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Flashcards in L1: Innate Immunity Deck (38):

List two arms of immunity. Describe in terms of specificity, peak response time, cells involved, cell receptors used, circulating molecules, soluble mediators, amplification, memory.

1.) 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
2.) 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?

1.) Cell associated pattern recognition receptors (PRRs): eg. Toll-like and cytosolic receptors
2.) Cellular components: epithelial barriers, phagocytes, NK cells
3.) 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

1.) PAMP/TLR bind – NFkB (TFs) – result: acute inflammation, stimulation of adaptive immunity
2.) 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

1.) Mechanical: epithelial cells joined by tight junctions, flow of air or fluid, movement of mucus by cilia
2.) 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
3.) Microbiological: normal flora
4.) 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

1.) PMNs/aka neutrophils
2.) Monocyte/macrophage
3.) Dendritic cells


Describe process of phagocytosis. Include mechanisms by which microbes are killed

1.) Microbe binds to phagocyte receptors (mannose, integrins, scavenger receptors)
2.) Phagocyte membrane zips up around microbe, ingested
3.) Fusion of phagosome with lysosome
4.) Activation of phagocyte
5.) 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?

1.) Punch pores causing death by osmotic lysis
2.) Opsonize antigen for promotion of phagocytosis
3.) Produce chemokines to promote inflammation and recruit lymphocytes
4.) 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?

1.) Alternative: spontaneously activated by random cleavage of C3 on microbial surfaces
2.) Classical: activated by antibody such as IgG via Clq
3.) 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