscence
- Excessive strain and obesity
- increases risk of wound sepsis
Dysfunction during Inflammatory response
-Wound Healing
- Wound sepsis
- Hypovolemia
- Hypoproteinemia
- Anti-inflammatory steroids
- Hemorrhage
- Fibrous adhesion
- Infection
- Excess scar formation
Debridement
- Cleaning up the dissolved clots, microorganisms, erythrocytes, and dead tissue cells
Chronic Inflammation
-Characteristics
- Dense infiltration of lymphocytes and macrophages
- Granuloma formation
- Epithelioid cell formation
- Giant cell formation
- Caseous necrosis w/ TB
