Immunity to infection: Sequence and timing Flashcards
What are the steps of the immune response to infection?
Congenital immune deficiencies:
- Microbial Detection
- Innate immune response
- Autoimmune and autoinflammatory diseases - Adaptive immune response
- Memory response
What is part of the innate immune response?
- epithelia
- Phagocytes (neutrophils, macrophages, DC)
- NK cells
- . Innate lymphoid cells
What is part of adaptive immunity response?
- lymphoid tissues
- T and B lymphocytes
- Antibodies
- Cytoxic T cells response
What is part of memory response?
- T and B cells
- Quick and specific response
- Life long immunity
What are examples of extracellular pathogen niches during infection?
e.g. Staphylococcus, Streptococcus, Candida, microbiota, worms
What are examples of intracellular pathogen niches during infection?
e.g. Salmonella, Chlamydia, Legionella, Coxiella, Plasmodium, helminths
What are examples of surface adherent pathogen niches during infection?
e.g. enteropathogenic & enterohaemorrhagic E. coli
What are examples of intracellular by cytosolic pathogen niches during infection?
e.g. viruses, Listeria, Burkholderia, Mycobacterium
What are the characteristics of innate immunity?
Fast acting, first line of defence, germline encoded receptors
What are some physical barriers?
•Skin, mucous, epithelial cells
What is involved in the humoral response for innate immunity?
Complement, Lectins (collectins, ficolins), Pentraxins, Antimicrobial peptides
What cells are involved in infection for innate immunity?
•Neutrophils, Macrophages, Dendritic cells, Natural Killer (NK)-cells
What are the features in adaptive immunity?
Slower but long-lasting, variable receptors that mature over time (DNA recombination)
What is involved in the humoral response in adaptive immunity?
- Antibodies (immunoglobulins of various types)
* Complement
What cells are involved in adaptive immunity ?
•Cytotoxic T-cells, T helper cells, T regulatory cells, B lymphocytes & Plasma cells
What are the differences in innate and adaptive immunity?
- Timing of the response
- Cell types
- Receptors & ligands
- Cytokines & chemokines
- Molecular effector machineries
- Both arms of the immune system together provide sterilising immunity and long-term memory
What is the specificity like in innate immunity?
For structures shared by called of microbes (pathogen-associated molecules patterns)
What is specificity like in a adaptive immunity?
for structural detail of microbial molecules (antigens); may recognise nonmicroblal antigens
What is the number of microbial molecule recognised in innate immunity?
About 1000 molecules patterns (estimated)
What is the number of microbial molecule recognised in adaptive immunity?
> 10^7 antigens
What are the receptor like in innate immunity?
Encoded in germiline; limited diversity (pattern recognition receptors)
What are the receptor like in adaptive immunity?
Encoded by genes produced by somatic recombination of gene segments; greater diversity
What is the number and types of receptors in innate immunity?
<100 different types of invariant receptors
What is the number and types of receptors in adaptive immunity?
Only 2 types of receptors (Ig and TCR) with millions of variations of each
What is the distribution of receptors in innate immunity?
Nonclonal: Identical receptors on all cells of the same lineage
What is the distribution of receptors in a adaptive immunity?
Clonal: clones of lymphocytes with distinct specificities express different receptors
How does an immune response to infection start?
- Tissue damage
2. Detection of pathogens
What are the first responder in an immune response?
-neutrophils and macrophages
1. Neutrophils are the first to respond (short-lived, ~6 h), followed by macrophages
2, “Naïve” cells become “activated” upon interaction with microbes
3. Phagocytes control infection and limit/repair tissue damage
4. Uncontrolled activities of phagocytes is not good
5 .Granulomas
6. Excessive inflammation & inappropriate adaptive immunity
7. Tissue damage
What is the communication within the system?
- Microbial ligands - detection
- Naiive host cell - gene expression changes
- Cytokines and chemokines - signal transduction
- “activated” host cells
What are activated macrophages?
•Macrophages are tissue resident or circulatory (from bone-marrow)
•Macrophage “activation” = expression of many new genes
•Induced by microbes & cytokines
•“Alternatively” activated macrophages are anti-inflammatory
Crosstalk between macrophages & lymphocytes during infection by intracellular pathogens
What does activated macrophages display enhance?
- Phagocytosis & Migration
- Cytokine/chemokine production
- Expression of cell surface molecules
- Antimicrobial activity
- Antigen presentation & T cell activation
What is an immune response for Bacteria?
Immune response •Inflammatory cytokines •Antimicrobial genes •Metabolic genes •Immunomodulatory genes No immune response: -Resolution of inflammation
What is the immune response for fungi?
- Proinflammatory cytokines
- Antimicrobial genes
- Metabolic genes
- Immunomodulatory genes
What is the immune repose for virsus?
- Interferon production
- Proinflammatory cytokines
- Antiviral genes
- Immunomodulatory genes
What are interferons?
- Interferons are special cytokines
* They have direct antiviral activities
What are some antiviral genes?
- Nucleases
- Inhibitors of virus entry & exit
- Inhibitors of viral uncoating and replication
- Inhibitors of protein translation
- Immunomodulatory roles
- Enhanced T-cell responses
- Anti-inflammatory actions
- Tissue repair
What are some innate immune cells?
Neutrophils Macrophages Dendritic cells NK cells Complement
What are barriers for innate immunity?
epithelium, acid, commensals etc
When does innate immunity happen?
Hours – day(s)
“Non-specific” BUT different routes/cells for different pathogens
What are interleukins?
- Activate cells (via genes, transcription factors)
- Inflammation
What are interferons?
- Anti-viral cytokines
- Produced when cells infected, prevent further infection
What do chemokine do?
-Bring cells to infection areas
What are phagocytes?
-Neutrophils + macrophages
1. Detect pathogens by pathogen components (lipids etc) or cell damage
2. Activated:
Inflammatory cytokines + chemokines
3. Phagocytose pathogens + destroy them
-Reactive oxygen species (ROSs
What are NK cells?
- Kill virus-infected cells
- Activated by activating/inhibitory signals on cells
- These signals will change when cells are infected
What is complement?
- Protein cascade
- Activated by pathogens entering body
- Opsonise, lyse + neutralise pathogens
What are dendritic cells?
- Link between innate -> adaptive immunity
- Located throughout the body, e.g. skin
- Samples area
What happens when dendritic cells detect pathogens?
- Activates -> presents pathogen antigens via MHC I, II
- Moves to lymph node to activate T, B cells
When does adaptive immunity happen?
-5-7 days after infection Takes time for cells to proliferate -T cells -B cells -Pathogen-specific So, much more effective at clearing pathogen
What do T cells do?
- Cytotoxic (CD8+) and Helper (CD4+) T cells
- Helper T cells “help” activate B cells; produce cytokines
- Cytotoxic T cells kill virus infected cells
What do B cells do?
- B cells differentiate into plasma cells
- Plasma cells -> produce pathogen-specific antibodies
- These cover, neutralise + kill pathogens
Why is the death of infected cells a paradox?
- Virus-infected cells are killed by the actions of cytotoxic T lymphocytes (CTLs) or Natural Killer (NK) cells
- Cell death removes viral replicative niches
- CTLs and NK cells directly kill infected cells (contact-dependent)
- Host cells infected with intracellular bacterial pathogens also undergo forms of cell death (contact-independent)
What are soluble effector mechanisms?
- Complement mediated bacterial destruction
- Lectin-binding to neutralise cell attachment or entry
- Iron chelation (siderophores) to prevent replication
- Antibiotic-like peptides
What are cellular effector mechanisms?
- Reactive Oxygen and Nitrogen radicals
* Acidification and digestion within phagosomes
What is the summary of innate immunity to infection?
- Phagocytes are the first responders
- Phagocytes are “activated” for more effective killing of pathogens
- Inflammatory cytokines drive inflammation and adaptive immunity and interferons promote antiviral responses
- Gene expression changes are important in phagocyte activation
What do a activtaed macrophages and DCs present?
ntigens in combination with MHC-I or MHC-II to T cells
What do cytokines produced by antigen presenting cell produce?
- Cytokines produced by antigen-presenting cells produce a suitable milieu for T-cell activation
- E.g. IL-12 promotes T-cell replication
What to T cells provide?
- T cells provide cytokines that activate phagocytes
- E.g. IFNg upregulates MHC-II expression for antigen presentation
- Responses are specific to general class of pathogens
How doe T cells help B cells produce antibodies?
- Antigen presenting cell activation by infection and cytokines
- DCs, macrophages
- T cell activation by cognate MHC + foreign peptide recognition
- B cell activation for antibody production against antigen
- Antibody-mediated enhanced antimicrobial response
- Phagocytosis (opsonisation)
- Complement activation
Whats a broad classification of T cell functions?
- Phagocyte activation: enhanced killing of pathogens and inflammation
- Direct killing of infected cells: removal of replicative niches
- B cell activation: antibody production and affinity maturation
- Innate lymphoid cell/ gamma delta T cells: a type of early responders (MHC independent actions)
What is Th1?
- Defining cytokines: IFN-gamma
- Principle target cells: macrophages
- Major immune reactions: macrophage activation
- Host defence: intracellular pathogens
- Role in disease: autoimmunity; chronic inflammation
What is Th2?
- Defining cytokines: IL-4, IL-5, IL-13
- Principle target cells: Eosinophils
- Major immune reactions: Eosinophil and may cell activation; alternative macrophage activation
- Host defence: Heminths
- Role in disease: Allergy
What is Th17?
- Defining cytokines: IL-17. IL22
- Principle target cells: Neutrophils
- Major immune reactions: Neutrophil recruitment and activation
- Host defence: Extracellular bacteria and. fungi
- Role in disease: Autoimmunity and inflammation
What is a summary of. adaptive immunity to infection?
- T and B cells play special roles in adaptive immunity
- Lymphocytes rely on appropriate antigen presentation and innate immune responses
- Long-term responses rely on memory T and B cells which can be quickly activated and deployed upon subsequent exposure to the same pathogen
Whats the sequence of immune response?
- Sequential change from “resting/naive” to “activated” state
- Driven by gene expression changes driven by specific combination of cytokines
- Naïve to activated macropahge
- Differentiation of ‘precursor’ cells into specific lineages of cells
- T cells to Th1/Th2/Th17 or other types
What happens if complement defect?
Varied complement genes dysfunction
What happens in leukocyte adhesion?
Dysfunction in genes involved in migration and adhesion
What happens in chronic granulomatous disease?
Loss of reaction oxygen species production
What happens in Chediak-Higashi syndrome?
Compromised lysosomes
What happens in cytokine genes and their receptors?
Loss of cell-to-cell communication
What happens in SCID?
Severe reduction and function of T and B cells
What happens in X linked agammaaglobulinaemia?
Decrease seri, OgG of all types
What happens in HIV?
reduced CD4 helper cells
What happens in irradiation and chemotherapy (cancer treatment)?
Loss of bone marrow precursors
What happens in immunosuppression (graft rejection/chronic disease)
Depletion or impairment of lymphocytes
What is a summary of immunity to infection?
- First responders detect infection and try to control microbial growth
- Secreted effectors such as chemokines & cytokines trigger inflammation & activate cells
- Phagocytes (DCs & macrophages), as well as B cells, present antigens and activate T cells
- T cells activate B cells and together contribute to humoral and cellular immunity to infection
- Genetic and environmental factors can predispose individuals to infections
