Immunology - Immune Response to Infection Flashcards
Phagocytes
Internalize pathogens and degrade them
Lymphocytes (B and T cells)
Have receptors that recognize specific molecular components of pathogens and have specialized functions
B cells
make antibodies (effective against extracellular pathogens)
Cytotoxic T lymphocytes (CTLs)
kill virally infected cells
Helper T cells
coordinate the immune response by direct cell-cell interactions and the release of cytokines
Cell + soluble mediator - leukocytes (lymphocytes)
B cell -> antibodies
T-cell + large granular lymphocyte (LGL) -> cytokines
Cell + soluble mediator - leukocytes (phagocytes)
mononuclear phagocyte -> complement and cytokines
neutrophil
eosinophil
Cell + soluble mediator - leukocytes (auxiliary cells)
basophil -> inflammatory mediators
Cell + soluble mediator - auxiliary cells
mast cells + platelets -> inflammatory mediators
Cell + soluble mediator - other cells
tissue cells -> interferons + cytokines
Specificity and memory
Essential feature of adaptive immune responses, B&T lymphocytes mount a more effective response on second and subsequent encounters with a particular antigen, non-adaptive (innate) immune responses (mediated for example by complement, phagocytes, and NK cells) do not alter on repeated exposure to infectious agent
Antigens
molecules that are recognized by receptors on lymphocytes
B cells antigen recognition
usually intact antigen molecules
T cells antigen recognition
antigen fragments displayed on the surface of dendritic cells
Immune response 2 phases
antigen recognition and antigen eradication
Antigen recognition
clonal selection involves recognition of antigen by particular clones of lymphocytes leading to clonal expansion of specific clones of T and B cells and differentiation to effector and memory cells
Antigen eradication
effector phase, specific T and B cells coordinate an immune response which eliminates the antigen source
Pathogen niches during infection
extracellular (ie staphylococccus, streptococcus, candida, microbiota, worms), intracellular vacuolar (ie salmonella, chlamydia, legionella, coxiella, plasmodium), surface adherent (ie enteropathogenic and enterohaemorrhagic E. coli), intracellular cytosolic (ie viruses, listeria, burkholderia, mycobacterium)
How does an immune response to infection start?
tissue damage (ie injury), molecular detection of microbes, inter-cellular communication (ie interleukins), priming the adaptive immune response
How does an immune response to an infection end?
Clearing infection, stopping inflammatory cytokine production, repairing tissue damage, immune memory
Innate immunity - general
Fast acting, first line of defence, germline encoded receptors
Innate immunity - physical barriers
Skin, mucous, epithelial cells
Innate immunity - humoral
complement, lectins (collectins, ficolins, detect carbohydrates), pentraxins, antimicrobial peptides
Innate immunity - cellular
neutrophils, macrophages, dendritic cells, NK cells
Adaptive immunity - general
slower but long-lasting, variable receptors that mature over time (DNA recombination)
Adaptive immunity - humoral
antibodies (immunoglobulins of various types), complement
Adaptive immunity - cellular
cytotoxic T-cells, T helper cells, T regulatory cells, B lymphocytes and plasma cells
Specificity - Innate vs Adaptive Immunity
INNATE: for structures shared by classes of microbes (Pathogen Associated Molecular Patterns), identical toll-like receptors
ADAPTIVE: for structural detail of microbial molecules (antigens), may recognize non-microbial antigens, distinct antigen-specific antibodies
Number of microbial molecules recognized - Innate vs Adaptive Immunity
INNATE: about 1000 PAMPs (Pathogen Associated Molecular Patterns)
ADAPTIVE: > 10^7 antigens
Receptors - Innate vs Adaptive Immunity
INNATE: encoded in germline = limited diversity (pattern recognition receptors; toll-like receptors, N-Formyl methionyl receptor, mannose receptor, scavenger receptor)
ADAPTIVE: encoded by genes produced by somatic recombination of gene segments = greater diversity (Ig (immunoglobulin), TCR (T-cell receptor))
Number and types of receptors - Innate vs Adaptive Immunity
INNATE: <100 different types of invariant receptor
ADAPTIVE: only 2 types of receptors (Ig and TCR) with millions of variants of each
Distribution of receptors - Innate vs Adaptive Immunity
INNATE: nonclonal (identical receptors on all cells of same lineage)
ADAPTIVE: clonal (clones of lymphocytes with distinct specificities express different receptors)
General differences - Innate vs Adaptive Immunity
response timing, cell types, receptors and ligands, cytokines and chemokines, molecular effector machineries
Common aspects - Innate vs Adaptive Immunity
Together provide sterilizing immunity and long-term immunity
Immune response mechanism
- Microbial molecules — detection by ligands or activities—> naïve host cells (T-cells, undergo fine-tuning by dendritic cells (DC) into CD4/CD8) —gene expression changes—> antimicrobial molecules communication signals (interleukins, chemokines, interferons…) —signal transduction—> activated host cells (fight and tell others)
- general principle: sequence of molecular and cellular events and crosstalk
First responders: neutrophils
Short-lived (~6hrs), followed by macrophages, naïve cells become activated upon interaction with microbes
First responders: phagocytes
Control infection and limit/repair tissue damage, uncontrolled activity = granulomas, excessive inflammation and inappropriate adaptive immunity, tissue damage
Pathogen-specific phagocyte responses: bacteria
PHAGOCYTOSIS OF LIVE BACTERIA: bacterial mRNA released resulting in immune response (inflammatory cytokines, mature IL-1ß released, antimicrobial genes, metabolic genes, immunomodulatory genes)
PHAGOCYTOSIS OF DEAD BACTERIA: no bacterial mRNA released, so no immune response and resolution of inflammation
Pathogen-specific phagocyte responses: fungi
Clustering of dentin 1, exclusion of phosphatases, phagocytosis and production of pro-inflammatory cytokines and reactive oxygen species, antimicrobial + metabolic + immunomodulatory genes
Pathogen-specific phagocyte responses: viruses
Entry, uncoating, reverse transcription (RNA, ssDNA, dsDNA), interferon production, pro inflammatory citokines, antiviral genes, immunomodulatory genes
Phagocyte activation and pathogen killing
Macrophages are tissue resident or circulatory (recruited from the bone-marrow), macrophage activation = expression of new genes induced by microbes and cytokines, activated macrophages exhibit enhanced phagocytosis and migration + cytokine/chemokine production + expression of cell surface molexules + antimicrobial activity + antigen presentation and T cell activation
Crosstalk between macrophages and lymphocytes during infection by intracellular pathogens
FROM MACROPHAGES TO LYMPHOCYTES: IL -12 + -18 + -1 + -6 and TNF (tumor necrosis factor)
OTHER WAY: interferon IFN-γ
RESULT: killing of phagocytosed microbes
Interferons - general
special cytokines that promote antiviral defence, antiviral genes include nucleases + inhibitors of virus entry and exit & viral uncoating and replication & protein translation, immunomodulatory roles enhanced T-cell responses + anti-inflammatory actions + tissue repair
Interferons - mode of action
Detection of viruses/gram negative bacteria -> interferon (IFN) production and transcription of antimicrobial genes
IFN-γ -> antibacterial, antiprotozoal and antiviral host defence programmes (Signal transducer and activator of transcription 1 & 2 bind to GMP-AMP synthase on DNA)
IFN-α/ß -> antibacterial and antiviral host defence programmes (Signal transducer and activator of transcription 1 & 2 bind to Interferon regulatory factor 9 which binds to interferon stimulated response element on DNA)
Death of infected cells
virus infected cells are killed by the action of cytotoxic T lymphocytes, cell death removes viral replicative niches, CTLs (cytotoxic T lymphocytes) and NK cells directly kill infected cells (contact-dependent), host cells infected with intracellular bacterial pathogens also undergo forms of cell death (contact-dependent)
Humoral innate immunity and cell activation - soluble effector mechanisms
Complement mediated bacterial destruction, lectin-binding to neutralize cell attachment or entry, iron chelation (siderophores) to prevent replication, antibiotic-like peptides
Humoral innate immunity and cell activation - cellular effector mechanisms
reactive oxygen and nitrogen radicals, acidification and digestion within phagosomes
Humoral innate immunity and cell activation - microbe
Toll-like receptor -> cytokines (TNF, IL-1, IL-6, IL-12) -> inflammation, enhanced adaptive immunity
Humoral innate immunity and cell activation - cytokine
Cytokine receptor -> phagocyte oxidase -> reactive oxygen species (ROS) -> killing of microbes
Humoral innate immunity and cell activation - complement fragment
Complement receptor then:
- > Inducible nitric oxide synthase -> nitric oxide -> killing of microbes
- > phagocytosis of microbe into phagosome -> killing of microbes
DCs and macrophages can activate T cells
activated macrophages and DCs present antigens in combination with major histocompatibility complex MHC-I or MHC-II to T cells, cytokines produced by antigen-presenting cells produce a suitable milieu for T-cell activation (ie IL-12 promotes T-cell replication, TNF), T cells provide cytokines that activate phagocytes (ie IFN-γ upregulates MHC-II expression for antigen presentation, IL-17), responses are specific to general class of pathogens
T cells help B cells produce antibodies
Antigen presenting cells (ie DCs and macrophages) are activated by infection and cytokines, helper T cells are activated by cognate MHC and foreign peptide recognition, B cells become licensed for antibody production against antigen being presented on the B cell receptor (BCR) with T cell help, antibody-mediated enhanced antimicrobial response (phagocytosis (opsonization), complement activation)
Timing of cellular immune response
Innate immunity (epithelial barriers, mast cells, phagocytes, dendritic cells, complement, NK cells and innate lymphoid cells; 0-12 hrs after infection) -> adaptive immunity (B-lymphocytes-> plasma cells producing antibodies, T-lymphocytes -> effector T cells; hr 12 - day 5)
Timing of antibody response
primary -> less strong, slower; naive b-cells -> plasma cells -> memory B cells
Thymic output as age increases
Decreases; more memory T cells than naive T cells after 30
Innate and adaptive immune responses are specific to…
the broad classes of pathogens and their virulence strategies
Viruses (Type 1 immunity)
Sensor: Batf3-dependent CD141+ (cluster of differentiation antigens) -> PRR (pattern recognition receptors): RLR, TLR3, CDS, NLR, AIM2 -> cytokines: type I, IL-6, IL-1ß -> lymphocyte differentiation: cytotoxic T lymphocyte (CTL)
Bacteria and protozoa (type 1 immunity)
Sensor: Batf3-dependent CD207+ CD103+ DCs -> (pattern recognition receptors): TLR, NLR -> cytokines: IL-12, IL-6, IL-1ß -> lymphocyte differentiation: T_H_1 cell
Bacteria and Fungi (type 1 immunity)
Sensor: CD1c+ CD11b+ -> PRR (pattern recognition receptors): Dectins, TLR, NLR -> cytokines: IL-23, IL-6, IL-1ß, TGF-ß -> lymphocyte differentiation: T_H_17 cell
Helminth, allergens and venoms (type 2 immunity)
Sensor: langerhans cells -> lymphocyte differentiation: T_H_2 cell
Genetic immunodeficiency - complement defect (1), leukocyte adhesion (2), chronic granulomatous disease (3)
(1): various complement genes involved, (2): genes involved in migration and adhesion, (3): loss of reactive oxygen species production
Genetic immunodeficiency - Chédiak-Higashi syndrome (1), cytokine genes and their receptors (2), severe combined immunodeficiency (SCID, 3), X-linked agammaglobulinaemia (4)
(1): compromised lysosomes, (2): loss of cell-to-cell communication, (3): severe reduction of function of T and B cells, (4): decreased serum IgG of all types
Acquired immunodeficiency - HIV (1), irradiation and chemotherapy (cancer treatment, 2), immunosuppression (graft rejection/chronic disease 3)
(1): reduced CD4T helper cells, (2): loss of bone marrow precursors, (3): depletion or impairment of lymphocytes
First cell types that arrive at infection site
neutrophils and macrophages
C5 complement cascade
C3b-Bb-C3b complex, C5 convertase acts on C5 on it, release of C5a = inflammation, C5b remains on complex, C6 and C7 bind to C5b, C8 binds to C6 and C7, C9 binds forming poly-C9 = cell lysis
Against which class of pathogens are interferons active
Viruses and intracellular bacterial pathogens
How do cytotoxic T-cells promote immunity against viruses?
killing virus infected cells
Macrophage activation
expression of host-defence genes after detecting microbes and cytokines
Main characteristic of macrophages
Capable of ingesting and killing pathogens
Principal function of the immune system
Defence against microbial infections
Cytokine - type of response
IFNg - Th1 immunity
IL-4/-5/-13 - Th2 immunity
IL-17/-22 - Th17 immunity
T cell mechanisms
- Th1 cell (CD4T cell) binds to antibody presenting cell (APC) with intracellular bacteria, releasing cytokines and causing inflammation + phagocytosis + killing of microbes
- Cytotoxic T cell (CD8T cell) binds to antibody presenting cell (APC) with intracellular virus causing the killing of infected cell
Broad classification of T cell functions
Phagocyte activation (enhanced killing of pathogens, inflammation), direct killing of infected cells (removal of replicative niches), B cell activation (antibody production and affinity maturation), innate lymphoid cells/γδ T cells (early responders, MHC independent actions)
Microbe-specific phagocyte responses induce the appropriate lymphocyte phase
- Effector T cells: Th1, defining cytokines: IFN-γ, principal target cells: macrophages, major immune reactions: macrophage activation, host defense: intracellular pathogens, role in disease: autoimmunity + chronic inflammation
- Effector T cells: Th2, defining cytokines: IL-4/-5/-13, principal target cells: eosinophils, major immune reactions: eosinophil and mast cell activation + alternative macrophage activation, host defense: helminths, role in disease: allergy
- Effector T cells: Th17, defining cytokines: IL-17/-22, principal target cells: neutrophils, major immune reactions: neutrophil recruitment and activation, host defense: extracellular bacteria and fungi, role in disease: autoimmunity + inflammation
Sequence of the immune response
sequential change from resting/naive to activated state through antigen recognition + proliferation + differentiation, driven by gene expression changes driven by specific cytokine combinations (naive to activated macrophage), differentiation of precursor cells into specific cell lineages
