L1: Innate Immunity Flashcards
List two arms of immunity. Describe in terms of specificity, peak response time, cells involved, cell receptors used, circulating molecules, soluble mediators, amplification, memory.
- ) Innate: non-specific, hours to 1-2 days, phagocytes / neutrophils / NK cells, Fc / complement / lectins / PR receptors, complement molecules, cytokines and other acute phase / inflammatory mediators, recruitment amplifies, no memory
- ) Specific: highly specific, 7-10 days to weeks, T and B cells, BCR/TCR, Igs, lymphocyte factors, clonal expansion amplifies, has memory
What are the components of innate immunity?
- ) Cell associated pattern recognition receptors (PRRs): eg. Toll-like and cytosolic receptors
- ) Cellular components: epithelial barriers, phagocytes, NK cells
- ) Soluble molecules: complement and cytokines
Classes of components that PRRs recognize?
1) PAMPs (pathogen-associated molecular patterns): ssRNA, dsRNA, flagellin, LPS/endotoxin on gram neg bacteria, lipoteichoic acid on gram pos bacteria
2) DAMPs (damage-associated molecular patterns): endogenous factors released from dying cells
What toll-like receptor recognizes LPS?
- TLR4
Where are TLRs expressed?
- Plasma membrane facing extracellular fluid – against extracellular microbes (bacterial cell wall)
- In endosome and cytosol – against intracellular microbes (DNA/RNA, peptidoglycans)
Describe response(s) caused by PAMP/TLR interactions
- ) PAMP/TLR bind – NFkB (TFs) – result: acute inflammation, stimulation of adaptive immunity
- ) PAMP/TLR bind – IRFs (TFs) – result: antiviral state
What is the inflammasome? What does generation of this cause the activation/release of?
- Inflammasome refers to the structure of an intracellular PRR called NLRP3 that when bound to pathogen, forms complex, leading to activation of caspase-1. This leads to release of IL-1beta (and IL-18) and acute inflammation
What is the effect of IL-1beta?
- Acute inflammation
What does dysregulated activation of the inflammasome cause?
- Gain-of-function mutations in inflammasome component leads to excess IL-1 production, which causes recurrent attacks of fever and localized inflammation (joints and intestines) – autoinflammatory syndromes
List and describe immunological barriers that are part of the innate immune system
- ) Mechanical: epithelial cells joined by tight junctions, flow of air or fluid, movement of mucus by cilia
- ) Chemical: fatty acids, low pH, enzymes, salivary enzymes (lysozyme), antibacterial peptides/antibiotics such as defensins/cathelicidins that are directly toxic and/or activate leukocyte response
- ) Microbiological: normal flora
- ) Cells resident in epithelium = intraepithelial lymphocytes (different to common lymphocytes)
Effect of lysozyme on pathogens
- Chews up peptidoglycans that are common to most/all bacteria
Function of phagocytic cells
- Initial step in generation of an immune response
- Required for development and maintenance of normal tissue homeostasis
List professional phagocytes
- ) PMNs/aka neutrophils
- ) Monocyte/macrophage
- ) Dendritic cells
Describe process of phagocytosis. Include mechanisms by which microbes are killed
- ) Microbe binds to phagocyte receptors (mannose, integrins, scavenger receptors)
- ) Phagocyte membrane zips up around microbe, ingested
- ) Fusion of phagosome with lysosome
- ) Activation of phagocyte
- ) Microbe killed by acidification, ROS products (most commonly superoxide o2-), NO and lysosomal enzymes
What are opsonins, what are their functions? Most common opsonins
- Soluble proteins that recognize phagocytic targets, bind and cause increased range, higher efficiency and effectiveness of phagocytosis by phagocytes
- Common opsonins: IgG and C3b
What is chronic granulomatous disease? What is the defect?
- Patients that are more susceptible to bacterial infection as a result of a defective NADPH oxidase in endosomal membranes that synthesize superoxide precursor (o2-), a specific ROS used to kill microbes
What is the most potent cytokine for activating macrophages? What cell type produces it?
- IFN-gamma
- Produced by NK and T-cells
Besides phagocytosis and killing of microbes, what are other functions of phagocytic cells?
- Inflammation (cytokines)
- Enhanced adaptive immunity (chemokines)
NK cells. Do they recognize specific antigens? What cells do they kill? How?
- Don’t recognize specific antigen
- Kills virus-infected cells and certain tumor cells. All nucleated cells express MHC class I. When virally infected or cancerous, class I MHC expression is downregulated or removed and this is recognized by NK cells via their inhibitor and activating receptors.
Is downregulation of MHC 1 sufficient for NK cells to kill cells?
- No, also require use of their activating / inhibitory receptors. One such activating receptor is the Fc receptor to see if antibody is bound to self cell via a process called ADCC: antibody-dependent cell-mediated cytotoxicity
What cytokine causes highly activated NK cells?
- IL-2
Function of IL-5/IL-13
- allergic inflammation (helminths)
Function of IL-17/IL-22
- intestinal barrier for lymphoid organogenesis
What are the innate lymphoid cells? Describe their function
- Gamma-delta T cells: less common T cells that reside in epithelial barriers
- NKT cells: characteristic of T and NK cells, express TCRs with little diversity and some of these recognize lipid antigens
Function of complement system?
- ) Punch pores causing death by osmotic lysis
- ) Opsonize antigen for promotion of phagocytosis
- ) Produce chemokines to promote inflammation and recruit lymphocytes
- ) Shuttle immune complexes out of body
What chemokines are produced in the complement cascade? Function?
- C5a and C3a
- Inflammation and recruitment of leukocytes
3 complement pathways. What activates each of these pathways?
- ) Alternative: spontaneously activated by random cleavage of C3 on microbial surfaces
- ) Classical: activated by antibody such as IgG via Clq
- ) Lectin: activated by sugars such as mannose
What is the central soluble mediator to all 3 complement pathways? Describe its use
- C3 is central
- Cleavage of C3 by C3 convertase generates C3a and C3b.
- C3a is chemokine that triggers leukocyte recruitment
- C3b is opsonin that stimulates phagocytosis
What antibodies cause activation of classical complement pathway? Is single IgM and IgG sufficient? Which antibody is most efficient at activating this pathway?
- Free antibody not sufficient. Require two IgGs:antigen appropriately space or one IgM pentamer
- IgM is more efficient than IgG
What is the MAC complex? Function?
- C5b6789 = membrane attack complex that destroys cells via pores in cell membranes that causes osmotic cell lysis
What is paroxysmal nocturnal hemoglobinuria?
- DAF and CD59 are examples of regulators of complement. DAF dissociates C3 convertases and CD59 prevents binding of C9 to complete MAC formation
- In this disorder, DAF and CD59 are lacking or defective and this leads to intravascular lysis of RBCs by complement
What is hereditary angioneurotic edema (HAE)?
- C1 inhibitor restricts spontaneous activation of C1 in plasma and regulates Hageman factor, molecule that functions in the coagulation cascade.
- HAE is a deficiency in the C1 inhibitor. As a result of emotional stress or trauma, complement is activated and bradykinins are produced. Results in edema in skin and larynx, a potentially life-threatening disorder.
Deficiency in what complement proteins leads to immune-complex diseases such as Lupus?
- C1, C2, C4
- Sometimes C3 deficiency leads to immune-complex disease
Deficiency in what proteins leads to bacterial infections mainly in childhood?
- MBL, MASP1/2, C2 and C4
Deficiency in what proteins leads to infection with pyogenic bacteria and Neisseria spp.?
- Factor D and P
- C3 deficiency leads to this, but sometimes also immune-complex disease
- C5,6,7,8,9 leads to Neisseria spp infections only
What does C5,6,7,8,9 deficiency lead to? Does it lead to pyogenic bacterial infections?
- Leads to Neisseria spp. Infections only
- Not pyogenic bacterial infections
What are cytokines? Effects?
- Proteins that affect the behavior of other cells
1. ) Local inflammation: adhesion molecules, increased permeability
2. ) Systemic protective effects: fever, acute phase proteins, leukocyte production
3. ) Systemic pathologic effects
Actions of type 1 IFNs (alpha and beta)
Secreted by virus-infected host cells:
- inhibit viral replication via paracrine action
- enhance cytolytic capability of NK cells
- increased cellular expression of class I MHC molecules
