Introduction Flashcards
what is the purpose of our immune system (5)
- prevent invasion by pathogens/parasites
- kill pathogens/parasites/microorganisms
- kill infected cells and cancer cells
- detect and remove dying cells
- repair injured tissues
what are essential functions to our immune system to not compromise our own bodies (2)
- must be able to discriminate between self and not-self; discriminate between dangerous from innocuous such as pathogens, microbes, cancerous cells vs. commensal microbes, normal cells, food, pollen, etc
- should function quickly and then re-establish homeostasis
what occurs if our immune system malfunction
- disease
what are examples of the diseases that result from immune system malfunction (4)
- autoimmunity or inflammatory disease
- allergies and asthma
- obesity
- cancer
what is the most common cause of premature death in human history
- infectious disease
what makes COVID-19 fatal for humans (3)
- acute respiratory distress syndrome (ARDS) becomes a major issue in critically ill patients
- injury to the lungs from viral infection and unchecked inflammation results in rapid and progressive shortness of breath
- respiratory failure
what percentage of deaths were due to infectious disease in min-19th century England
- 60%
what can explain variance in the deaths from infectious diseases in different places (3)
- hygiene
- vaccines
- antibiotics
which organisms have defences against pathogens
- multicellular organisms
what are jawed vertebrates’ three layers of defence (3)
- physiological and anatomical barriers (epithelia, mucus, stomach acid, peptides, commensals)
- innate immune responses
- adaptive immune responses (T and B cells)
what is the epithelia structure and main general function (2)
- composed of cells packed tightly together
- provides a physical barrier between internal and external environments
what does the epithelia comprise
- comprise skin and linings of body’s tubular structures (gastrointestinal tract, respiratory tract, urogenital tract)
mucosal epithelial cells (2)
- secrete mucous, a thick and viscous fluid
- mucous coats microorganisms and prevents their attachment to the epithelia
what do epithelial cells express (2)
- toll-like receptors that can detect and respond to infection from pathogens secreting cytokines and anti-microbial peptides
- results in induction of inflammation
how are the adaptive and innate immune systems connected (2)
- they are interdependent
- in the first week of infection, the innate immune responses limit the infection and activate the adaptive immune responses
what is the adaptive immune response comprised of (2)
- T cell and B cell-mediated responses
- random and highly diverse repertoire of T and B cell receptors, followed by clonal selection and expansion
what are the characteristics of the adaptive immune response (2)
- highly specific
- generates immunological memory (basis of vaccines)
what is the main limitation of adaptive immunity
- clones need to expand and differentiate before participating in host defence (clonal selection takes times)
what are disadvantages of the adaptive immune system and examples (2)
- inappropriate responses
- allergies, autoimmunity
innate immune system
- universal and evolutionarily conserved mechanism of host defence
what is the innate immune system comprised of (3)
- surface pattern recognition receptors (PRR) that identify dangerous microbes, membrane bound attachment receptors, and “opsonic receptors” on macrophages and dendritic cells
- secreted PRR’s and complement
- intracellular PRRs to detect pathogens within cells
innate immune system
- universal and evolutionarily conserved mechanism of host defence
what are the key features of the innate immune system (3)
- controls the infection by limiting spread during the first few days; this is sometimes sufficient to protect against infection
- provides protection against a wide variety of pathogens (non-specific)
- controls the type of adaptive immune response that will develop by “sensing” the nature (what and where) of the infectious agent
what are the main functions of the innate immune system (6)
- opsonization
- activation of complement cascades
- coagulation cascades
- phagocytosis
- activation of pro-inflammatory cytokines/chemokines
- induction of apoptosis
where are cells in the immune system produced (2)
- in the bone marrow through hematopoiesis
- cells are constantly replenished as needed
how does the immune system responses change over time and why (2)
- the immune responses to infections decrease with time
- as we grow older, there are fewer hematopoiesis sites, decreasing our ability to replenish new immune cells
innate immune system cells: neutrophils
- key characteristics (4)
- short lived
- abundant in the bloodstream
- abundantly produced each day
- key soldier for innate immunity; they are essential to living
innate immune system cells: neutrophils
- activation (2)
- not activated in the blood; when activated, they migrate to the tissues and survive for 1-2 days
- highly motile and attracted to sites of infection by cytokines produced by epithelial cells and resident macrophages, and complement C5a
innate immune system cells: neutrophils
- strategies for killing pathogens (3)
- phagocytic dependent
- phagocytic independent
- NETs
innate immune system cells: neutrophils
- phagocytic dependent killing of pathogens
- phagocytosis of antibody-opsonized pathogens and killing of ingested bacteria by production of reactive oxygen and nitrogen species
innate immune system cells: neutrophils
- phagocytic independent killing of pathogens
- degranulation: various digestive proteins are released in 3 types of granules to kill pathogens
innate immune system cells: neutrophils
- NETs (2)
- release of neutrophil extracellular traps which contain fibres of chromatin and serine proteases
- trap and limit the spread of pathogens
innate immune system cells: monocytes
- categories (2)
- differences (2)
- inflammatory (classical and conventional)
- patrolling (non-conventional)
- differ in chemokine receptors, cytokine production, antigen uptake and presentation
- can be differentiated by expression of CD14 and CD16 markers in humans
innate immune system cells: monocytes
- inflammatory monocytes
- differentiate into macrophages or dendritic cells depending on cytokine environment
innate immune system cells: monocytes
- patrolling monocytes (4)
- crawl along blood vessels looking for injury to the endothelium
- do not differentiate into macrophages
- armed with PRRs
- have a role in Alzheimer’s, long-COVID, and another diseases
innate immune system cells: macrophages
- general characteristics (3)
- relatively long-lived cells, but limited self-renewal potential
- some derived from monocytes (gut), but other populate tissue during embryogenesis and can self-renew (brain, liver)
- arrive at sites of infection after neutrophils
innate immune system cells: macrophages
- receptors (4)
- full of receptors that differ depending on location in the body
- various chemokine receptors for substances released by damaged cells, histamine from resident mast cells and basophils, and cytokines/chemokines released by resident macrophages and dendritic cells
- various phagocytic receptors, mannose receptors, Fc receptors, complement receptors
- various signalling receptors
innate immune system cells: macrophages
- methods of killing pathogens (2)
- highly phagocytic; can ingest 100+ pathogens before dying of their own digesting compounds
- ingest pathogens into phagosomes which fuse with lysosomes where pathogens are killed because of the production of several reactive oxygen and nitrogen species
innate immune system cells: macrophages
- invasion by pathogen
- some bacteria can evade macrophage defences and grow within cells
innate immune system cells: macrophages
- types (3)
- M1 macrophages produce inflammatory cytokines
- M2 macrophages produce chemokines and enzymes arginase which may be important for tissue repair
- Mreg macrophages produce significant amount of IL-10
innate immune system cells: dendritic cells
- general characteristics (3)
- present in small numbers
- many different subsets
- similar lifespan to macrophages
innate immune system cells: dendritic cells
- activation (2)
- immature cells in tissues that act as guarders of infection
- once activated, they mature and migrate to lymph nodes to interact with T cells, innate lymphoid cells (ILCs like NK cells), and B cells
innate immune system cells: dendritic cells
- characteristics of immature cells (6)
- high antigen capture
- low co-stimulatory molecule expression
- low MHC class I and II expressions
- negligible inflammatory cytokine expression
- poor activation of T cells susceptible to NK killing
- role in maintaining tolerance
innate immune system cells: dendritic cells
- characteristics of mature cells (6)
- low antigen capture
- high co-stimulatory molecule expression
- high MHC class I and II expression
- high inflammatory cytokine expression
- migrate to lymphoid organs
- potent T cell and NK cell activation
innate immune system cells: innate lymphoid cells (ILCs)
- general characteristics (2)
- cells that belong to the lymphoid lineage, but don’t express antigen specific receptors like BCRs and TCR of B cells and T cells
- do not undergo clonal selection or expansion when stimulated
innate immune system cells: ILCs
- counterparts (2)
- NK cells though as innate counterparts of CD8 cytotoxic T cells and often grouped with ILC1 type cells
- ILC1s, ILC2s, and ILC3s may be innate counterparts of T helper cell 1, T helper cell 2, and T helper cell 17 subsets
innate immune system cells: ILCs
- activation (2)
- response to signals from infected or injured tissue
- migrate from site of production to infected or injured tissue and complete maturation into one of the ILC subsets
innate immune system cells: ILCs
- functions (2)
- secrete various cytokines that induce innate responses and regulate DC activity/maturation
- ILC-derived cytokines help drive CD4 T cell subset differentiation
innate immune system cells: NK cells
- functions (4)
- kill tumours and virally infected cells by inducing apoptosis
- modulate T cell development
- major source of important innate immune cytokines (IFN gamma)
- can kill cells with antibody bound to surface
innate immune system cells: NK cells
- activation (3)
- activated by dendritic cells
- receptors for MHC I molecules and stress induced ligands act as inhibitory and activating receptors; complex balance of signalling determines if NK cell will be activated to kill or not
- IL-12 is a potent NK cell activator
NKG2D
- NKG2D on NK cells binds to the NKG2D ligand on tumour cells to induce cytotoxicity ad IFN-gamma production
SH2 domains
bind tyrosine-phosphorylated sequences in specific protein targets
innate immune system cells: NK cells
- methods of killing target cells (2)
- direct release of cytotocic granules using perforin and granzyme
- receptor-mediated apoptosis via expression of Fas ligan or TRAIL
innate immune system cells: eosinophils
- general characterIstics (2)
- phagocytic cells, but less efficient than neutrophils
- important in immune responses to parasites
innate immune system cells: eosinophils
- method of killing (2)
- binding of IgG-opsonized parasite to Fc receptors on eosinophils triggers degranulation
- eosinophil peroxidase and cationic proteins of granule are deposited onto parasite surface to kill it
innate immune system cells: basophils (4)
- least abundant granulocyte
- involved in immune response to parasites as they express IgE receptors and IL-4
- associated with vide variety of inflammatory conditions as they contain histamine
- strong association with allergies
innate immune system cells: mast cells
- types (2)
- mucosal mast cells
- connective tissue mast cells
innate immune system cells: mast cells
- mucosal mast cells
- stimulate non-inflammatory responses against gut microbiota and IgE-mediated responses against intestinal parasites
innate immune system cells: mast cells
- connective tissue mast cells (2)
- release granules of pro-inflammatory mediators when activated and proteases that break down extracellular matrix
- synthesize and secrete chemokines, cytokines, prostaglandins, and leukotrienes
T cell activation (4)
- requires 3 signals
- signal 1: TCR/MHC-peptide interaction
- signal 2: co-stimulation
- signal 3: specific cytokines or combinations of cytokines from variety of accessory cells
what are the effector CD4 T cell types (5)
- Th1 cells
- Th17 cells
- Th2 cells
- Tfh cells (follicular helper)
- T regulatory cells
what does the appropriate activation of DCs allow for
- appropriate organization of other adaptive and innate immune system cells
what causes inflammation
- physical or chemical insults or invasion by microorganisms
types of inflammation (2)
- acute: typically short duration and an initial response to infectious agent
- chronic: last months or year and could be due to the persistence of an infectious agent, aging and senescent cells, high fat diet, etc
inflammatory response: resident mast cells
- release histamine, prostaglandins, leukotrienes, pro-inflammatory cytokines, etc
inflammatory response: resident macrophages/dendritic cells
- secrete pro-inflammatory cytokines/chemokines, prostaglandins, ad leukotrienes upon pathogen recognition
pro-inflammatory cytokines
- TNF-alpha, IL-1, IL-6
what do pro-inflammatory cytokines TNF-alpha, IL-1 and IL-6 do (2)
- induce fever
- induce production of acute phase proteins that function similar to antibodies by binding bacteria, opsonizing for phagocytosis, and activating complement
what do pro-inflammatory cytokines TNF-alpha and IL-6 do
- stimulate vascular endothelial cells and macrophages to secrete CSFs, which induce hematopoiesis in bone marrow
what do pro-inflammatory cytokines TNF-alpha and IL-1 do (2)
- act on vascular endothelial cells to increase blood vessel permeability and expression of cell adhesion molecules (CAM) and E-selectin
pro-inflammatory chemokines (2)
- activate G protein coupled receptors on leukocyte surface
- cause integrins to change conformation, increasing affinity for CAMs on endothelial walls and enabling neutrophils to bind tightly to vessel wall
PAMP (3)
- what does the acronym stand for
- definition
- what is it recognized by
- pathogen-associated molecular pattern
- not a host structure, but shared by large groups of pathogens and is essential for their survival (LPS, LTA, etc)
- recognized by PRRs that are germ-line encoded (not associated with TCR and BCR random recombination of gene segments)
toll-like receptors
- activation (2)
- activated when binding of ligand to its leucine rich region induces formation of a dimer
- generally functions as homo-dimers, but formation of hetero-dimers increase ligand diversity
toll-like receptors
- structure (3)
- extracellular domain: contains leucine-rich regions that interact with ligans
- single pass transmembrane domain
- cytoplasmic tail with Toll-IL-1 domain to interact with signalling protein
toll-like receptors
- location (2)
- some located in plasma membrane of cells and detect pathogens present in extracellular space
- some located in endosome membranes and detect pathogens that entered cell by phagocytosis/endocytosis and are being degraded in phagosome/endosome
toll-like receptors
- function (2)
- binding of ligand to TLR can initiate signalling cascade that results in activation of transcription
- activated TF can promote transcription of gees that encode pro-inflammatory cytokines, interferons, anti-microbial peptides or chemotactic factors depending on the TLR activated
NF-kappa-beta (2)
- family of transcription factors
- sites located in many pro-inflammatory cytokine genes
inactive NF-kB (2)
- retained in cytoplasms by I-kB (I = inhibitor) through non-covalent interactions
- I-kB has a cytoplasmic retention signal
activation of NF-kB
- activation of I-k kinases results in phosphorylation of I-kB subunit, causing it to dissociate from NF-kB and become degraded
- NF-kB has a nuclear localization signal and is translocated to nucleus where it can promote transcription of genes with kB sites in their promoter
RIG-I-like receptors (RLR) (3)
- detect viral RNA in cytoplasm of cells during virus replication or gene expression
- can recognize uncapped RNA or dsRNA
- recognition results in signalling cascade that causes production of type I interferons
cGAS-STING pathway
- function
- pathway steps (2)
- detects dsDNA in cytoplasm of cell (viral or bacterial DNA)
- cGAS catalyzes production of cyclic GAMP from GTP and ATP
- cGAMP bind to STING, leading to activation of transcription factors that results in type I interferon production
what do interferons do (2)
- interfere with virus propagation inside infected cells
- lead non-infected cells to start protective methods against pathogen
