Innate Host Responses Flashcards
Cellular components of innate responses
- Phagocytes
- Cells of the Monocyte-Macrophage Lineage
- Immature Dendritic Cells
- Dendritic Cells
- Natural Killer, γ / δ T Cells, and NKT Cells
3 lines of protection from microbial world
- Natural barriers
- Innate, antigen-nonspecific immune defenses
- Adaptive, antigen-specific immune responses
Natural barrier examples
- Skin
- Mucosal surfaces
- Stomach acid
Soluble innate components
- Complement components
- Type 1 interferons
Cellular innate components
- Phagocytes
- Monocytes
- Macrophages
Neutrophils have a major role in
- Antibacterial and antifungal protection
- Lesser role in antiviral protection
Phagocyte (neutrophils) features
- Reptors to bind microbes
- Granules
- Terminally differentiated cells
- Component of “pus” at the site of infection
Phagocyte (neutrophil) life span
- Spend less than 3 days in the blood
- Die rapidly in tissue
Macrophages mature from
- Monocytes
Macrophage similarities to neutrophils
- Opsonin receptors to promote phagocytosis
- Receptors for PAMPS to initiate activation
- Cytokine receptors to promote activation
- Express MHC II proteins
Macrophages differences from neutrophils
- Live longer and can divide
- Must be activated to kill phagocytosed microbes
- Remain at site of infection or inflammation
M1 macrophages
- Classical Activation” – mediated by IFN-γ produced by NK cells and CD4 and CD8 T cells
- Part of TH1 response
- Able to kill phagocytosed bacteria
- Produce cytokines and enzymes
- Reinforce local inflammation by producing cytokines
- Activation makes them more efficient to kill
M2 macrophages
- “Alternatively Activated” by cytokines IL-4 and IL-13
- Part of the TH2 response
- Anti-parasitic responses
- Wound repair
M2 macrophages form
- Granulomas to surround chronic infections such as unresolved mycobacterial infections
- Macrophages fuse to become multinucleated giant cells and enlarge to become epitheloid cells
Effects of binding & ingestion of microbes by monocytes and macrophages
- Promote the release of interleukin-1 (IL-1), IL-12, and tumor necrosis factor (TNF), which initiate inflammatory reactions
IFN-γ made by NK or T cells activates
- Killing mechanisms in macrophage
- Creating “activated macrophage”
Activation of the macrophages makes them more efficient killers of
- Phagocytosed microbes
- Virally infected cells
- Tumor cells
Immature dendritic and dendritic cells
- Bridge between innate and the adaptive immune responses
- Octopus-like arms (dendrites)
- Antigen-sticky cell surface
- Produce cytokines
- Present antigen to T and B Cells
Protein antigens of microbes that enter the body are captured mainly by
- Dendritic cells
- Concentrated in the peripheral lymphoid organs, where immune responses are initiated
Microbes enter the body through
- Skin by contact
- Gastrointestinal tract by ingestion
- Respiratory tract by inhalation
Interfaces between the body and external environment are lined by
- Continuous epithelia
- Function is to provide a physical barrier to infection
Toll-like receptors (TLRs)
- Cell surface and endosomal receptors
- Pattern recognition receptors for many different pathogen-associated molecular patterns
Pathogen-associated molecular patterns (PAMPs) for TLRs
- LPS
- Peptidoglycan
- Fungal glycans
- Microbial nucleic acids
TLRs are linked to
- Signal transduction pathways
- Activate genes that promote inflammation
TLRs sense the presence of microbial infection by
- Binding to these characteristic patterns within molecules on the outside of bacteria, fungi and viruses
Immature dendritic cells located in
- Blood and tissue
- Provide early cytokine-mediated warning system
Cytokine mediated warning system of iDCs
- Cytokine-secreted proteins that function as mediators of immune and inflammatory responses
Types of immature dendritic cells
- Langerhans cells in the skin
- Dermal interstitial cells
- Interdigitating cells (lymph node and spleen)
- Splenic marginal DCs
iDCs present antigen to
- T cells on MHC I and MHC II molecules
iDCs constantly acquiring antigenic material by
- Macropinocytosis, pinocytosis, or phagocytosis of apoptotic cells, debris, and proteins in normal tissue and at sites of infection or tumor
Upon activation of the iDC by a TLR cascade in response to infection
- The iDC matures into a DC and its role changes
TH1 function
- First, early local response
TH1 inducer
- IL12 by D
TH1 mediator
- INF-gamma
- IL-2
TH1 response
- Cellular, inflammatory reactions
TH1 targets
- Intracellular viral, bacterial, fungal, parasitic infections
- Tumors
TH2 function
- 2nd to TH1
- Later, systemic
TH2 inducer
- IL4
TH2 mediators
- IL-4
- IL-5
- IL-6
- IL-10
TH2 response
- Humoral (antibody)
TH2 targets
- Blood borne microbes
- Some viruses
- Most bacteria
Mature activated dendritic cells lose
- Ability to phagocytize, preventing it from acquiring irrelevant antigenic material other than the microbial debris
- Adhesiveness for epithelia
Mature activated dendritic cells express
- Surface receptor specific for chemoattractant cytokines produced in T cell areas of the lymph node
Mature activated dendritic cells progress to
- T cell areas of the lymph node
- Trigger the response to the microbial challenge
Mature activated dendritic cells upregulate
- Class II MHC molecules for antigen presentation
DCs present antigenic material attached to MHC class I and CD1 molecules to
- CD8 T and NKT cells
DCs present antigenic material attached to MHC class II molecules to
- CD4 T cells
Natural killer cells
- Large granular lymphocytes
- Share characteristics with T cells
- Target cell recognition different from T cells
Natural killer cells are stimulated by
- IFN-α and IFN-β - produced early in response to viral and other infections
- TNF-α
- IL-12, IL-15, and IL-18 - produced by pre-DCs and activated macrophages
- IL-2 - produced by CD4 TH1 cells
NK cells express
- CD2, CD7, IL-2 receptor and Fas ligand
- Fc receptor for IgG (CD16)
NK cells complement receptors for
- ADCC
Activated NK cells produce
- IFN-γ
- IL-1
- Granulocyte-macrophage colony-stimulating factor (GM-CSF)
Cytokines reinforce local initial protective responses (TH1) by
- Encouraging the production of IL-12 by pre-DCs and activated macrophages
NK cells characteristics different from T cells
- Do not express a TCR or CD3
- Cannot produce IL-2
- Do not recognize a specific antigen
- Do not require presentation of antigen by MHC molecules
- NK system does not involve memory
- Cannot be enhanced by specific immunization
Process of NK cells killing cells
- See every cell as potential victim
- Cells that appear in distress are targeted
- Class I MHC on target cell interacts with KIR inibitory receptor on NK cells
- If all is normal with the target cell (then it provides an inhibitory signal to prevent killing)
- “stress related receptors” – expressed by virally infected cells and tumor cells as signal (often depleted of Class I MHC – become NK target)
Granules in an NK cell contain perforin and granzymes
- A pore-forming protein and esterases
- Similar to the contents of the granules of a CD8 cytotoxic T lymphocyte (CTL)
ADCC binding of NK cell to antibody-coated target cells
- Also initiates killing
Apoptosis
- Process of cell death triggered by interaction of FasL on the NK cell with Fas protein on target cell
NKT cells and γ / δ T cells reside in
- Tissue and blood
- Differ from other T cells because they have a limited repertoire of T-cell receptors
- Produce IFN- γ - which activates macrophages and DCs to enforce a TH1 response
NKT cells and γ / δ T cells are unlike other T cells because
- Able to sense non-peptide antigens
- Glycolipids of mycobacteria
- Phosphorylated amine metabolites from some bacteria
Bacteria activate
- Innate protective response
- Inflammatory responses well
Bacterial cell wall components
- Teichoic acid
- Peptidoglycan
- Lipopolysaccharide (LPS)
Bacterial cell walls contain
- Repetitive structures easily recognized
- PAMP receptors
- Toll-like receptors (TLRs)
- Strong activators of DCs, macrophages
Inflammasome
- Multiprotein complex present in epithelial cells, DCs, and macrophages
Inflammasomes activated by
- Several proteins induced by response to the PAMPS, tissue damage or indications of intracellular infection
Activated inflammasome can initiate
- Apotosis-like cell death for cells with intracellular infections
Chemokines
- Cytokines that stimulate leukocyte movement & regulate the migration of leukocytes from blood to tissues
Chemotaxis
- Movement of a cell directed by a chemical concentration gradient
Neutrophils respond to
- Inflammatory signals
- C3a, C5a, TNF-α
Diapedesis
- Process by which PMNs extravasate the capillary wall to the site of inflammation
Phagocytic responses
- PMNs, monocytes: 1st responders at site of infection, macrophages follow later
- Provide a major antibacterial response
- Contribution to inflammation
Bacterial infection indicated by
- Increased number of neutrophils (“polys”) in the blood, body fluids (cerebrospinal fluid), or tissue
Left shift
- Accompanies mobilization of neutrophils
- An increase in the number of immature band forms released from the bone marrow
Phagocytosis of bacteria by macrophages and neutrophils involves 3 steps:
- Attachment
- Internalization
- Digestion
Attachment step of phagocytosis
- Macrophages - mediated by receptors for bacterial carbohydrates receptors for opsonins - C3b, mannose-binding protein, Fc portion of antibody
Internalization step of phagocytosis
- A section of plasma membrane surrounds the particle to form a phagocytic vacuole around the microbe
Digestion step of phagocytosis
- Vacuole fuses with the primary lysosomes (macrophages) or granules (PMNs) to allow inactivation and digestion of the vacuole contents
Activation of macrophages promoted best by
- IFN – γ, also by TNF-α
- Activation required for killing
2 mechanisms of killing bacteria
- Oxygen dependent or oxygen independent
- Depends on the antimicrobial chemicals produced by the granules
Oxygen dependent mechanism of killing bacteria
- Powerful oxidative burst
- Formation of H2O2
neutrophil - Myeloperoxidase transforms chloride ions into hypochlorus ions to kill
Oxygen independent mechanism of killing bacteria
- Fusion of the phagosome with azurophilic granules containing cationic proteins (cathepsin G) & specific granules containing lysozyme and lactoferrin
- Proteins kill gram-negative bacteria by disrupting their cell membrane integrity
- Far less effective against gram-positive bacteria, killed principally through the oxygen-dependent mechanism
Neutrophils contribute to inflammation response in several ways
- Prostaglandins and leukotrienes, which increase vascular permeability, are released, causing swelling (edema) and stimulating pain receptors
- During phagocytosis the granules may leak their contents to cause tissue damage
- Neutrophils have short lives and become pus
Innate responses are constantly stimulated by
- Normal flora of the skin, nose, mouth, urogenital and GI tracts
PAMPRs on the intestine “see” the LPS, LTA, flagella, and other components of
- Bacteria of the gut lumen
- An equilibrium is maintained between the innate response & immunoregulatory responses & the microbes
Disruption of the established equilibrium between innate and immunoregulatory responses can occur by
- Altering the species with antimicrobial treatment or disruption of the innate response
- Can result in inflammatory bowel disease, autoimmune disease or gastroenteritis
LPS & other bacterial cell wall components stimulate immature DCs & macrophages to release
- Interleukins IL-1, IL-6
- TNF-α (cachetin)
- Chemokines
Endogenous pyrogens
- Released from macrophages in response to bacterial cell wall components
- Promote fever production & enhance the inflammatory response
- Causes further activation of macrophages, promoting acute phase response
Acute-phase response
- Occurs as part of the innate response to infections
- Proteins are synthesized by the liver (C-reactive protein, fibrinogen) in response to inflammatory cytokines, especially IL-6 and TNF-α (C-reactive protein, fibrinogen)
Acute phase response promotes changes that support host defenses
- Fever
- Anorexia
- Sleepiness
- Metabolic changes
- Production of proteins
Acute phase proteins
- C-reactive protein
- Complement components
- Coagulation proteins
- LPS-binding proteins
- Protease inhibitors
- Adherence proteins
C-reactive protein (CRP)
- Complexes with the polysaccharides of bacteria & fungi
- Activates the complement pathway
Acute-phase proteins reinforce
- Innate defenses against infection
- But excessive production during sepsis can cause serious problems, such as shock
Acute inflammation
- Early defense mechanism to contain an infection, prevent its spread, & signal subsequent specific immune responses
3 major events of acute inflammation
- Expansion of capillaries to increase blood flow (redness or a rash, releasing heat)
- Increase in permeability of microvasculature to allow escape of fluid, plasma proteins, & leukocytes from the circulation (swelling or edema)
- Recruitment of neutrophils & their accumulation & response to infection at the site of injury
Cytokine storm
- Overwhelming release of cytokines in response to bacterial cell wall components, toxic shock toxins, and viremia
Vascular leakage of fluids into tissue
- Causes shock
Septic shock
- Form of cytokine storm caused by systemic action of large amounts of TNF-a
Bridge to antigen-specific responses
- Innate response is often adequate to control an infection
- An infection can also stimulate antigen-specific immunity
- Dendritic cells are the key to the transition and determine the nature of the next response
