Lecture 1: Innate Immunity Flashcards
Innate immunity
The initial response to microbes that prevents, controls and eliminates infection. It keeps you alive in the first hours and days after an infection
Barriers of innate immunity
- anatomical barriers, Primarily epithelium
- complement: antimicrobial enzymes and peptides
- pattern recognition receptors: “see pathogens” then promote the release of cytokines. Recognition of PAMP’s. activation of effector cells.
- if these steps fail, the adaptive immunity steps in
Physical barriers- skin
- epithelial tight junctions
- longitudinal flow or air or fluid
- fatty acids
- antibacterial peptides
- normal flora
Physical barriers: Gut
- epithelial right junctions
- longitudinal flow of air or fluid
- low ph
- enzymes: pepsin
- antibacterial peptides
- normal flora
Physical barriers: lungs
Epithelial tight junctions
Movement by mucous/cilia
Physical barriers: eyes/nose
Epithelial tight junctions
Salivary enzymes/lysozymes
Complement cascades
- Promotes inflammation
- Opsonizes pathogens to promote phagocytosis
- Generates pores in the cell surface- death by osmotic lysis 😈
Produces chemokines- C3a, c3b, c5a = inflammation and chemotaxis
Alternative, classical, lectins pathway
MAC
The membrane attack complex
Complement cascade
(Major components of all 3 methods)
Alternate, classical and lectin
- Binding of complement proteins to the microbial cell surface or antibody
- Formation of C3 convertase ( with all 3 systems)
- Cleavage of C3 inter C3a and C3b
- Formation of C5 convertase
- C5 is cleaved into C5b ( big piece that sticks to the surface, helps form MAC) and C5a (potent chemokine that causes inflammation)
C5a
Most potent chemokine/anaphylatoxin that attracts luekocytes to the sight of infection , also degranulation of mast cells.
More potent than C3a
C3
- Central to all the pathways
- anaphylatoxin
- most abundant chemotoxin,1mg/ml
Classical pathway
- activated by complement component C1, made up of C1q and C1r and C1s (enzymes), this is the recognition component- recognizes igM (x1) or igG (x2)
Note: there must be antibodies present that recogniZe the microbe
Lectin pathway
- Mannose binding lectin and ficolin are the recognizing compenents that recognize sugars that are present in microbe/bacteria that are not present in human cells
Alternative pathway
- a spontaneous mechanism of complement activation
Spontaneously cleavage of C3
Regulation of complement systems
Examples:
DAF= decay accelerating factor dissociates C3 convertase
- CD59 prevents binding of C9 to complete the MAC
- w/o DAF and CD59 ➡️ paroxysmal nocturnal hemoglobinuria (intravascular lysis of red blood cells by complement)
- C1 inhibitor- binds to C1 complex (no classical pathway activation) also inhibits factor XIIa and Kallikrein involved in clotting
C1 INH
C1 inhibitor: inhibits C1r and C1s for the C1 complex which is needed for classical complement pathway
Also deactivates XIIa and kallikrein needed for clotting
Emotional stress or trauma- complement activation + bradykinin production - edema in the skin and larynx - life threatening in the absence of C1 INH
C1 INH deficiency= hereditary angioneurotic edema
Deficiency in the classical pathway
Leads to a build up antibody and antigen complexes that cause massive inflammation. The classical pathway is responsible for removal of these complexes.
E.g. Lupus, C1 deficiency
Deficiency in the lepton pathway
Leads to more bacterial infection when MBL is deficient
MAC deficiency (A component of all pathways)
Leads to possible infection of neisseria species. Gonorrhoeae and n. Meningitidis
Cytokines
Proteins made by cells that affect the behavior of other cells
E.g. TNF alpha produced by an activated macrophages causes inflammation
Triggers epithelium and express adhesion molecules through out the vasculature to allow cells to leave he blood.
Pattern recognition receptors
Germline encoded Expressed by cells Recognizing molecular structures that are produced by microbial pathogens called PAMPs Pathogen associated molecular patterns Eg. LPS endotoxins on gram negative rods
Also damages and dying cells are recognized. Damage associated molecular patterns DAMPs
TLR
Toll like receptors
Most well studied if the pattern recognition receptors that bind to PAMPs
There are many types of each
TLR4 is an example that binds to LPS (a PAMP)
One of the ways the immune system
Recognizes microbes
TNF, IL-1 and IL-6
Cytokines that promote inflammation
INF alpha and beta
Interferons that promote an antiviral state.
This gene expression can Be promoted by TLRs
Opsonin
Soluble proteins that bind to microbes and are recognized by specific receptors and on phagocytosis cells
They increase the range of microbes recognized as potential pathogens
They contribute to the efficiency of target removal
Complement C3b and igG anyibodies are good examples
Phagocytosis recognition
IgG binds to microbe
Microbe with igG binds to phagocyte Fc receptor (FcR1)
Fc receptors triggers activation of the phagocyte.
Microbe gets eaten and killed
Or
C3b binds to the microbe
C3b is recognized by C3b receptors on the phagocyte
Respiratory burst
NADPH oxidase enzyme creates Super oxide species from O2 molecules
CGD chronic granulamatous disease
Defective NADPH oxidase results in susceptibility to bacterial infections
Phagocytic cell functions
Cytokines: TNF, IL-1 and IL-6 (classic pro inflammatory cytokines)
Make NO and superoxide ions
Neutrophils
Poly nuclear leukocytes- phagocytes
- bacterial infections
Eosinophils and basophils
Granulocytes
Protect against parasites
Mast cells
Release histamine, found in skin, mucosa
Innate lymphoid cells
NK cells- defend against virus and tumors aka ILC1 cells
Large granular lymphocytes. Innate cells
1. releases perforin to forms pores on target cells, granzymes then enter the cell to initiate apoptosis
- ADCC- NK cell that is bound to bad cell by antibodies that are recognized by the FC receptor on the NK cell.
NK cell cytokines
Interferon gamma- IFN-gamma activated macrophages
