Immune Response To Infection Flashcards
What are the 4 different pathogen niches during infection?
- Extracellular e.g. Staphylococcus, Streptococcus, Candida, microbiota, worms
- Surface adherent e.g. enteropathogenic & enterohaemorrhagic E. coli
- Intracellular vacuolar (that occupy specialised compartment in host cell e.g. modified lysosome or ER) e.g. Salmonella, Chlamydia, Legionella, Coxiella, Plasmodium
- Intracellular cytosolic e.g. viruses, Listeria, Bukholderia, Mycobacterium
How does an immune response to an infection start
- Tissue damage (e.g. injury or by toxins produced by infectious agent)
- Molecular detection of microbes- wrong thing in wrong place at wrong time
- Then, intercellular communication happens e.g. interleukins
- This leads to priming of the adaptive immune response
How does an immune response to infection end
- Clearing infection
- Stopping inflammatory cytokine production- more production of these can lead to tissue damage
- Repairing tissue damage
- Remembering the infection- immune memory
What are the 3 broad differences between innate and adaptive immunity?
Innate:
Fast acting
First line of defence
Germline encoded receptors
Adaptive:
Slower but long lasting
Variable receptors that mature over time
Also innate provides physical barriers whereas adaptive doesn’t.
Physical barriers provided by innate immunity
Skin,mucous,epithelial cells
Is complement part of innate or adaptive
Both
What are the key cellular components of innate immunity?
Neutrophils, macrophages, dendritic cells and natural killer (NK) cells
What are the key cellular components of adaptive immunity?
Cytotoxic T-cells, T helper cells, T regulatory cells, B lymphocytes and plasma cells
What is the difference in specificity between innate and adaptive?
Innate is less specific than adaptive as innate detects broad classes of pathogens via PAMPs (e.g. cell membrane components such as peptidoglycan) whereas adaptive can detect structural detail of antigens and may even recognise non-microbial antigens
Why is there greater diversity in adaptive immune receptors in comparison to innate immune receptors
Adaptive immune receptors are encoded by genes produced by somatic recombination hence they produce TCRs and Ig’s that have millions of different variations
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List the general sequence of molecular and cellular events of an immune response?
Microbial molecules detected
Naïve host-cells are changed - gene expression leads to their activation
Production of antimicrobial molecules which send communication signals to alert neighbouring cells
Leads to the production of activated and specialised host cells
First responders to site of injury
Neutrophils are short lived~6 hours
Followed by monocytes that differentiate to become macrophages
Uncontrolled activity can lead to granulomas,excessive inflammation and tissue damage
How do phagocytes and other immune cells identify the class of pathogen?
Bacteria- typically cell wall components like LPS in E. coli
How does live vs dead bacteria elicit different immune responses?
- Live E. coli elicits immune response-
- inflammatory cytokines produced (e.g. IL-1beta that’s responsible for fever)
- antimicrobial genes (that are directly toxic to bacteria)
- metabolic genes (that help macrophage cope with these high, demanding jobs)
- immunomodulatory genes (so that adaptive immune system appropriately primed)
- Dead E. coli results in no immune response- macrophage tries to resolve inflammation rather than causing more
- Live E. coli elicits immune response-
Cell surface molecules unique to fungi
Beta glucans
What type of immune response do fungi produce
- Different kind of proinflammatory cytokines
- Antimicrobial genes
- Metabolic genes
- Immunomodulatory genes
What type of immune response do viruses produce?
- Interferon production that interfere with viral replication
- Proinflammatory cytokines
- Antiviral genes
- ## Immunomodulatory genes
What do activated macrophages display
Phagocytosis and migration
Cytokine/chemokine production
Expression of cell surface molecules
Antimicrobial activity
Antigen presentation and T cell activation
What are interferons
Are special cytokines
Have direct antiviral activities
Detects viruses and gram negative intracellular bacteria
3 types of interferons
Type I-IFN alpha/beta
Promotes antiviral response
Every primary infected cell can produce type I IFN
TypeII-IFN gamma
Only produced by lymphocytes
Promotes antibacterial immunity
Type III-lambda
Only produced at epithelial surfaces
Promote antiviral responses
What are the immunomodulatory roles of IFNs?
- Enhanced T-cell responses
- Anti-inflammatory actions
- Tissue repair
How are virus infected cells killed
Cytotoxic T lymphocytes or natural killer cells
2 anti microbial enzymes that are produced by a cytokine binding to a cytokine receptor
Phagocyte oxidase which produces reactive oxygen species
Inducibke nitric oxide synthase produces nitric oxide
What are the soluble effector mechanisms of innate immunity?
- Complement mediated bacterial destruction
- Lectin-binding to neutralise cell attachment or entry
- Iron chelation (siderophores) to prevent replication
- Antibiotic-like peptides
What are the cellular effector mechanisms of innate immunity?
- Reactive oxygen and nitrogen radicals made by phagocyte oxidase and iNOS respectively- these genes never present in naive cells- only expressed when pathogen encountered
- ## Acidification and digestion within phagosomes
How are T cells activated
Activated macrophages and DCs present antigens in combination with MHC I and MHC II
Cytokines produced by apc produce suitable millieu for T cell activation eg IL12 promotes T cell replication
T cells provide cytokines that activate phagocytes eg IFN gamma upregulates MHC II expression for antigen presentation
How are dendritic cells better able to respond to viral infections than macrophages?
Produce type I IFN
How do T cells help B cells produce antibodies?
- APCs become activated by infection and cytokines and present antigen to T cell which becomes activated to Th cell
- Th cell helps activate the B cell with the correct BCR which produces antibodies against original antigen
What are the 2 main T cell types?
- Th1 cell (CD4 T cell) produced during bacterial infections that produce IFN-gamma and other cytokines that promote inflammation, phagocytosis and killing of microbes
- Tc cell (CD8 T cell) produced during viral infections and will directly kill virus infected cells leading to apoptosis of the host cell, removing viral replicating niches
What are some T cell functions
- Phagocyte activation- T cell derived cytokines activate phagocytes which leads to enhanced killing of pathogens and more inflammation
- Direct killing of infected cells- removal of replicative niches
- B cell activation- antibody production and affinity maturation
- Innate lymphoid cells (aka gamma delta T cells)- reside in mucosal surfaces and are a type of early responders to infection (act independently to MHC)
Impact of age
Immune response gets weaker due to reduced thymic output
What kind of genetic dysfunction leads to chronic granulomatous disease?
Loss of reactive oxygen soecies
What genetic dysfunction leads to chediak higashi syndrome
Compromised lysosomes
What genetic dysfunction is in immunosuppresion
Depletion/impairment of lymphocytes
What kind of genetic dysfunction is present in HIV
Reduced CD4 T helper cells
genetic dysfunction in the genes controlling what leads Severe Combined Immunodeficiency (SCID)?
Reduction of T and B cells
What genetic disfunction leads to X-linked aggamaglobulinaemia?
Decreased serum IgG of all types
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To which pathogens are Th17 made?
Fungi
Extracellular bacteria
To which pathogens are Th1 made
Bacteria
Protozoa
To which pathogens are Th2 made
Helminths
Allergens
Venom
Intracellular pathogens
Macrophages are activated causing release of interferon gamma which causes T cells to differentiate into Th1
Excessive can cause autoimmunity and chronic inflammation
Helminths
Causes mast cells and eosinophils to be activated which causes lease of IL-4,IL-5, IL-13. This causes T cells to differentiate into Th2
Excessive can cause allergy
Extracellular bacteria and fungi
Causes neutrophil activation which causes release of IL-17 and IL-22. This causes T cells to differentiate into Th17
PAMPs vs DAMPs
PAMPs are released by pathogens and are conserved structures eg bacteira have lps,fungi have beta glucan cell walls,viruses have surface glycoprotein
DAMPs are released by distressed or dying tissues recognized by ato released from dead cells,alarmins and some cytokines
Apoptosis vs pyroptosis
Caspase 8,9,3,6,7
Caspase 1,4,5 for pyroptosis
Phagocyte and T cell response
Intracellular pathogens cause macrophages to be activated causing release of IFN-gamma. Thus causes T cells to differentiate into Th1 cells. If left for too long it can cause autoimmune disease and chronic inflammation
Helminths activate eosinophils causing release of IL-4,5,13 which causes T cells to differentiate into Th2 cells. If left for too long ca cause allergy
Extracellular bacteria and fungi activate neutrophils to release IL-17,22 which activates Th17. If left for too long it causes autoimmunity and inflammation
