Outcome 2 Flashcards
PAMPs
Pathogen-associated molecular patterns. Conserved structural components of microbes that are essential for the microbes survival. These are recognized by innate immune cells. They are not super specific, but can determine if something is a virus, bacteria, etc
What are the three major routes of entry for microbes to enter the body? (location)
Damaged skin, GI Tract, and respiratory tract
DAMPs
Damage Associated Molecular Patterns
Signals that activate the Immune system when tissue damage occurs and a cell dies form necrosis.
How is the skin connected to the innate immune system?
When intact skin is impermeable to most infectious agents, this is due to skin being composed of keratinized stratified squamous epithelium. Additionally the skin contains biochemical agents that provide proteins with antimicrobial properties.
How are mucous membranes connected to the innate immune system?
Mucous traps non-self materials preventing their entry and proliferation in the body. Hairs and cilia within the mucous membranes also help mechanically remove non-self materials.
What are some common things that can reduce the effectiveness of mucous membranes in the innate immune system?
Alcohol, cigarettes, and certain narcotics damage hairs and cilia within the respiratory tract.
What body fluids work with the innate immune system?
- Tears – flush antigens out of the eyes, and contain lysozymes which can break down the cell walls of some bacteria.
- Salvia – washes antigens from the surface of the teeth and reduced colonization. Contains lysozymes.
- Urine – urination flushes antigens from the urinary system. pH inhibits some microbes, but encourages others.
- Vaginal secretions – acidic inhibiting certain microbial growth.
- Semen – contains an antimicrobial called spermine that inhibits microbial growth
- Gastric Juices – acidic, and contains HCL, enzymes and mucus.
- Sebaceous glands – secrete sebum which is rich in unsaturated fatty acids that inhibit the growth of certain microbes.
- Sudoriferous glands – secrete fatty acid and latic acid, increasing acidity.
What is the innate immune systems 1st line of defense?
Skin, mucous membranes, body fluids, normal flora, antimicrobial properties.
What is the innate immune systems 2nd line of defense?
Inflammation, cellular defenses, phagocyte recognition, phagocytosis, NK cells, antimicrobial substances, fever, and acute phase reactants.
How is inflammation initiated?
Tissue damage
What are the hallmark signs of inflammation?
Swelling, redness, heat, pain, and loss of function.
What are the key functions of inflammation?
- To destroy pathogens, and prevent colonization
- Mobilize and attract immune components to the site of injury
- Tissue repair
What are the three basic stages to the inflammatory response?
- Vasodilation and increased permeability of the blood vessels
- Emigration of phagocytes from the peripheral blood into the interstitial fluid
- Tissue repair
What are the major substances involved in vasodilation and increased permeability?
Histamine, kinins, prostaglandins, leukotrienes, and complement.
Kinins
Proteins in the blood that serve as chemotactic agents for phagocytes,
Prostaglandins
lipids that are released by damaged cells and intensify the effects of histamine and kinins
leukotrienes
produced by basophils and mast cells; cause increased permeability, adherence of phagocytes to pathogens and chemotactic agent for phagocytes
complement
different proteins within the complement system stimulate histamine release, attract neutrophils and lyse bacteria
Extravasation
The process of inflammation attracting phagocytes from the blood to sites of damaged tissue.
Antibody-dependent cell-mediated cytotoxicity
NK cells ability to recognize target cell-bound antibodies
f
f
How does fever inhibit microbial growth?
The increase of temperature inhibits the growth of micro-organisms and appears to enhance the immune response to the pathogen.
Define innate immunity.
Innate immunity is the always present, non-specific immunity. It contains both cellular and humoral components. Its main role is to control and eliminate pathogens before the adaptive immune system is activated. It achieves this role by preventing adherence, invasion, colonization and spread of pathogens.
List the major routes of entry for microbes to enter the body. (method)
Direct contact
Inhalation
Ingestion
Injection
identify the first line defences of innate immunity – external.
Intact healthy skin and mucous membranes
Body secretion
Normal flora
Antimicrobial Substances
Intact skin
Keratinization of the skin provides a strong protective barrier that prevents pathogens from entering the body. As keratin is shuffled off, any pathogen attached to the keratin will also be shuffled off the body.
Squamous cells are packed so tightly together that it forms an impenetrable barrier.
Sebum secreted on the surface of the skin is toxic for many microbes.
mucus membranes
Forms a thin permeable barrier that baths and traps potential invaders.
Mechanical removal flushes pathogens out of the body. (Coughing, urination, peristalsis. )
Some membranes have antimicrobial properties.
(Small intestine, mouth, lungs, vagina.)
Some membranes will have a pH that cannot support pathogen life.
(Vagina, stomach (acid), small intestine (base).)
Body secretions
Many body secretions will have a pH that cannot support pathogen life or will have antimicrobial properties.
Antimicrobial Substances
Enzymes and other proteins that have antimicrobial properties. (lysozyme and defensins)
Lysozymes
Enzymes in tears and saliva that degrade the cell wall peptidoglycan of gram-positive organisms
Defensins
Form ion-permeable channels in membranes of microorganisms, causing cell lysis. Produced by neutrophils and epithelium.
Identify the second line defences of innate immunity – internal.
The second line of defence acts rapidly once the first line has been broken. It includes:
- Inflammatory response
- Antimicrobial subsances
- Phagocytic cells
- APCs
Identify the main cells involved in innate immunity.
Phagocytes:
Macrophages
Neutrophils
Dendritic cells (APC), mast cells, basophils, eosinophils, NK cells and innate lymphoid cells.
phases of inflammation
- Acute vascular response
- Acute cellular response
- Chronic cellular reponse
- Resolution/tissue repair
Acute vascular response
Tissue damage causes the release of histamine from basophils or tissue mast cells.
- Causes vasodilation, vasopermeability, and increased expression of adhesion molecules on endothelial cells.
- Hyperemia
The rush of blood into the affected area. - Transudation
Fluids and proteins move from the blood vessels into tissues.
-Fibrin plug forms
Inflammation activates the coagulation cascade.
Acute cellular response
Neutrophils migrate to the site of infection and phagocytose damaged tissue or pathogens. This produces lactic acid which contributes to pain.
- Neutrophil extracellular traps (NETs)
Dying neutrophils expel their contents to trap bacteria. bind to bacteria and prevents them from spreading - Monocytes/macrophages/lymphocytes arrive later.
They will be phagocytic and act as APCs to help activate the adaptive immune system
T helper cells will produce cytokines to help stimulate antibody production.
Chronic cellular response
The arrival of more monocytes and macrophages (if the damage is severe). Macrophages produce IL-1 (which causes fever).
Adaptive immunity may be activated at this point.
Resolution/tissue repair
Damage repair begins within 18 hrs and peaks at 48-72 hrs.
Fibroblasts produce mucopolysaccharides to neutralize the chemical mediators.
List the hallmark signs/features of inflammation and what causes them.
- Redness (rubor)
Capillaries have increased permeability, causing fluid to release into tissues. - Heat (calor)
Capillaries are widened causing an increased blood flow. - Swelling (tumour)
Capillaries have increased permeability, causing fluid to release into tissues. - Pain (dolor)
Leukocytes are attached to the site of infection or damage.
Fever and proliferation of leukocytes occur.
List the functions of inflammation
Destroy and eliminate the injuring and/or infectious agents.
Clear the infection- remove debris, and neutralise toxins.
Limit the spread of injuring factors.
Recruit and activate the specific immune response.
Help initiate the healing process.
Acute inflammation
Short-term inflammatory response that can lead to chronic inflammation if unresolved.
Chronic Inflammation
Ongoing inflammation that is unresolved. It is the result of foreign bodies, persistent infection, and autoimmune disease. Results in major tissue damage.
Extravasation/Transendothelial migration
The movement of leukocytes into tissues at the site of inflammation.
Extravasation Steps:
- Tethering/rolling
Cytokines stimulate the endothelium of blood vessels to increase the expression of adhesion molecules (E-Selectin and P-Selectin). Phagocytes then bind weakly to the selectin adhesions. This causes phagocytes to roll along the endothelium. - Activation
Tissue macrophages produce cytokines that stimulate the endothelial cells to produce chemokines. These chemokines stimulate the rolling phagocytes to “up-regulate” their adhesion molecules to draw phagocytes out of circulation and to the site of infection. - Adhesion
High-affinity integrins bind firmly to the intracellular adhesion molecules on the endothelium. Results in the stable adhesion of the phagocyte to the endothelial surface. - Trans endothelial migration
Chemokines stimulate the phagocyte to flatten and extend pseudopods to allow them to migrate across the blood vessel wall through endothelial cell junctions.
Phagocytosis
Ingestion by individual cells of forgein invaders.
Phagocytosis Steps
- Attachment
Phagocyte recognizes a PAMP/opsonin coated microbe, and binds to the microbe using PRRs. Pseudopods from a “hug of death” around the invader. - Ingestion
A phagosome is created (An internal membrane-bound vesicle containing a microbe). The phagosome moves toward the lysosome within the cell cytoplasm. - Fusion with lysosome
Phagosomes fuses with lysosomes (vesicles within a phagocyte containing digestive enzymes and bacterial substances) to form a phagolysosome. - Digestion
Enzymes kill and digest the microbe, and toxic by-products (Reactive oxygen species) are created. - Release
The digested end-products from the cell are ejected into the surrounding environment. This “defecation” acts as a beacon to other macrophages to clean up.
Examples of PAMPs
Bacterial lipopolysaccharides (Gram negative)
Bacterial peptidoglycan (Gram positive)
Terminal mannose residues
Flagella
Double stranded RNA
PRRs (Pattern Recognition Receptors)
Receptors found on our innate immune cells that recognize PAMPs. Can be membrane bound, cytoplasmic, or secreted
TLRs (Toll-like Receptors)
A family of structurally similar signalling PRRs. They are membrane bound or cytoplasmic, and their receptors are involved in signal transduction.
Chemotaxis
Movement of cells up a concentration gradient of chemotactic factors.
C5a
Opsonization
The coating of a particle such as a bacterium with antibody or opsonin that lead to increased phagocytosis by phagocytic cells.
C3b
CRP
C reactive protein binds to polysaccharides in bacteria cell walls and activates the classical pathway of complement.
MLB
Mannose-binding lectin.
Binds to bacteria and certain fungi to begin the lectin pathway.
Enhances opsonization.
Fibrinogen
Coagulation function- converts fibrinogen to fibrin. Wound healing.
Role of natural killer (NK) cells
Destroys viral and tumour cells. Secrete cytokines such as IFN-y and TNF-a which activates phagocytes.
explain how NK cells recognize target cells
They recognize alterations in the presentations of MHC1 molecules and target-cell bound antibodies.
explain the role of complement in the innate immune system
Complement proteins are a series of proteins that are primarily produced by the liver. They circulate in plasma in an inactive form. When stimulated these proteins follow a cascade to promote an inflammatory response.
Classical Pathway
Antigen/antibody complexes - bind with C1 (C1r, C1q, and C1s). Ultimately, C1 will cleave C4 which will cleave C2 to form a complex called the C3 convertase.
Lectin Pathway
Terminal mannose CHO is expressed by bacteria and certain fungi. MBL binds to terminal mannose on the pathogen, MASP-2 cleaves C4 and C2 to form C3 convertase (C4b2a).
Alternative Pathway
Started by any foreign substance without an antibody. C3b deposition on the surface of a pathogen. C3b binds with Factor B to make the C3Bb complex. Factor D cleaves factor B in the complex, creating C3bBb. C3bBb is stabilised by properdin (factor P).
C3bBb = C3 convertase
Terminal Pathway
Beings with C3 convertase. C3 convertase cleaves C3 into C3a, and C3b. C3b binds to the cell. C5 convertase cleaves C5 into C5a, and C5b. C5b binds to the cell. C6-C9 bind to the C5b, and forms the MAC (membrane attack complex).
what happens when complement is not regulated
Uncontrolled complement activation can rapidly deplete complement components, and induce potent inflammatory responses which may damage the host. (adverse role in autoinflammatory conditions)
recurrent bacterial infections
how are host cells protected from spontaneous C3b binding?
Factor B binds to the cell surface so C3b cannot bind to the cell.
C1 inhibitor (C1INH)
A plasma protein that inhibits the first step in the classical pathway by binding to C1r and C1q, causing them to dissociate from C1s.
Regulates the alternative pathway by inhibiting the function of C3bBb.
Hereditary Angioedema is a C1 INH deficiency (results in edema)
CD55 (DAF)
Delay-accelerating factor that can bind to C4b and displace the activated C2a component. Regulates the classical and lectin pathways.
Paroxysmal nocturnal hemoglobinuria - type of anaemia.
CD59
Host cell membrane protein that binds to the C5b-C8 complex, preventing C9 polymerization and cell lysis.
Factor I
Plasma protein that cleaves C4b into C4c and C4d after C2a is displaced.
discuss the biological role of the complement components produced
• C3a
Anaphylatoxin. Induces the inflammatory response.
• C3b
Opsonin. Coats the surface of the cell or immune complexes. Enhances phagocytosis.
• C4b
Anaphylatoxin. Induces the inflammatory response.
• C5a
Chemotaxis. Attracts neutrophils and monocytes to the site of infection. Most potent anaphylatoxin.
describe the role of cytokines in the immune response
Soluble mediators of the immune response that provide cell-to-cell communication that regulates many processes.
state which cells are the primary secretors of cytokines
TH Cells, macrophages, and dendritic cells.
autocrine
Acts on the cell that secreted it.
paracrine
Acts on a nearby cell.
endocrine
Travel through the bloodstream to reach the target.
synergy
The combined effect of two cytokines is greater than that of a single cytokine.
pleiotropic
Induces different biological effects depending on the target cell.
redundancy
Two or more cytokines that mediate similar functions.
antagonism
Effects of one cytokine inhibits/antagonise the effects of the other.
cytokines that induce differentiation of distinct T-Cell lineages – TH1, TH2, TH17, Treg
TH1 (Intracellular bacteria/viruses) = IL-12: cell-mediated response
TH2 (Parasitic helminth infections) = IL-4: Humoral/Antibody response
Th17 = IL-17: Inflammatory response
cytokines that promote inflammatory responses - pro-inflammatory cytokines
IL-1, IL-6, TNF-α (endogenous pyrogens), IL-17
cytokines that affect leukocyte movement – chemokines
IL-8
cytokines that stimulate hematopoiesis (CSFs)
G-CSF: Stimulates neutrophil proliferation and differentiation
GM-CSF: Stimulates hematopoietic progenitor cells and differentiation of monocytes, neutrophils, eosinophils, and basophils.
M-CSF: Stimulates the growth of monocyte progenitor cells.
IL-1
Facilitates the immune response. Endothelial cell inflammation.
Secreted by: Macrophages, monocytes, endothelial cells, and epithelial cells.
IL-2
T Cell growth factor.
Secreted by T cells.
IL-3
Growth factor for hematopoietic cells.
Secreted by: TH cells, NK cells, mast cells.
IL-4
Promotes TH 2 cells differentiation, guided towards parasitic response.
IL-5
Stimulates B cell growth, And Ig growth.
IL-6
Synthesis of acute phase proteins influences the adaptive immunity.
Secreted by: Macrophages and endothelial cells.
IL-8
Chemokine that attracts/activates neutrophils to the site of inflammation. Helps bind neutrophils to the infection.
TGF-β
Plays a role in terminating the inflammatory response. Promotes the accumulation and proliferation of fibroblasts for tissue repair.
IL-10
Inhibits production of TH Cells and macrophage function.
Secreted by: TH2 cells, macrophages
IL-12
NK cell Activation, influences the adaptive immune system. T cell differentiation.
Secreted by: Macrophages and dendritic cells.
IL-17
Proinflammatory cytokine that promotes neutrophil migration and differentiation.
CSFs
Growth factors for hematopoiesis.
IFN-α/β
Induces an antiviral state, and increases MHC class 1 expression.
IFN-γ
Macrophage activation.
TNF-α
Inflammation regulation, and synthesis of acute phase proteins.
discuss the role of cytokine receptor chains (low/high affinity)
Cytokines-specific subunits exhibit low-affinity, and the association of both subunits results in a high-affinity receptor that can transmit a signal across the membrane when the cytokine is bound.
There are five families of cytokine receptors
Immunoglobulin superfamily receptors
Class I cytokine receptor family (hematopoietic)
Class II cytokine receptor family (interferon)
TNF receptor family
Chemokine receptor family
Signal Transduction
Receptors consist of multiple subunits. One will bind to the cytokine and another transfers a signal across the membrane to stimulate a particular cellular pathway.
Endogenous pyrogens
promote fever and the inflammatory response
Acute phase proteins
A class of proteins whose concentrations in blood plasma either increase or decrease in response to inflammation.
