ICS- Immunlogy Flashcards
.Immunology
List the humoral components of the immune system
- coagulation system
- complement system
- fibrinolytic system
- kinin system
Immunology
how does the coagulation system function as a humoral component of the immune system?
Clots act to immobilize microorganisms and prevent entry into blood and lymph
Immunology
how does the complement system function as a humoral component of the immune system?
it enhances the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism
Immunology
how does the fibrinolytic system function as a humoral component of the immune system?
it decomposes the clot when it’s no longer required to promote wound healing
Immunology
how does the kinin system function as a humoral component of the immune system?
it widens blood vessel lumens and increases capillary permeability thus increasing supply of soluble and cellular material to the site of infection
Immunology
what is the function of neutrophils?
- first responders to infection
- phagocytose bacteria
- most abundant (70%)
Immunology
what is the function of lymphocytes?
B-lymphocytes: produce antibodies, differentiate into plasma cells or memory B cells
T- lymphocytes: cell mediated immunity
Immunology
what is the function of eosinophils?
they are involved in allergic reactions and defence against parasites
Immunology
what is the function of basophils?
they mediate allergic and inflammatory responses by releasing histamine and other mediators
Immunology
what is the function of monocytes?
- precursors to macrophages and dendritic cells
- phagocytose pathogens
- present antigens
- produce cytokines
Immunology
what is the complement system?
it is a series of protein activations that help the body’s immune system remove foreign particles and pathogens. it forms a part of the innate immune system.
Immunology
where do the plasma proteins involved in the complement cascade come from?
the liver
Immunology
what are the activation pathways involved in the complement cascade?
- Classical
- Lectin
- Alternative
Immunology
describe the classical activation pathway of the complement cascade
Antibody (IgG & IgM) binds to antigen on a microbe which causes C3 to be converted into C3a and C3b.
Immunology
Describe the Lectin activation pathway of the complement cascade
Mannose-binding Lectin (MBL) binds to mannose carbohydrate found on pathogen surfaces. this converts C3 into C3a and C3b.
Immunology
Describe the Alternative pathway of the complement cascade
It is activated by bacterial endotoxin, a lipopolysaccharide present on the outer membrane of gram negative bacteria. this results in spontaneous hydrolysis of C3 into C3a and C3b.
C3b combines with other factors to form C3 convertase which converts C3 into C3a and C3b.
Immunology
what is the inflammatory boost mode of action involved in the complement cascade?
C3a and C5a attract more leukocytes to the site of infection
Immunology
what is the opsonisation mode of action involved in the complement cascade?
when C3b binds to pathogens to promote phagocytosis
Immunology
what is the direct lysis mode of action onvolved in the complement cascade?
When C5b forms the membrane attack complex (MAC) which creates pores in the pathogen membrane, leading to cell lysis.
Immunology
Through which ways does the protein C3a help fight infection?
C3a attracts more leukocytes to the site of infection. this is called an inflammatory boost
Immunology
Through which ways does the protein C3b help fight infection?
- C3b combines with other factors to form C3 convertase which converts more C3 into C3a and C3b (Self-amplification loop)
- C3b binds to pathogens to promote phagocytosis (opsonisation)
- C3b converts C5 into C5a and C5b which also cause inflammatory boost and produce the MAC respectively.
Immunology
Through which ways does the protein C5a help fight infection?
C5a attracts more leukocytes to the site of infection (Inflammatory boost)
Immunology
Through which ways does the protein C5b help fight infection?
C5b forms the membrane attack complex (MAC) which forms pores in the membranes of the pathogens, leading to cell lysis
Immunology
Describe IgM’s structure
- It’s produced early in immune response
- has low affinity, high avidity
- activates the complement cascade
- it’s a monomer (B-cell receptor) or pentamer (agglutination, opsonisation); key in the primary immune response.
Immunology
Describe IgA’s structure
- Mucosal immunity (Gut and lung)
- found on mucosal surfaces
- Secreted as a dimer joined by a J chain
Immunology
Describe IgG’s structure
- > 80% circulating antibodies are IgG
- Used to diagnose pas/ persistent infections
- 4 subclasses: IgG1, IgG2, IgG3, IgG4
- High affinity
Immunology
Describe IgD’s structure
- B cell receptor
- Monomer
- function still uncertain
Immunology
Describe IgE’s structure
- Binds mast cells
- Mediates allergic reactions
- low serum concentration
- Monomer
- involved in allergies and type 1 hypersensitivity
- found in mucosa (respiratory, GI, urogenital)
- found in lymphatic tissue
Immunology
What do the ‘Fab’ arms of an antibody do?
they bind to the antigen
Immunology
What is the ‘Fc’ part of an antibody?
it determines the class of the antibody (GAMED) and what mechanism will be used to destroy the antibody
Immunology
What functions do antibodies carry out?
- Neutralisation
- Agglutination
- Opsonization
- Complement activation
Immunology
How do antibodies carry out neutralisation?
- they bind to pathogens, preventing them from entering host cells
- or they bind to toxins, neutralising them
Immunology
how do antibodies carry out agglutination?
they bind pathogens together so that phagocytes can engulf multiple bacteria at once
Immunology
how do antibodies carry out opsonization?
they mark pathogens for phagocytosis
Immunology
what are cytokines?
- proteins that are secreted by immune and non immune cells
- they act as signalling molecules via specific receptors on target cells
- they act as immunomodulatory agents in autocrine, paracine and endocrine signalling
Immunology
what physiological processes are cytokines involved in?
- immune response
- wound healing
- inflammation
- cell growth and differentiation
Immunology
what can dysregulation of cytokine production lead to?
- auto immune diseases
- cancer
- chronic inflammatory diseases
Immunology
describe interleukins (IL)
- can be pro-inflammatory or anti-inflammatory
- they can cause cells to divide, differentiate and secrete other factors
Immunology
describe interferons (IFN)
they induce a state of antiviral resistance in uninfected cells and lmit the spread of viral infection
Immunology
give an example of ILs that are pro-inflammatory and anti-inflammatory
pro: IL-1
anti: IL-10
Immunology
What are the types of interferons and their sources?
IFNα and IFNβ: Produced by virus-infected cells.
IFNγ: Produced by activated Th1 cells.
Immunology
what do tumour necrosis factors (TNF) do?
they mediate inflammation and cytotoxic reactions
Immunology
what do colony stimulating factors (CSF) do?
they’re involved in directing the division and differentiation on bone marrow stem cells- precursors of leukocytes
Immunology
what are chemokines
they’re a group of small proteins that direct movement of cells from the bloodstream into the tissues or lymph organs
e.g. during inflammation by binding to specific receptors (Chemotaxis)
Immunology
how are classes of chemokines defined?
by the arrangement of the conserved cysteine (C) residues in the mature proteins
Immunology
what are the two main classes of chemokines?
CC chemokines- 2 adjacent cysteine residue near the amino terminus
CXC chemokines- equivalent cysteine residues are separated by a single amino acid
Immunology
what are the classes of chemokines?
- CC
- CXC
- CCL
- CXCL
- CX3CL
- XCL
Immunology
what cells are attracted to the CCL class of chemokines?
Monocytes
NK cells
T lymphocytes
eosinophils
Basophils
dendritic cells
Immunology
what cells are attracted to the CXCL class of chemokines?
mainly neutrophils
naive T lymphocytes
Immunology
what cells are attracted to the CX3CL class of chemokines?
Mainly monocytes
T lymphocytes
Immunology
what cells are attracted to the XCL class of chemokines?
Mainly T lymphocytes
Inflammation
what is inflammation?
A series of reactions that brings cells and molecules of the immune system to sites of infection or damage
what is acute inflammation?
the complete elimination of a pathogen followed by resolution of damage, disappearance of leukocytes and full regeneration of tissue
what are the steps of acute inflammation?
- vascular stage
- cellular stage
- amplification
- resolution
what does the vascular stage of acute inflammation involve?
- vasodilation and increased vascular permeability occur, allowing immune cells and proteins to enter the tissue
- exudation leads to swelling (oedema), redness and heat
what does the cellular stage of acute inflammation involve?
- neutrophils (then monocytes later on) are recruited to the site of inflammation
- phagocytosis occurs to remove pathogens and debris
what does the amplification stage of acute inflammation involve?
inflammation is amplified by the release of pro-inflammatory cytokines and other mediators
what does the resolution stage of acute inflammation involve?
inflammation resolves if the cause is removed, leading to tissue repair
* inflammation is controlled, anf tissue healing occurs through regeneration or fibrosis
* anti-inflammatory cytokines help terminate the inflammatory process.
what is chronic inflammation?
persistent, unresolved inflammation
Adaptive vs. innate immunity
what are the features of innate immunity?
- inherited (natural)
- acts rapidly (hours/ days), vital to triggering intial adaptive responses
- triggered by threat/ damage
- activated by general microbial patterns and damage
- can have some immunological memory
what are some features of adaptive immunity?
- acquired (learned)
- relatively slow to develop (days/ weeks)
- triggered by exposure to specific antigen
- very focused, targens specific antigen
- excellent rapid immunological memory
define some physical barriers of the immune system
- enzymes in mucus, tears and saliva
- cilia in respiratory tract trap foreign material
- acid in sweat
- acid in stomach
- intact skin
- competitiomn from commensal bacteria in gut and genital tract
what cells are involved in innate immunity?
- neutrophils
- mast cells
- eosinophils
- macrophages
- natural killer cells
- basophils
- dendritic cells
how are neutrophils involved in innate immunity?
- they are the most abundant WBC but short lived
- phagocytic
- mainly involved in inflammation
how are mast cells involved in innate immunity?
involved in anaphylaxis and asthma- IgE binds to allergen which then binds to mastcells, causing them to release histamines, causing the response, e.g. bronchoconstriction
how are eosinophils involved in innate immunity?
involved in parasitic infections
how are macrophaged involved in innate immunity?
- when monocytes migrate from blood to tissue they become macrophages
- phagocytosis, antigen presenting, cytokine secretion
how are natural killer cells involved in innate immunity?
they release lytic granules that kill virus infected cells
how are basophils involved in innate immunity?
- they act like circulating mast cells- release histamine upon IgE crosslinking
- involved in allergic reactions, eczema, hay fever
how are dendritic cells involved in innate immunity?
they act as antigen presenting cells
what are PAMPs?
Pathogen-associated molecular patterns
what are DAMPs?
Damage-associated molecular patterns
what has the innate immune system evolved to recognise?
- highly conserved strucutres expressed by large groups of pathogens (PAMPs)
- common biological consequences of infection (DAMPs and missing self)
what receptor families recognise microbial non-self (PAMPs)?
- toll-like receptors (TLRs)
- Rig-I- like receptors (RLRs)
- NOD-like receptors (NLRs)
- C-type lectins (CLRs); Pentraxins
what receptor families recognise consequences of infection or injury (DAMPs)?
- toll-like receptors (TLRs)
- NOD-like receptors (NLRs)
- RAGE family
what receptor families recognise missing self?
MHC class 1 specific inhibority receptors
what mechanism is used by viruses anbd cancer to evade cytotoxic T cells?
MHC class 1 receptor loss or downregulation
which cells detect missing self and how do they deal with it?
natural killer cells
they induce apoptosis in those cells
what PAMPs can be found in gram + bacteria?
lipoteichoic acid (LTA)
peptidoglycan (PGN)
lipoproteins
what PAMPs can be found in gram - bacteria?
- lipoteichoic acid (LTA)
- peptidoglycan (PGN)
- lipoproteins
- lipopolysaccharide (LPS)
what PAMPs are found in viruses?
Coat protein
Nucleic acid
what PAMPs are found in parasites?
GPI anchors
what PAMPs are found in yeast?
Zymosan (B-glucan)
Give examples of some DAMPs molecules
DNA
RNA
extracellular ATP
hyaluronic acid
glucose
fibrinogen
fibronectin
heat shock proteins
IL-1-A
IL-33
Give examples of some DAMPs particles
uric acid
amyloid-B
silica
nanoparticles
alum
asbestos
hemozoin
What are PRRs and what are their function?
- Pattern recognition receptors
- Families of receptors that exist to detect PAMPs and DAMPs in fluids, cell surfaces and compartments and intracellularly
- they have roles in damage recognition
Give some examples of PRRs
Secreted and circulating PRRs
Lectins and collectins
what are secreted and circulating PRRs?
antimicrobial peptides secreted into lining fluids (from epithelia and phagocytes)
Give an example of secreted and circulating PRRs
pentraxins
* proteins like C-reactive protein (CRP), produced in response to pro-inflammatory cytokines
* activates comeplement, promotes phagocytosis
what are lectins and collectins?
carbohydrate- containing proteins which bind to carbohydrates of lipids in microbe walls, e.g. mannose binding lectin which activates the complement cascade wia the lectin pathway
activates complement, improves phagocytosis
What are the 2 type of C-type lectin receptors?
Dectin-1: specific receptor for beta-glucans, important role in anti-fungal innate immunity
Dectin-2: binds high mannose type carbohydrates, role in fungal infection and the induction of Th17 immunity
What are toll-like receptors?
membrane bound pattern recognition receptors that detect specific molecular patterns on pathogens or damaged cells, triggering innate immune responses.
how do Toll-like receptors work?
they activate downstream signalling pathways, leading to the production of pro-inflammatory cytokines and the initiation of adaptive immunity
which TLRs are found on cell surfaces?
what do they recognise?
1, 2, 4, 5 and 6
bacterial components
what are some examples of bacterial components?
lipopolysaccharides
peptidoglycan
flagellin
which TLRs are endosomal TLRs?
what do they recognise?
3, 7, 8, 9
viral RNA or DNA such as single stranded RNA and unmethylated CpG DNA.
+
what are NOD-like receptors?
NLRs are intracellular pattern recognition receptors that detect PAMPs and DAMPs in the cytoplasm
what is the function of NOD-like receptors?
they play a key role in recognising microbial infections and cellular stress.
What do NLRs do when they detect PAMPs and/ or DAMPs?
form inflammasome which produced pro-inflammatory cytokines
antigen presentation
what is the function of RIG-I-Like receptors?
they are involved in detecting cytoplasmic viral RNA in the early stages of antiviral immunity
how does pattern recognition receptor signalling contribute to inflammatory disease?
- high levels of DAMPs are associated with many inflammatory and autoimmune diseases and cancers
- excessive activation of PRRs contribute to inflammation due to the release of pro-inflammatory cytokines
- inflammasome activation contributes to inflammation due to release of pro-inflammatory cytokines
- over release of pro-inflammatory cytokines due to PRR signalling can lead to inflammatory disease.
describe extravasation (diapedesis)
- Neutrophils exposed to inflammatory signals such as cytokines, released by infected or damaged tissue
- These cytokines active endothelial cells leading to the expression of E-selectin
- Selectins bind to carbohydrate ligands on neutrophils e.g. CD15
- This interaction slows neutrophils causing them to roll along the endothelium (rolling adhesion)
- Chemokines e.g. CXCL8 secreted by endothelial cells and resident immune cells bind to G-coupled protein receptors on neutrophils (chemokine receptor), this increased the affinity of integrins for their ligands
- Activated neutrophil integrins bind strongly to endothelial cell adhesion molecules such as ICAM-1
- Neutrophils migrate laterally towards intercellular junctions and migrate through the endothelial cell junctions, this involved PECAM-1 (CD31) which mediates neutrophil passage through endothelial junctions
what is the definition of phagocytosis?
the cellular uptake of particulates/ pathogens within a plasma-membrane envelope
(particulates including dead host cells, cellular debris and host macromolecules.)
what cells can be classed as phagocytes?
Neutrophils
macrophages
immature dendritic cells
monocytes
eosinophils
osteoclasts
what are the different phases of phagocytosis?
- detection of the particle to be ingested
- activation of the internalisation process
- formation of a phagosome
- maturation of the phagosome into a phagolysosome
what types of receptors are involved in the ‘dection of the particle to be ingested’ phase of phagocytosis?
opsonic receptors
non opsonic receptors
what are opsonic receptors?
they detect opsonins
what are opsonins?
give examples
host-derived proteins
antibodies, complement proteins, mannose binding lectin
what are non-opsonic receptors?
they are pattern recognition receptors
* they can identify PAMPs and DAMPs on target particles
* they are TLRs, not phagocytic receptors but they can cooperate with them to increase phagocytic efficiency
what is involved in the ‘activation of the internalisation process’ phase of phagocytosis?
- particle size
- multiplicity of receptor-ligand interactions
- involvement of the cytoskeleton
what is involved in the ‘formation of a phagosome’ phase of phagocytosis?
- the plasma membrane engulfs a particle
- the membrane pinches off to form an early phagosome
what is involved in the ‘maturation of the phagosome into a phagolysosome’ phase of phagocytosis?
- interactions with early endosomes
- acidification
- transition into a late phagosome
- fusion with lysosomes
what happens in the early phagosome stage?
(mention pH)
it interacts with early endosomes, acquiring markers like Rab5, which regulate vesicle trafficking and fusion
pH: 6.1 - 6.5
what happens in the acidification stage?
why is it important?
- The early phagosome begins to acidify due to the action of vacuolar ATPase (v-ATPase), which pumps protons (H+) into the phagosome.
- Acidification is critical for subsequent enzymatic activity.
what happens in the ‘transition to late phagosome’ stage?
(mention pH)
● The early phagosome matures into a late phagosome, characterised by the loss of Rab5 and acquisition of Rab7, another small GTPase critical for lysosome interaction.
● The late phagosome becomes more acidic (pH ~5.5-6.0) and begins to acquire hydrolytic enzymes from the Golgi or lysosomes.
what happens in the ‘fusion with lysosomes’ stage?
● The late phagosome fuses with lysosomes, forming a phagolysosome.
● This fusion requires several key molecules, including:
○ Rab7: Promotes docking of lysosomes.
○ LAMP proteins: Help stabilise the phagolysosome.
what happens after a phagolysosome is formed?
the degradation and recycling stage where the engulfed aterial is broken down into basic components (e.g. amino acids, lipids, sugars) which are either:
* exocytosed as waste
* recycled for cellular use
what are the antimicrobial mechanisms of phagocytes?
- acidification
- toxic oxygen-derived products
- toxic nitrogen oxides
- antimicrobial peptides
- enzymes
- competitors
how are natural killer cells used by the immune system?
they recognise missing self cells (abnormal MHC class 1 expression on cells) and induce apoptosis of these cells
what is the difference between MHC class 1 molecules and MHC class 2 molecules?
MHC class 1- used to present self antigens
MHC class 2- used by antigen presenting cells to present non-self antigens
how can abnormal MHC class 1 expression come about?
from viral infections or cancer
in what ways can pathogens fight back against the immune system?
- Secrete membrane damaging toxins that cause cell lysis and death
- Interfere with maturation of the phagosome
- Develop resistance to phagolysosome contents
- Physically escape from the phagosome
- Cause the phagosome to fuse with the cell wall and get vomited out the cell
how does the innate immune system help initiate adaptive immunity?
- dendritic cells reside in tissues surveilling for infection or damage
- if infection or damage is deteced they become localised to the nearest lymphnode for antigen presentation to naive T cells
- they provide 2 signals to naive T cells:
-signal 1: peptide fragments of antigens via MHC molecules
-signal 2: costimulatory signals via B7 family ligands - naive T cells become activated, undergo clonal expansion and differentiate into effector T cells
which cells are Professional APCs?
Dendritic cells, macrophages and B cells
which cells are atypical APCs?
Mast cells
basophils
eosinophils
ILC3s
What are the key features of dendritic cells (DCs) and macrophages as professional antigen-presenting cells (APCs)?
- Phagocytic
- Express receptors for apoptotic cells, DAMPs, and PAMPs
- Localize to tissues
- DCs localize to the T cell zone of lymph nodes following activation
- Constitutively express high levels of MHC class II and antigen-processing machinery
- Express co-stimulatory molecules following activation
What are the key features of B cells as professional APCs?
- Internalize antigens via B cell receptors (BCRs)
- Constitutively express MHC class II and antigen-processing machinery
- Express co-stimulatory molecules following activation
What are the general features of atypical APCs?
- Inducible expression of MHC class II molecules
- Antigen presentation functions are limited to specific immune environments, especially type 2 immune settings
what are MHC class 1 molecules?
molecules that capture and present peptides from antigens on cell surface membranes of infected or abnormal cells.
what are MHC class 2 molecules?
molecules that capture and present peptides from antigens in endosomes outside the cell.
how do CD8+ cells become activated?
the T cell receptor recognises antigen-MHC1 complexes on infected cells (Clonal selection). the CD8 co-receptor ensures that the T-cell only interacts with MHC1 molecules. Then, the B7 family ligands attach to CD28 receptors and create costimulatory signals for full activation
how do CD4+ cells become activated?
the T cell receptor recognises antigen-MHC2 complexes on infected cells (Clonal selection). the CD4 co-receptor ensures that the T-cell only interacts with MHC2 molecules. Then, the B7 family ligands attach to CD28 receptors and create costimulatory signals for full activation
what happens after CD8+ cells are activated?
Naive CD8+ T cells differentiate into cytotoxic T cells and memory cytotoxic T cells. Upon re-exposure memory cytotoxic T cells quickly proliferate and mount a stronger response.
what happens after CD4+ cells are activated?
Naive CD4+ T cells differentiate itno Th1, Th2, Th17 or Treg cells and each subset has its own memory cell.
which cytokines stimulte the differentiation of the CD4+ cells into the different types?
- Th1- IL12
- Th2- IL4
- Th17- IL6, 21, 23
- Treg- IL2
how do cytotoxic (CD8+) cells carry out their function?
they kill abnormal cells by releasing perforin which forms pores in the target cell membrane, and they by releasing granzymes which enter through perforin pores and trigger apoptosis.
how do Th1 cells carry out their function?
Th1 cells activate macrophages by releasing INFy and enhancing their ability to phagocytose and kill intracellular pathogens. they also release TNFa.
how do Th2 cells carry out their function?
Th2 cells:
* secrete interleukins 2, 4 and 5
* activating B cells to produce IgE
* recruiting eosinophils for parasitic defense
* contributing to allergic responses and mucosal immunity
what do IL4 and IL5 do specifically?
IL4 activates B-lymphocytes and causes proliferation (Clonal expansion).
IL5 causes differentiation of B-lymphocytes to form plasma cells and memory B-cells
how do Th17 cells carry out their function?
they release IL-17 which causes chemokine release from fibroblasts and epithelial cells. these chemokines recruit neutrophils to sites of infection and hence drives inflammation.
how do Treg cells carry out their function?
Treg cells are responsible for supressing overactive immune response, preventing the immune system from attacking the body’s own tissues.
how are millions of unique antigens produced on T and B-cells?
through VDJ recombinations, somatic hypermutation and affinity maturation.
how do B-cells carry out antigen recognition?
A B-cell receptor on a naive B cell recognises and bings to an antigen that may be free-floating or presented by another cell.
which ways can B-cells be activated?
By T-dependent activation or T-independent activation
how are B-cells activated through T-dependent activation?
Most antigens requite CD4+ T helper cells to fully activate B-cells. T helper cells recognise the same antigen (presented on MHC2 molecules by the B-cell) a d provide cytokines (e.g. IL4, 5) which activate B cells.
how are B-cells activated through T-independent activation?
Some antigens stimulate B cell activation without T-cell help but this produces weaker responses.
what cells do B-cells differentiate into?
- plasma cells: antibody secreting factories
- memory B-cells: persist long term and enable faster, stronger responses upon re-exposure to the same antigen
explain the process of T-cell genesis and maturation
T-cells originate from hematopoietic stem cells in the bone marrow, which differentiate into common lymphoid progenitors. these precursors travel to the thymus, where they mature into naive CD8+ and CD4+ cells. here they undergo the thymic tolerance test.
what is thymic tolerance? how does it work?
it is a process that ensures the T cells dont attack the body’s own tissues. There’s 2 steps:
- positive selection: examines wheter a T-cell can recognise and bind to MHC molecules
- Negative selection: Examines whether a T-cell binds too strongly to self-peptides presented by MHC molecules.
why is thymic tolerance important?
It ensures that the immune system can differentiate between self and non-self. it prevents autoimmune diseases. it allows the development of functional T-cells that can effectively respond to infections and other foreign antigens.
what happens to mature T-cells that pass the thymic tolerance test?
mature T cells that passs the thymic tolerance test leave the thymus and enter the bloodstream where they travel to lymph nodes and other lymphoid organs where they wait to encounter their specific antigen on an APC such as a dendritic cell.
what happens to self-reactive T-cells that don’t pass the thymic tolerance test but manage to escape the thymus?
Peripheral tolerance mechanisms such as supression from Treg cells prevent them from causing harm.
why do all T-cells have CD3 complexes?
it transmits signals from the T-cell receptor to the molecules since the T cell receptor can’t do this due to its tail being too short
how does the CD3 complex work?
CD3 contains ITAMs (Immunoreceptor tyrosine-based activation motifs) that become phosphorylated upon TCR activation, triggering a signalling cascade that activates genes necessary for T-cell responses (such as proliferation)
why do T-cells have a TCR and a CD3 complex instead of one protein?
the separation of roles ensure the TCR specialises in antigen recognition while CD3 facilitates intracellular signalling for T-cell activation and function
what is the difference between T-cells and B-cells in terms of antigen binding?
T cells dont bind free antigens, they must be presented on the cell surface in association with molecules of the major histocompatibility complex. whereas, B cells can recognise both free-floating antigens and ones that have been presented on the MHC molecule of an APC
what is an epitope?
A part of an antigen that can trigger an immune response
why do T-cells require APCs to recognise antigens?
because the apitopes are often buried within antigens and so antigens need to be processed by APCs and epitopes need to be presented on MHC molecules
how are antigens processed in APCs to present epitopes?
By phagocytosis
why do B-cells not require APCs?
because B cell epitopes are conformational (often on the surface of the 3D structure of the antigen)
what is senescence?
the process by which cells cease to divide and enter a state of permanent growth arrest without undergoing cell death
what characteristics define cellular senescence?
Cell cyle withdrawal
Macromolecular damage
secretory phenotype (SASP)
Deregulated metabolism
what is secretory phenotype or SASP (senescence associated secretory phenotype)?
the collection of bioactive molecules that senescent cells secrete into their surrounding environment (e.g. proinflammatory cytokines)
what is immunosenescence?
the gradual decline in immune system function associated with ageing
what is inflammaging?
the chronic low-grade i/
how do T-cells change with ageing?
due to a reduction in the size of the thymus there is:
* a reduction in the number of naive T cells
* an increase ijn memory T cells
* An increase in senescent T cells
how do B-cells change with ageing?
Reduction in:
* B cell progenitor cells (Stem cells)
* hematopoietic bone marrow
* naive B cells
* Antibody production
and an increase in memory B cells
how do neutrophils change with ageing?
- reduced chemotaxis (Unable to travel to the site of injury)
- reduced phagocytosis
- reduced superoxide generation (Molecules that kill pathogens)
how do monocytes change with ageing?
- reduced chemotaxis (Unable to travel to the site of injury)
- reduced phagocytosis
- reduced superoxide generation (Molecules that kill pathogens)
- reduced cytokine secretion
what is efferocytosis?
the process by which phagocytes engulf dead cells
how does impaired efferocytosis contribute to ageing?
when the process is impaired apoptotic cells are not cleared and transition into secondary necrosis.
necrotic cells release histotoxic neutrophil contents (DAMPs) which are detected by phagocytic PRRs. these PRRs release proinflammatory cytokines (to attract more PRRs)
Ageing is a cause of impaired efferocytosis, leading to chronic inflammation (inflammaging)
how do natural killer cells change with ageing?
- become more mature
- dont work as well as naive NK cells
- reduced cytotoxicity
how do dendritic cells change with ageing?
- reduced antigen presentation
- reduced phagocytosis
- reduced recruitment to lymphoid organs
how does exercise support healthy ageing in terms of immunity?
- helps maintain muscle mass
- boosts the immune system
- improved cognitive function
- reduces inflammation
how do dietary interventions support healthy ageing in terms of immunity?
- eating anti-oxidant foods such as vitamin C and E rich foods reduces oxidative stress
- healthy fats, such as olive oil- which contains omega 3, reduces inflammation
- protein helps maintain muscle mass
how does weight loss support healthy ageing in terms of immunity?
reduces blood pressure and cholesterol- improves cardiovascular health
improved insulin sensitivity- lower risk of type 2 diabetes
explain how understanding the changes that occur during ageing can be used to develop theraputics against age-related diseases
vaccines designed to work with the immunosenescence and inflammaging seen in the ageing immune response could be developed
some design strategies include:
* high dose vaccines
* multivalent vaccines (protection against multiple diseases/ strains)
* adjuvanted vaccines (contains an adjuvant- a substance that helps the immune system mount a stronger response)
* inhibiting chronic inflammation
* inhibiting immunosenescence
describe immunodeficiency
immunodeficiency refers to a condition where the immune system is unable to mount an effective response to pathogens, making individuals more susceptible to infections. this can be either primary (congenital) or secondary (acquired)
give examples of primary immunodeficiency
- common variable immunodeficiency
- chronic granulomatous disease
give examples of secondary immunodeficiency
HIV/ AIDS
Immunosupressants (e.g. after a transplant)
describe autoimmunity
when the immune system mistakenly targets and attacks the body’s own cells, tissues or organs. this results in autoimmune diseases where the immune sytem fails to distinguish self from non-self.
give examples of autoimmunity
- Rheumatoid arthritis (attacks synovial joint lining)
- multiple sclerosis (attacks myelin sheath)
- type 1 diabetes (attacks insulin producing beta cells)
describe the series of events that occur during the sensitisation phase of type 1 hypersensitivity
the body encounters allergens at various points of contact between the body’s surface and the environment. allergens that bypass the physical barriers are captured by APCs, which process and present then on MHC2 molecules. these allergens are then recognised by naive T cells which differentiate into Th2 cells. Th2 cells release IL 4 and IL13 which stimulate B cells to class-switch (switch from expressing one class of immunoglobulin to another) to IgE production. this results in the release of large amounts of IgE specific to the antigen. these IgE molecules attach themselve to IgE receptors on mast cells and basophils.
what happens during re-exposure to the same allergen in type 1 hypersensitivity?
re-exposure causes cross-linking of the bound IgE and degranulation (release of histamine) of mast cells and basophils, releasing potent vasoactive molecules.
what molecules can be released by mast cells and basophils during degranulation?
- histamine
- tryptase
- chymotrypsin
- carboxypeptidase A
- leukotrienes
- prostaglandins
- interleukins
- PAF
- TNF-a
how long does Type 1 hypersensitivity take to onset?
Minutes
what are some signs and symptoms of an allergy?
- vasodilation
- increased capillary permeability
- bronchoconstriction
what makes proteins allergenic?
- protease activity
- surface features of proteins
- glycloysation patterns of proteins
give an example of how protease activity can make proteins allergenic?
by degrading certain lung surfactant proteins which normally bind and block inhaled allergens, more can reach the APCs
what surface features of proteins make them allergenic?
usually high proportion of hydrophobic areas
what is the hygiene hypothesis?
the theory suggests that reduced exposure to infections, microbes and parasites early in life can lead to an increased risk of developing allergies. the immune system when not exposed to a variety of pathogens may become overly sensitive to harmless substances, e.g. pollen, dust, etc.
it may favour a Th2 response (associated with allergies) over a Th1 response (protects against infections.
what are some common diseases associated with allergies?
- allergic rhinitis
- allergic conjunctivitis
- atopic dermatitis
- urticaria/ angiodema
- asthma
- food allergy
- drug allergy
- venom allergy
what are some current and future treatments for allergies?
- adrenaline/ epinephrine
- antihistamines
- corticosteroids
- fluid resuscitation
- bronchodilation
- allergen avoidance
what are pseudo type 1 reactions?
instances where there is non-IgE mediated mast cell degranulation
give examples of things that can bring on pseudo type 1 reactions
- physical stress
- concurrent infection
- autoimmune disease
- iron, vitamin B12, vitamin D deficiencies
- psychological stress
which families of drugs can bring on pseudo type 1 reactions?
- opiates
- non-steroidal anti-inflammatories
- IV contrast media
- ACE inhibitors
what is type 2 hypersensitivity?
An IgG or IgM mediated cytotoxic reaction that occurs when the immume system mistakenly targets and attacks specific cells or tissues in the body because of antibodies binding to antigens on the surface of those cells. this destroyed the cells by activating the complement cascade or phagocytosis
what are some examples of type 2 hypersensitivity reactions?
- haemolytic disease of the newborn
- graves’ disease
- goodpasture’s syndrome
how long does Type 2 hypersensitivity take to onset?
hours to days
what is type 3 hypersensitivity?
it’s an immune complex-mediated hypersensitivity reaction. it occurs when soluble antigen in the circulation is bound by antibodies forming antibody- antigen complexes. these complexes can precipitate out of the circulation and deposit in certain tissues. they can then trigger the classical complement cascade, recruiting inflammatory cells like neutrophils that release enzymes and free radicals causing tissue damage.
which tissues are more likely to be affected by Type 3 hypersensitivity?
- blood vessels
- synovial joints
- glomerular basement membrane
what are some type 3 hypersensitivity reactions?
- rheumatoid arthritis
- serum sickness
- post-streptococcal glomerulonephritis
how long does Type 3 hypersensitivity take to onset?
hours, days, weeks
what is type 4 hypersensitivity?
Also known as delayed hypersensitivity, it is a T cell medicated immune response where T cells and inflammatory cells cause inflammation in response to an antigen. T cells differentiate into Th-1 which releases INF-y and TNF-a cytokines to recruit macrophages and neutrophils to the site. these immune cells release enzymes and reactive molecules which cause tissue damage
what are some type 4 hypersensitivity reactions?
- contact dermatitis
- tuberculin skin test (mantoux test)
- granulomatous inflammation
- type 1 diabetes
how long does Type 4 hypersensitivity take to onset?
24-72 hours
which immunoglobulin is involved in Type 1 hypersensitivity reactions?
what is the mechanism?
IgE
Mast cell degranulation
which immunoglobulin is involved in Type 2 hypersensitivity reactions?
what is the mechanism?
IgG and IgM
cell bound antigens are attacked
which immunoglobulin is involved in Type 3 hypersensitivity reactions?
what is the mechanism?
IgG and IgM
Immune complex deposition
which immunoglobulin is involved in Type 4 hypersensitivity reactions?
what is the mechanism?
no immunoglobulins
cytokine (INF-y and TNF-a) release leads to cell damage
