Innate immunity 1 Flashcards
4 ways to describe innate immunity
- not antigen specific
- fast
- no memory
- phylogenetically ancient
The adaptive immunity is designed to discriminate __________ while the innate immunity is designed to discriminate ___________.
- adaptive:substance A from substance B
- innate: dangerous from self
-if an innate receptor is activated, it is automatically a dangerous substance, whether it is self or nonself
What 2 main things does the innate immune system do with danger?
- try to fix the problem (kill, eat, wall off, repair)
- communicate the danger to other components of the immune system ( to other innate cells, non-immune cells, to the adaptive immune system)
Humoral vs. cellular face of innate immunity
H: cytokines, complement
C: neutrophils, macrophages, dendritic cells, NK cells, Eosinophils/basophils/mast cells..etc
Define cytokines. Give 2 broad categories of them with examples.
- Soluble factors produced by immune cells to communicate in an autocrine, paracrine, or endocrine manner
- Inflammatory: TNFa, IL-6, IL-12
- Anti-inflammatory: IL-10, TGFb
Innate vs. Adaptive immunity cytokines
- Innate: cytokines produced by macrophages and NK cells mediate the early neutrophil dominated inflammatory reactions to microbes and promote their elimination
- Adaptive: cytokines stimulate proliferation and differentiation of antigen-stimulated lymphocytes and activate specialized effector cells; important in fine tuning lymphocyte responses
Complement is a multi-component host defense system consisting of more than 35 proteins that participate in a highly regulated fashion to provide many of the effector functions of humoral immunity and inflammation. What are the 3 effector functions?
- opsonization
- lysis
- chemotaxis to recruit other immune cells
Opsonization by the complement component ______; recruitment of other inflammatory cells by complement components _________; lysis of pathogens by activation of _______.
- C3b
- C3a and C5a
- MAC:membrane attack complex
What are the 3 complement pathways that can be activated?
- classical: triggered by antibodies that bind pathogen
- alternative: “always on”, but held in check by regulatory factors
- Mannose binding lectin: triggered by mannose found on the surface of pathogens
Active _______ is the central event that turns on complement no matter which pathway is the starting point.
-C3b
The classical pathway is activated by _________ which turns on C1a which does what? Describe the rest of the cascade.
- surface bound IgM which turns on C1a
- C1a cleaves C4 to active C4b which cleaves C2 to active C2b. C4b2b cleaves C3 to make C3b which initiates activation of the rest of the cascade
- eventually reach C9 and drill pore into cell
The alternative pathway works because C3 is constantly being cleaved into C3b by hydrolysis. Normally this C3b is ___________. What happens, though, int he presence of bacteria or other pathogens?
- inconsequential because it is inhibited by factors found on our own cells
- in presence of bacteria or other pathogens, this C3b can bind to their surface and in combination with Factor B can initiate the complement case of C5-C9
What needs are bypassed by the alternative pathway of complement activation?
-surface antibody and the C1,4,2 steps
Mannose Binding Lectin (MBL) binds to ______, a carbohydrate found on the surface of pathogens and in combination with __________ which when organized into multimolecular complex can cause what?
- mannose
- Mannan-binding lectin Associated Serine Proteases which cleave C4 and C2 and activate complement in manner identical to classical pathway except no antibody binding occurs
Opsonization as a result of complement activation
- complement receptors bind to complement fragments to enhave phagocytosis
- coat with C3b
Osmotic lysis
- outcome of complement activation
- membrane attack complex (MAC) punches holes in bacterial membrane, allowing extracellular fluid in and osmotic lysis
Chemotaxis
- outcome of complement activation
- C3a, C4a, and C5a are potent signals calling for the influx of neutrophils and macrophages
MBL works in conjunction with ________ to activate complement pathway.
-MASPs
Pros and cons of complement pathway
- positive amplification via cascading of proteins allows for rapid amplification of a small signal
- need a lot of control; negative regulation via a number of mechanisms
2 main ways complement activation is regulated
- complement activation is localized due to the covalent binding of activated complement proteins to surfaces; complement only works when it becomes surface bound; therefore, the availability of surface limits complement activation–only when pathogen surfaces are present
- our own cell surfaces are filled with molecules that inhibit complement–so if it binds out own cells, it is inactivated
Neutrophils aka ________. How long do they take to develop? What drives their production?
- polymorphonuclear cells or granulocytes (PMNs)
- 14 days to develop in BM and 6 hr half life in peripheral blood
- Cytokine G-CSF drives their production
________ are the first line of innate defense.
-neutrophils
Neutrophils come from bone marrow precursors. So when the BM is revved up and trying to spit out neutrophils, immature neutrophils called ________ are sometimes seen in the blood. What can their presence signify?
- band cells
- since infections often result in an attempt to make more neutrophils, the presence of bands often signifies infection
In the olden times, having a lot of band cells in one’s blood smear would be stated has being ______ shifted.
-left
Neutrophil granules
-granules filled with toxin (ROS, proteases, etc)
Role of neutrophils, but why this is also bad.
- phagocytose viruses, bacteria, fungi within the tissues
- first line defense in infection and very effective, but also very toxic and result in tissue damage which is why it is nice to have an adaptive immune system for a more surgical strike
There are many different receptors for phagocytosis, all of which get the pathogen into the cell where it will ultimately end up in a __________ where what happens?
- phagolysosome
- ROS (bleach) and NO will kill the pathogen
3 general killing pathways of neutrophils
- Oxygen independent: granule contents
- Oxygen dependent: MPO independent
- Oxygen dependent: MPO dependent (myeloperoxidase-ROS)
Functions and origin of macrophages
- arise from monocytes in the peripheral blood
- primarily function to eat: pathogens, damaged tissue, dead cells
- produce cytokines and can present antigen to T-cells
- phagocytosis, cytokine production, APC
Macrophage receptors to respond to pathogen
-CD14 and TLR-4
Dendritic cell function
- like macrophages, these cells eat their surroundings
- however, these cells are uniquely poised to present antigen efficiently** main role is to sample antigen in peripheral surroundings to present to T cell in LN
- high levels of MHC I and II
- produce cytokines that are good at activating T cells
Natural Killer (NK) cells
- lymphoid derived, but still innate cell type
- mediate cell death via release of toxic granules
- kill cells that lack MHC I
- large producer of cytokines IFNy
Do NK cells have antigen receptors?
-No, remember their main role is to kill cells lacking MHCI
What types of cells lack MHC I?
- virally infected cells
- malignant cells
NK cell activation
- NK cells have sets of activating and inhibitory receptors that balance eachother out and result in the NK cell remaining quiet
- inhibitory receptors are normally turned on my MHC I, but when it is missing, only activating R are on and without the counterbalancing inhibiting R, the NK cells carries out effector action of killing the cell
Do NK cells kill viruses directly?
-no, just the cells they invade
Difference between eosinophils and neutrophils
-similar size but E have larger and orange granules, fewer lobes, and much less frequent
Eosinophils are important for what immune responses?
- parasitic infections
- allergies
3 major types of mediators in eosinophils
- granule components (MBP)
- cytokines
- eicosanoids
What is the least common cell in the blood?
-basophils
3 major types of mediators of basophils
- lipids: LTC4
- cytokines: IL4, IL13
- Granule components: histamine, proteases, etc
