Innate Immune System Flashcards
What components of the immune system would be beneficial in fighting an infection of bacteria or worms/helminths in epithelial surfaces (mucosa)?
- antibodies
- intraepithelial polymorphonuclear cells (PMNs) (e.g. neutrophils, phagocytes)
What components of the immune system would be beneficial in fighting an infection of bacteria, protozoa, viruses, fungi, or worms/helminths in the blood or lymphatics?
- antibodies
- PMNs
- complement system
What components of the immune system would be beneficial in fighting an infection of bacteria or mycobacteria in the vesicular part of the cell?
- T cells
- NK cells
- macrophages (phagocytes)
What components of the immune system would be beneficial in fighting an infection of bacteria, protozoa, or viruses in the cytoplasmic part of the cell?
- cytotoxic T cells (CTLs)
- NK cells
- T cells
- macrophages (phagocytes)
What are the 4 main functions of the innate immunity?
- prevents/controls/eliminates infection before engagement of adaptive immunity
- if the pathogen load is significant, the innate immunity keeps infection in check until adaptive immunity can kick it
- directs adaptive immunity toward either Ab-mediated or cell-mediated response
- eliminates host damaged cells and initiates tissue repair through: recognition (host cells that are stressed/damaged/dead), phagocytosis of cell debris, and stimulation of tissue remodeling
What are the circulating effector cells and their roles within innate immunity? (3)
- neutrophils: early phagocytosis and killing of microbes
- macrophages: effecient phagocytosis and killing, secretion of cytokines that (+) inflammation
- NK cells: lysis of infected cells, activation of macrophages
What are the circulating effector proteins and their roles within innate immunity? (3)
- complement proteins: kill microbes, opsonize microbes, activate leukocytes
- mannose-binding lectin (collectin): opsonize microbes, activates complement (lectin pw)
- C-reactive protein (pentraxin): opsonize microbes, actives complement
What are the cytokines and what are their roles within innate immunity? (6ish)
- TNF, IL-1, chemokines: inflammation
- IFN-α, -β: resistance to viral infection
- IFN-γ: macrophage activation
- IL-12: IFN-γ production by NK cells and T cells
- IL-15: proliferation of NK cells
- IL-10, TGF-β: control inflammation
What happens within the innate immunity when a host cell is infected by an extracellular pathogen?
- the host cell is activated to possibly release cytokines and/or chemokines that causes systemic effects (e.g. fever), inflammation (recruitment of immune cells and complement to infection site), and trigger adaptive immune response
- the host cell can also release anti-microbial substances (e.g. peptides, interferons)
- the host cell signals to macrophages and dendritic cells that it is infected, triggering phagocytosis and degradation by macrophage
- the dendritic cell will trigger adaptive immune response
What is the innate immune repsonse to viral infection? (2)
- type I IFN (IFN-α/β) render antiviral resistance to host cells
- NK cells kill virus infected host cells
Where do natural killer (NK) cells originate from?
- lymphoid lineage: have a T-cell precursor (different from all other cellular components of innate immunity)
How do NK cells function?
- recognize ligands on infected/stressed host cells
- kill infected/stressed host cells by inducing apoptosis
- release intracellular pathogens for phagocytosis by macrophages
- must act in concert w/ macrophages, b/c they can kill infected host cells but CANNOT produce harm to viruses
- IFN-γ primed macrophages phagocytose pathogens that have been released
How does the IFN-γ/IL-12 amplification loop work?
- macrophage with phagocytosed microbe produces IL-12
- IL-12 is pontent inducer of IFN-γ synthesis in NK cells
- the NK cell “goes off” and produces the IFN-γ that activates phagocytosis and killing of microbs by other macrophages
How do macrophages respond to IFN-γ produced by NK cells?
- the IFN-γ activates classical pathway within macrophages:
- activates phagocytosis
- increased syn of proinflammatory cytokines
- increased prod of ROS and syn of NOS
- increased prod of lysosomal enzymes
- enchanged Ag presenting properties
What 2 types of receptors do NK cells have on their surface?
- activating (KAR)
- inhibitory (KIR)
How do NK cells recognize infected/stressed cells?
- infected/stressed cells have MICA/MICB “kill me” signals on their surface
- when NK cell KAR binds with the MICA/MICB, protein tyrosine kinase (PKT) is activated
- all cells (except erythrocytes) have MHC I molecules that binds NK cells KIR and activates tyrosine phosphatase (PTP), negating the activation signal by KAR
- any disbalance in expression of MICA/MICB or MHC I molecules trigger activation in NK cells
*NK cells are not activated by antigens
How does NK cell kill infected host cells? (4 steps)
- NK releases perforins, make holes in infected cell wall
- release granzymes into hole, degrades infected cell enzymes
- infected cell dies by apoptosis
- macrophage engulfs and digests dying cell
How do viruses usually infect host cells?
receptor-mediated endocytosis
What type of cytokines do viral infected host cells release?
type I IFNs (IFN-α/β)
What occurs in the IFN-α/β autocrine feedback loop?
- viral infected host cell releases cytokines (IFN-α/β)
- IFN-α/β inhibit viral gene replication
- IFN-α/β increases expression of MHC I receptors
- viral peptides ub MHC I binding groove allow for recognition of infected cell by CTLs
- CTLs induce apoptosis
What are PAMPs and DAMPs role in a viral infection?
- PAMPs (e.g. ss-RNA) and DAMPs locally activate tissue macrophages and dendritic cells
- activated macrophages release cytokines/chemokines to create acute inflammation
- DCs engulf viruses and transport viral antigen to local lymph nodes (to activate T cells)
- viral antigens transported to lymph nodes (to activate B cells)
What is the role of cytokines and chemokines in a viral infection?
- cytokines ( TNF-α > IL-1) produ by tissue macrophages and mast cells up-regulate endothelial expression of adhesion molecules (P/E selectin, ICAM-1/VCAM-1)
- chemokines (e.g. IL-8 to neutrophils, MCP-1 to monocytes) attract cells through endothelium to site of infection
- IL-1, TNF-α, and IL-6 prod by tissue macros enter blood stream to prod systemic effects:
- fever (IL-1 > TNF-α > IL-6)
- acute phase proteins (CRP in liver) (IL-6 > IL-1 > TNF-α)
- arthralgia/myalgia (TNF-α)
What happens when dendritic cells enter the lymph node with the viral antigen?
- DCs present viral antigen to CD4+ and CD8+ T cells
- T cells that have complementary receptors to viral peptide are activated
- CD4+ cells become Th1 or Th2, CD8+ cells become CTLs
What happens when viral antigen particles are brought (via lymphatic system) back to lymph nodes?
- naive B cells are activated
- they produce low affinity/high avidity IgM antibodies
- mature B cells (by Th 2 cells) differntiate and switch prod of antibodies to high affinity IgG or IgA, with same specificity
What happens once CD8+ T lymphocytes are activated to cytotoxic T cells (CTLs)?
- CTLs leave LN and find host cells infected with virus
- they are able to find the infected cells, as they are producing the viral antigen on their surface
- CTLs kill the infected host cell by inducing apoptosis
- Th 1 cells produce IL-2 which create strong proliferation of virus-specific CTLs
- IFN-γ and IL-2 increase CTLs resistance to apoptosis (so they can keep killing ;))
Why must CTLs act in concert with macrophages?
- CTLs only kill infected cells, but do not produce harm to viruses
- macrophages prompty phagocytose released viruses from CTL killed cells, preventing infection of new host cells
What is the main cytokine that triggers macrophage phagocytosis? What cells produce it?
IFN-γ
Produced by lots of cells! NK cells, infected host cells, Th 1 cells, and CTLs
How do B cells participate in innate immunity?
- complementary activation of B cells leads to production of anti-viral antibodies that neutralize viruses, binding to their surface, and tagging them for phagocytosis
What happens to T and B cells after infection resolution?
- some will turn into memory T and B cells that reside long term in LNs, sleen, and bone marrow
- ensure long term circulation of protective virus-neutralizing antibodies
What are the local effects of IL-1, TNF-α, and IL-6 during an infection?
- endothelial cells: IL-1 and TNF increase adhesion and vascular permeability (inflammation)
- they also activate leukocytes to release IL-1, IL-6, and chemokines (inflammation)
What are the systemic protective effects of IL-1, TNF-α, and IL-6 during an infection?
- TNF, IL-1, and IL-6 act on hypothalamus in brain to cause fever
- IL-1 and IL-6 act on liver to release acute phase proteins (e.g. CRP)
- TNF, IL-1, and IL-6 act on bone marrow to increase leukocute production
What are the systemic pathologic effects of IL-1, TNF-α, and IL-6 during an infection?
- TNF reduces output of heart
- TNF creates increased permeability, could lead to thrombus
- TNF increases insulin resistance in multiple tissues
If there are 3 stages to a COVID-19 infection (asymptomatic, mild symptomatic, and severe symptomatic) what stage would cytokine storm during?
stage III: severe symptomatic
What are the clinical features of a cytokine storm? (10)
- fever
- impaired hematopoietic function
- disseminated intravascular coagulation
- decreased serum protein
- debilitating
- hyperlipidemia
- liver damage
- acute kidney injury
- anemia
- acute phase protein
When do young patients usually die during a cytokine storm happening within a COVID-19 infection?
Young patients usually die within the first 2-3 weeks due to overwhelming SIRS (systemic inflammatory response syndrome)
When do older patients usually die during a cytokine storm happening within a COVID-19 infection?
Older patients usually die after 7-8 weeks due to persistent immunosuppression and reccurent infections of compensatory anti-inflammatory response syndrome (CARS)
What is the “master switch” gene (during infection) that is central to signal transduction pathways and serves as switch for transcription of many proinflammatory genes?
NF-κB
What are the roles of following cytokines during SIRS?
TNF-α
IL-1
IL-6
IL-10, IL-1 receptor agonist, IL-4, TGF-β
TNF-α: induces shock (inhibition in experimental models did not improve shock)
IL-1: sepsis response, fever
IL-6: increases sepsis, regulates acute phase proteins
IL-10, IL-1 receptor agonist, IL-4, TGF-β: anti-inflammatory, partially responsible for CARS (late mortality due to immuno-paralysis)
Helminth/worm parasite infections are characterized by the expansion and activation of ______, ______, ____ _____ and adaptive responses of high levels of ___ antibody.
- eosinophils, basophils, mast cells
- IgE
Activation of what type of cell may lead to development of chronic funal infections?
Th 2 cell
What are the 2 main pathogenic mechanisms of extracellular bacteria?
- inflammation: causes tissue destruction at site of infection
- toxins: triggers pathological effects
- extracellular bacterial toxin
- components of bacterial cell wall that are NOT released by live bacteria
- potent activators of macrophages, DCs, and endothelial cells (prod of cytokines)
endotoxins
- extracellular bacterial toxin
- constantly produced and secreted by the bacteria
- interfere with normal functions of host cells, stimulate host cytokine production
- many of these are cytotoxic (e.g. diphtheria toxin, cholera toxin, tetanus toxin)
exotoxin
What does CRP activate when it binds to microbial polysaccharides and LPS?
classical complement pathway
What are the chemotactic mediators that signal leukocytes to cross the walls of blood vessels and migrate toward site of infection?
IL-8 (neutrophils) and MCP-1 (monocytes)
Which TLR recognize gram positive bacteria?
TLR2/TLR6
Which TLR recognize gram negative bacteria?
TLR4
How do T and B cells massively enter local lymph nodes?
- local inflammation up-regulates adhesion molecules on high endothelial venules (HEV)
- T and B cells become trapped in the local node, leading the painful/tender lymph nodes during infection
DCs present bacterial/pathogenic antigens to T cells, what affects the differentiation of T cells toward either Th1 or Th2 cells?
- Th1 cells control immune response to intracellular pathogens
- Th2 control response to extracellular pathogens (promote production of pathogen-specific antibodies by B cells)
IgM antibodies are produced during early stages of infection. They have ____ affinity and ____ avidity as they are non-specific and have multiple (10) binding sites. IgM is a potent activator of the _______ ______ that generates C3b
- low, high
- complement system
Why are C3b and antibodies crucial for opsonization?
Without an opsonin, the negatively charged cells walls of pathogen and phagocyte would repel each other, allowing pathogen to avoid destruction and continue replication
How are the innate and adaptive immunities linked?
- PRRs (e.g. TLRs) are important bridge, cause activation/maturation of antigen presenting cells (APCs)
- antigens present by APC to naive T cells
- cytokines direct development/maturation of T helper cells (Th1 or Th2)
- IL-12 directs development of Th1 for intracellular pathogens (Th1 helps CTLs)
- IL-4 directs development of Th2 for extracellular pathogens (Th2 helps B cells)
What protective mechanism is this?
- immune component: defensins, complement
- groups of pathogens: gram negative bacteria
membrane attack
What protective mechanism of immune system is this?
- immune component: neutrophils, macrophages, CR1 (C3b), FcR (IgG)
- groups of pathogens: extracellular bacteria, yeasts
opsonophagocytosis
What protective mechanism of immune system is this?
- immune component: phagolysosomes: ROS, nitric oxide
- extracellular bacteria, yeasts
intracellular killing
What protective mechanism of immune system is this?
- immune component: IgM, IgG, IgA; immune complexes
- groups of pathogens: exotoxin-producing, microbes
toxin neutralization
What protective mechanism of immune system is this?
- immune component: IgM, IgG, IgA; phagocytic cells, mucus
- groups of pathogens: respiratory and GI viruses
virus neutralization
What protective mechanism of immune system is this?
- immune component: neutrophils, macrophages
- groups of pathogens: filamentous fungi, parasites
extracellular killing
What protective mechanism of immune system is this?
- immune component: Th1 cells, NK cells, IFN-γ, nitric oxide
- groups of pathogens: obligate or facultative intracellular pathogens
macrophage-mediated intracellular killing
What protective mechanism of immune system is this?
- immune component: CD8+ T cells, MHC class I, CD4+ Th cells and IL-2
- groups of pathogens: viruses, many intracellular bacteria, fungi
cytotoxic T cell killing
What protective mechanism of immune system is this?
- immune component: eosinophils, IgE, FcεR
- groups of pathogens: intestinal parasites (helminths)
eosinophil-mediated cytotoxicity
What protective mechanism of immune system is this?
- immune component: type I interferons
- groups of pathogens: most viruses
inhibitors of intracellular respiration
What protective mechanism of immune system is this?
- immune component: NK cells MHC class I
- groups of pathogens: many viruses
NK cell-mediated cytotoxicity
What pathogens are antibodies beneficial in protecting against?
- extracellular bacteria, viruses, parasites, intracellular bacteria (minimal)
What pathogens is the complement system beneficial in protecting against?
- extracellular bacteria, viruses (enveloped), intracellular bacteria (minimal)
What pathogens are neutrophils beneficial in protecting against?
- extracellular bacteria, fungi, intracellular bacteria (only some)
What pathogens are Th2 cells beneficial in protecting against?
- extracellular bacteria, viruses, parasites
What pathogens are Th1 cells beneficial in protecting against?
- intracellular bacteria, viruses, fungi, parasites
NOT extracellular bacteria
What pathogens are macrophages beneficial in protecting against?
- everything lol
What pathogens are cytotoxic T cells beneficial in protecting against?
- viruses, intracellular bacteria
What pathogens are NK cells beneficial in protecting against?
- intracellular bacteria (cytokines), viruses (lysis), extracellular bacteria (cytokines)
