Immunity Flashcards
What is pathology?
Study of the causes and effects of diseases
What is aetiology?
The cause, set of cause, or manner of causation of a disease of a condition
What is pathogenesis?
Progressive changes as disease develops
What is the surgical sieve?
Is an approach to differential diagnosis.
Differential diagnosis is distinguishing of a particular disease or condition from others that present with similar clinical feature.
Can use mnemonic:
Vitamin CDEF
vascular infective trauma autoimmune metabolic iatrogenic neoplastic congenital degenerative endocrine functional
Differential diagnosis informs which pathological investigations may be required
What are the key organs of the immune system
1) Thymus Where T-cells mature 2) Bone Marrow Yellow tissue in centre of bones responsible for making white blood cells which later become lymphocytes 3) Lymph nodes Produce and store cells that fight infection and disease 4) Spleen Largest lymphatic organ in the body contains white blood cells helps control amount of blood in body
What is the lymphatic system
“the motorway” - linking key organs e.g adenoid tonsils, thymus, spleen, bone marrow
transports clean fluids back to the blood
Drains excess fluid from tissue
removed “debris” from cells of body
Transports fat from digestive system
What type of immunities are there?
1) Innate
2) adaptive
What is innate immunity?
First line of non-specific defense
What is adaptive immunity?
Specific and acquired - second line of defence
What occur in innate immunity
1) Physical barrier to infection e.g. Epithelium/ epithelial layers of skin and mucosal/ glandular tissue
or. Chemical barrier to infection e.g Acidic pH + anti-microbial proteins and peptides
- cytokines/chemokines
2) Cellular responses to infection using innate cell subsets and complement
- phagocytic cells (macrophages, neutrophils)
- antigen-presenting cells (dendritic cells)
3) Chemokines/cytokines
- Chemokine - cells recruitment
- Cytokine - cell activation/ proliferation -> inflammation response
How long does does innate immunity take?
1 - 3 days
-> regular contact with potential pathogens which are destroyed within minutes or hours - only rarely causing disease
What occurs in adaptive immunity
1) B cells (humoral response) (long term immunity)
- production of antibodies -> block infections and eliminate extracellular microbes
2) T cells (cell-mediated response) (communicate with innate cells)
- cell - cell communication
e.g. phagocytosed microbes in macrophages
responded to by - helper T lymph.
Activate macrophages to kill phagocytosed microbe
intracellular microbes e.g. virus replicating withun infected cells
responded to by - Cytolytic T lymp.
kill infected cells and eliminate reservoir of infection
How long does adaptive immunity take?
4 - 10 days
repeated infections met immediately with strong and specific response
What can cause inflammation?
1) Invading micro-organism
2) particular materials (dust, join prostheses)
3) Altered self cells
4) transformed malignant cells (cancer)
What is inflammation?
1) Initiation - response to harmful agent
2) Progression - containment of harmful agent
3) Amplification - modulation of immune response
4) Resolution - healing (acute inflammation) e.g. mild/severe gingivitis
acute - appropriate response to a threat, resolution when no longer required
5) Failure to resolve (chronic inflammation) e.g periodontitis
chronic - unresolved, failure in control mechanism self damage
What is periodontitis and what causes it?
- Chronic inflammatory disease
- Destruction of soft and hard tissues which support teetj
- Plaque build up - microbial dysbiosis (microbial imbalance/maladaption)
- immune dysregulation (ie. removal of plaque not always enough)
name the innate cell subset/ immune cells
- Cells of myeloid origin:
Mast cells Monocytes ->Macrophages Neutrophils Basophil Eosinophil
- Cells of lymphoid origin:
Natural killer cells
Origin?
Dendritic cell
Innate immune cells
Describe the character of monocytes/macrophages
Monocytes - in blood macrophages - in tissue early responder Phagocytose + present antigens bactericidal mechanism
Stimulates response of other immune cells
Describe the character of Mast cells
Granulocytes (contain histamines) Early responders Blood -> tissue Function: protect again pathogens - parasitic worms \+Allergy - histamines -> inflammation
Describe the character of neutrophils
Phagocytic granulocytes most numerous Blood - tissue contain granules bactericidal mechanism Neutrophil extracellular traps -> microbes
Describe the character of basophils and eosinophils
Granulocytes -> degrade enzymes and antimicrobials
large -> defense against parasites (b: anti-parasitic immunity. E: killing of antibody-coated parasites)
allergy -> basophil histamine -> inflammation
Where are defence cells derived from?
Common precursors in bone marrow
Give example of innate and adaptive like immune cells ie the inbetweeners
Natural killer cells
dendritic cells
innate lymphoid cells
Describe the character of dendritic cells
Derived from myeloid + lymphoid lineage several types e.g langerhans cells antigen presenting cell (APC) move tissue -> lymph nodes passing on info activate T cells and B cells (directly) star shaped degrade pathogens (not main function) bridge between innate and adaptive immune responses
How do dendritic cells present antigens?
1) Pathogen or extracellular antigen phagocytized by antigen-presenting cell (e.g dendritic cell)
- placed into a vesicle.
- lysosomes to extract antigens
2) antigens bins with MHC protein that enter vesicle
3) MHC (carrying antigen) released from vesicle and travel to outer surface of cell membrane
4) dendritic cell is now presenting antigens -> activate t-cells that bind with MHC proteins
What is the role of dendritic cells in memory generation?
Immature dendritic cells take up bacterial antigens in the skin.
-> migrate to lymph node + differentiate
-> mature dendritic cells can
: prime naive t-cells (co-stimulatory activity) +
transfer antigen to other dendritic cells in lymph node
Describe the character of natural killer cells
considered part of innate immunity
large
granules - lytic (kills some virus infected cells)
recognise and kill abnormal cells/tumours/viral infected cells
holds back virus before adaptive immunity
Describe the character of Innate Lymphoid Cells (ILC)s)
Non cytotoxic (NK cell family members)
link adaptive and innate
3 subsets ILC1, ILC2, ILC3
produce cytokines similar to T cell: TH1, TH2 and TH17
ILC1: bacteria + protozoa in cells. Chronic inflammation
ILC2: helminths, asthma, allergic diseases. Metabolic homestasis
ILC3: Bacteria in cells. Chronic inflam. also Lymphoid tissue development. Intestinal homeostasis.
Where do T-cells derive from and mature?
Derive in bone marrow
mature in thymus
Where do T-cells travels
Circulate through blood and lymph.
Found in large numbers in lymphoid organ
What type of immunity do T-cells have
cellular immunity
What to T-cells protect against
Intracellular microbes
How do T- cells recognise antigen presenting cells
T Cell Receptor (TCR)
What is the T cell repertoire?
The diversity in t cells receptors = can respond to numerous antigens
How do t cells avoid responding to self peptides?
checkpoints - so t cells only respond to foreign pathogens
What types of T cells are there?
1) T helper cells (CD4+) - support immune cells to fight threat
2) Cytotoxic T cells (CD8+) - destroy our infected cells (virus)
3) Regulatory T cells (Tregs) - regulate or suppress other cells in the immune system
How do T cell start out?
As naive cells +
have receptor for very specific proteins (e.g antigencs via DC presentation)
How do cytotoxic CD8+ T cells destroy infected self cells
1) cytotoxic T cells interacts with the MHC 1-epitope complex on infected cell -> granzymes and perforins
2) perforins form pores in the plasma membrane.
Granzymes enter the cells and break down protein - lysing the cell
How are T cells activated + their fate determined?
CD4+ T cells begins are naive t cells
three signals activate + determine fate of cells
1) Activation of T cell: MHC + TCR (t cell receptor) - signal delivered by antigen presenting cell
2) Survival and clonal expansion of T cell: Co stimulation molecule interactions (CD80/86/40 on DC + CD40L/28 on T cells)
Signal 1 but no signal 2 called anergy
3) Differentiation into subset of effector T cell (specifically for CD4+ helper T cells) : cytokines/ potential signal for interleukins - signal dictates which T helper cell the naive cell becomes
For CD8+ T cells signal 3 leads to effector function e.g. production of enzymes for degradation
T cell priming also results in the generation of memory T cells
What are the CD4+ T cell subsets and their functions
1) TH1 - support macrophages -> to destroy intracellular microbes
2) TH2 - produce cytokines -> recruit + activate mast cells, eosinophils + promote barrier immunity at mucosal surfaces
3) TH17 - secret IL-17 family cytokines -> induce local non-professional immune cells to release cytokine and chemokines.
4) TFH - induce specific B cell responses (promote opsonising antibody response)
5) Treg cell - suppress T cell activity to prevent autoimmunity
What occurs when a naive t cells are presented with antigens?
it undergoes:
expansion + differentiation into effector cells
- most effector cells are short lived
How do T cells become memory cells?
only a small % become memory t cells (> 20 year life span)
Activated -> expansion -> contraction -> memory
In B cells, what does clonal expansion lead to?
2 subsets:
1) Plasma cells - antibody factories
2) Memory B cells - quick antibody response
Memory generation - B cells
Interaction between T cell and B cell
Cytokine signals released from T helper cell
induce B cell proliferation
1) generates plasma cells which produce antibodies
Initally produce IgM
Switch to IgG
2) Generated memory B cells
What cells are phagocytic cells?
Neutrophils
Macrophages
TissueDCs
Mast cells
What cells are professional antigen presenting cells
Macrophages
dendritic cells
B cells
What cells fight parasite infection
Eosinophils
Basophils
What cells are involved in allergic reactions
Basophils
Mast Cells
What cells are innate and adaptive inbetweeners
Dendritic Cells
Natural Killer Cells
Innate Lymphoid Cells
Which cells direct and control magnitude of immune reaction?
T cells
How are defence cells relevant in oral pathology?
Immune dysregulation plays a role
gingivitis -> periodontitis = differences in gum structure.
increase in the number of immune cells in the tissue
tissue is destroyed in the process.
The majority of these cells are lymphocytes.
The balance between protective and destructive immune responses is essential
Describe the response to infection
1)Innate immune response: immediate 0- hours
infection
recognised by pre-formed, non specific and broadly specific effectors
removal of infectious agents
2) Early induced innate response: early 4-96 hours
infection
recruitment of effector cells
recognition of PAMPS (pathogen associated molecular pattern) + activation of effector cells and inflammation
removal of infectious agents
3)Adaptive immune response: late > 96 hours
infection
transport of antigens to lymphoid organs
recognition by naive B and T cells
clonal expansion and differentiation to effector cells
removal of infectious agents
Name the microorganisms
bacteria virus fungi protozoa helminths
What is the innate immune response?
First line of defence (1 to 4 days)
no memory or lasting immunity
Present from birth
Effective: regular contact with pathogens, destroyed in mins/hours, rarely cause disease
responses: broad/nonspecific
contribution of non professional immune cells: epithelial/endothelial cells + fibroblasts
recruit immune cells to site of infection
What are the components of of innate immunity
1) Physical/ anatomical barrier - epithelial tissue/ mucosal barrier/ oral gingival
2) cellular mechanism
3) Plasma factors
What compounds does the epithelial barrier produce in the oral cavity?
1) Antimicrobial peptides -
1) directly kill microbes /2) module host immunity
2) Immunoglobulins (Secretory IgA) - coat microbes for host recognition
3) Lactoferrins - transport or iron ions + antimicrobial activity
4) Lysozymes - target cell walls of bacteria
5) Cystatins - anti protease activities + supports minerlization of teeth
What are antimicrobial peptides
(Host defence peptides) - small ( < 50AA) - Positive charge (cationic) - polar (water soluble ) + non polar (non water soluble section/ lipophilic) - amphipathic - attach and disrupts membranes - effective in low concentrations > 45 families in oral cavity Major families: - Beta -defensins - Human Neutrophil Peptides (HNP) -Cathelicidins (e.g. LL-37) - Psorisin proteins (S100 family)
What are the major families of antimicrobial peptides
- Beta -defensins
- Human Neutrophil Peptides (HNP)
- Cathelicidins (e.g. LL-37)
- Psorisin proteins (S100 family)
What are the functions of antimicrobial peptides
1) directly kill microbes
can have weak or strong electrostatic interactions
which causes membrane rupture or inhibit intercellular function -> bacterial lysis
2) modulate host immunity
a) chemotactic - recruit or activate immunocytes (e.g neutrophils, monocytes, DC, T cells)
b) TLR response - neutralise bacterial products to suppress inflammation + enhance nucleic acid recognition to promote auto-inflammation
What is the function of secretory immunoglobulin A (SIgA)
Produced at mucosal surfaces
(by plasma B cells -> immature IgA -> secreted in to saliva. Blind to receptor on epithelial cells -> taken up IgA molecules, process release as -> S-IgA form)
Does not require interaction between T and B cells
Binds to:
- Flagella + prevents motility
- Bacterial toxins + neutralizes
Cross links -> target macromolecules + bacteria -> trapping them and preventing effects on mucosa
prevents attachment of bacteria to mucosal surface
Describe the anatomy of S-IgA
- Dimer (11s) - multiple ends which can attach to multiple microbes
- J chain
- Secretory piece - adsorb to the saliva forming a protective layer
Binds and neutralizes pathogens/ toxins externally and internally
What is the function of lactoferrin
Glycoproteins transport iron ions antimicrobial activity present in saliva produced by neutrophils
What is the function of Lysozyme
Present in saliva
produced by neutophils/macrophages
target cells walls of bacteria - cleaving part of peptidoglycan in cell wall
What is the function of cystatins?
Anti protease activity
support remineralisation of teeth
bind to hydroxyapatite on tooth surface
Discuss the cellular mechanism in innate immunity
- innate immune cells that patrol epithelium e.g. DC, macrophages, neutrophils + microbial recognition
Microbial recognition by host:
immune cells have receptors (Toll-like receptors) for microorganisms antigens (i.e. toxins + virulence factors)
receptor activation orchestrates the immune response
different receptors recognise different antigens for different pathogens
Which Toll-like receptors are the main types for perio/gingiva tissue
- intracellular - internalised viruses
- extracellular - can recognise different components of bacteria or fungal cell membrane
TLR2: TLR6 heterodimer -> orchestrate monocytes, DC, mast cells, eosinophils, basophils
TLR-4 (plus MD-2 and CD14) -> same (not basophils)
What other non-toll-like receptors are there in the innate immune cellular response?
Toll- like receptors : Bacterial + viral recognition
Dectin + glucan receptors : fungal recognition
NOD-like receptors: Bacterial recognition
Protease- activated receptors PARs) - microbial and allergen recognition
What are the main role of the other receptors in innate immunity cellular mechanism
Promote phagocytosis of microbes
promote activation of immune cells
(TLR are: )Pattern recognition receptors (PRRS) that recognize
Pathogen associated molecular patterns (PAMPs)
Describe the innate immune response : host cell - pathogen interaction
In epithelial cells
- > Bacteria binds with TL4/ TL2 of host cell
- > signalling cascade in host cell + tells cell what to do
- > NFkB transcription factors
- > chemokines/ cytokines -> produced to attract other cells
- > chemokines/cytokines translation and processing -> protein production
- > chemokines/cytokine secretion
- > inflammatory response
What do cytokines do?
They instruct the target cell what to do-
important in differentiation of naive T cells into different T helper subsets
(third signal)
What are cytokines?
Small proteins <80kDa
signaling molecules to co-ordinate immune response
called: interleukin 1-38
grouped in to families by structure:
- Interleukin family (e.g IL-1α, IL-1β, IL-6, IL-8)
- TNF family (e.g TNF-α)
- Interferons (e.g IFN-γ)
- “unassigned’ (e.g. TGF-β)
-> some pro inflammatory, some anti-inflammatory
What are the multiple functions of cytokines
1) Autocrine - alter behaviour of cell from which they are secreted e.g. self-regulating
2) Paracine - alter behaviour of neighbouring cells
3) Endocrine - enter circulation and alter behaviour as distant cells (e.g when attracting cells to a site of infection)
What do cytokine receptors do?
-They are present on target cells
- binding induced conformational changes - in most
receptors intercellularly
-signal transduction - leads to cell “programming”
-> transcription factors
-> gene regulation/ expression -> protein
-> e.g. autocrine cell signaling - cytokine will attach receptor on self telling it’self to produce more of that cytokine.
Cytokine - cytokine receptor signalling
PRR signaling + cytokine receptor signaling -> transcription + translation of proteins
Similar types of intracellular signalling
following receptor activation:
Antimicrobials - protection against invading microorganisms
Growth factors - tissue remodelling and repair
Receptors - differentiation and proliferation
What are chemokines
Small signalling proteins - chemotactic cytokines
involved in recruitment/directing
Tell cells where to go
What is chemotaxis?
The movement of a cell in a direction corresponding to a gradient of increasing of decreasing concentration of a particular substance (e.g. chemokines)
How many classes of chemokines are there?
4 - depending on the spacing of their first 2 cysteine residues
- C chemokines (2 members)
- CC chemokines (31 members)
- CXC chemokines (18 members)
- CX3C chemokines (1 members)
receptors present on a range of innate and adaptive immune cells
Which is the main chemokine in the oral mucosa
IL8 (CXCL8)
Immune system “homeostasis” is dictated largely by
Cytokines and Chemokines
some pro inflammatory, some anti-inflammatory include Treg
Is IL8 CXCL8 a cytokine or chemokine?
Both
What immune cells are present at the oral mucosa?
Neutrophils Macrophages/monocytes DC - present antigens to T cells ILC NK cells Mast cells - degranulation Eosinophils + Basophils - like neutrophils
what is the most abundant cell type at the oral mucosa in health and increase in number during inflammation
Neutrophil
In the oral cavity, how do neutrophils get to the site of inflammation?
Attracted by chemokine CXCL8 (IL8) - along a gradient to site of infection
What are cell adhesion molecules?
How cells move to a site of infection.
Cell adhesion molecules control interactions between immune cells (e.g. neutrophils) and endothelial cells
3 main families:
- Selectins (e.g P and E selectin)
- Integrins (e.g. LFA -I) e.g. monocytes, T cells, macrophages, neutrophils, dendritic cells, NK cells
- Immunoglobulin superfamily
promote cell-cell interaction
important for immune trafficking
Neutrophils contain granules, when do they release them?
Upon activation of receptors (TLR)
What are in neutrophil granules?
Antimicrobial peptides and enzymes
What is the neutrophil NETs
Neutrophil Extracellular Traps
Activation of receptors (TLR)
- > neutrophils release proteins and genetic material (Chromatin) to form extra-cellular fibril matrix
- > trap pathogens
- > many antimicrobials in NETs -> bacteria held while administered
How to monocytes migrate?
Via cell adhesion molecule (like neutrophils)
-> different immune cells have different cell adhesion molecule
Immune cells use cell surface adhesion to move through lymphatic vessels and tissue
What are the monocyte subsets
M1 - pro inflammatory
M2 anti inflammatory
What are granules
Vesicles containing preformed mediators
- Proteinases
- Antimicrobial (AMPS, lactoferrin etc)
- Chemical mediators (e.g. histamine)
in response to:
M(P)AMPS (e.g. microbial antigens)
Complement proteins
Cytokines and other inflammatory mediators
What are the types of antigen presenting cell (APC)
1) Non-professional (Epithelial cell, fibroblasts, endothelial cells)
2) Professional (macrophages and dendritic cells)
What occurs in phagocytosis?
Overview:
1) degradation and removal of pathogenic threat
2) antigen presentation
3) safely break down and disposal of apoptotic cells
detail:
1) chemotaxis and adherence of microbe to phagocyte
2) ingestion of microbe by phagocyte
3) formation of phagosome (phagocytic vesicle)
4) fusion of the phagosome with a lysosome to form a phagolysosome
5) digestion of ingested microbe by enzyme
6) formation of residual body containing indigestible material
7) discharge of waste materials (in non antigen presenting cells like neutrophils. But in APCs e.g. macrophages or DC they antigen present)
Whats the difference between MHC I and MHC II?
MHC I
virally infected cells
MHC1 found on all cells for interactions with cytotoxic cells
MHC II
intercellular + extracellular bacteria/fungi
only on APC for interaction with T helper cells
What is phagocytosis and antigen presentation important?
It is the link between innate and adaptive immunity.
T cell and B cell responses are driven by this interaction at MHC surface (signal 1)
- antigens from digested bacterium presented with MHCII on cell surface
- MHC II binds with T cell receptor of helper T cell
- Activated helper T cell releases cytokines
- In response to cytokines, the T cell clones itself
a) B cell clones itself - > humoral immune response
b) cytokines activate B cells and T cells - > T cells become cytotoxic
- > cell mediated immune response
What are plasma factors?
Plasma = 55% of human blood
contains water, salts, enzymes, antibodies, proteins
had 4 enzymatic cascade systems
What are the 4 enzymatic cascade systems of plasma factors?
1) complement
2) kinins
3) coagulation factors
4) fibrinolytic system
inflammatory mediators produced
What is complement?
- A collection of soluble proteins present in circulation
- drives inflammation or opsonisation
3 pathways:
1) classical - antibody (formed by B cell) attached to microbe
2) alternative - microbial cell wall of pathogen
3) Mannose binding lectin pathway (MBL) - carbohydrates on pathogen surface
leading to membrane attack complex
What is opsonisation?
coating/tagging of pathogens by antibodies or compliment proteins, for removal (capsulated organisms are protected)
What is the outcome in anaphylatoxins
leads to smooth muscle contraction and capillary leakage - allowing increased infiltration of immune cells to site of infection -> drives adaptive and immune responses
Describe the three pathways of complement
1) Bind of complement protein (C3) to
- antibody attached to microbe or
- microbial cell wall or
- carbohydrate on pathogen surface
2) formation of C3 convertase
3) Cleave of C3
3a) C3b
3b) C3a -> anaphylatoxins
4) Formation of c5 convertase
4a) C5a -> MAC
4b) C5b -> c6- c9 -> MAC
all pathways leads to formation of
C3 + C5 convertase -> fragments from degraded C5 and C3 => immune response
Anaphylatoxins
Glycyproteins e.g C3, C4, C5 + fragments drive immune responses
promote immune cell recruitment Increase adhesion of cells to vessel wall (vascular permeability) induces granulation promotes cytokines production induces antigen presentation regulate adaptive immune response
vascular permeability ->
- increased fluid leakage from blood vessels and extravasation of complement and other plasma proteins at the site of infection
- migration of monocytes and neutrophils from blood into tissue is increased. Microbicidal activity of macrophages and neutrophils is also increased
Complement in periodontitis
Murine model
Prophyromanas gingivalis -> alveolar bone loss
loss of complement system (removal of c3a. c5a receptors) leads to resolution of the disease
What do t-cells drive in adaptive immunity
It drives cell-mediated immunity
involves activation of
macrophages, NK cells, antigen-specific cytotoxic T lymphocytes
What do B cells drive
Humoral immunity, produce antibodies
What is immunological memory
Each pathogen is remembered by a signature T cell and / or B cell receptor
(Note: pattern recognition receptors recognise ANY microbe but T cell/ B cell receptors are specific for specific pathogen )
What is the kinetics of adaptive immunity?
- Adaptive immunity arises following innate immune response
- > 4-7 days following infection - hence why you feel unwell for 4 days
- Threshold level of antigen to activate adaptive immune response
- small amount only - can be clear by innate immunity without help
Innate immunity
- establishment of infection
- induction of adaptive response
Adaptive immunity
- adaptive immune response
- immunological memory - pathogen cleared roughly here in timeline
Rate of growth:
Rate threshold reaching depends on growth
- fast growing pathogen = early trigger
- slow growing pathogen = delayed trigger
What are the three main receptors in adaptive immunity?
T- cell receptors (TCR)
B - cell receptors (immunoglobulins Ig)
Major histocompatibility complex (MHC proteins)
adaptive receptors can rearrange structure depending on gene expression of each protein
multiple genes encoding each receptors -> allows for a repertoire of receptors with wide specificity
In innate receptors: pattern-recognition molecules -> attach to any antibody
What is Thymic education?
Checkpoints to ensure t- cells only respond to foreign pathogens and not self peptides
Pre-thymic T cells/ undifferentiated lymphocytes educated in Thymus:
- T cells interact with cortical epithelial cells in thymus
1) positive selection - no recognition = apoptosis
2) negative selection - recognise self antigen - apoptosis
( too strong a binding)
moderate binding = T cell survives
What do CD8 + T cells bind to
CD8 is a co-receptor which binds to MHC I
What do CD4 + T cells bins to
CD4 is a co-receptor which binds to MHCII
What does CD3 activate?
CD3 is a co-receptor involved in activating CD4+ and CD8+ T cells
What are the two classes of T cell receptors
α + β chains - expressed by majority of T cells (e.g CD4+, CD 8+)
γ + δ chains - 5%
What are the regions in the T receptors
Constant
Variable
- multiple genes code for each
What 3 gene sections encode the variable region in T receptors
V (variable) - α + β chains
D (Diversity) - β chain only
J (Joining) - α + β chains
What is somatic recombination/ VDJ recombination
The process why which genes are rearranged
driven my RAG (recombinase enzyme)
3*10^11 Combinations for V(D)J
recombination lead to different receptor structure -> recognise different antigens
-> transcribe + splice
-> translate + assemble.
What is T cell migration
After positive/ negative selection/ thymic education , T cells with rearranged T cell receptors leave the thymus and circulate in blood/lymphatics
- some reside in lymph nodes (secondary lymphoid organs)
- educated but still naive T cells
How are T cells activated by dendritic cells?
Immature dendritic cells, take up and process antigen in the epidermis
they migrate to lymph nodes and mature en route
mature dendritic cells have stimulatory activity + prime naive T cells
The can transfer antigen to dendritic cells resident in lymph node
What does TH1 cell do?
Main role: support macrophage function
Other numerous functions
Source of interferon-γ -> (+ CD40) activates macrophages to destroy and engulf bacteria
What does TH2 cell do?
Supporting humoral responses and allergic reactions
sources: IL4,5,6 -> instruct B cells to produce antibodies
activates B cell -> B cell proliferates and differentiation into antibody secretion plasma cell
What does TH17 cell do?
Supports innate immune response
enhances clearance of extracellular bacteria and fungi
produces: IL 17, IL22
IL17 and IL17 - induce the production of antimicrobial peptides by epithelial cells -> killing/inhibiting growth of bacteria.
What does TFH cells do?
T follicular helper cells are found in secondary lymphoid organs in B cell zone (not T cell zone)
work together with B cells for antibody production
IL-21 -> drives B cell proliferation
- loss of T follicular helper cells in animal nodes leads to dysfunctional antibody production in geminal centre of lymph node
What does Treg cells do?
inhibits cytokines (IL10) Inhibit T cell activation and dendritic cell activation - otherwise autoimmunity (with more T effector cells)
What are B cells?
Communicate with t cells
Receptors: specific B cell receptors for antigens
Produce antibodies
clonal expansion:
1) Plasma cells - antibody factory
2) Memory B cells - quicker response to future infection
Mature in bone marrow
circulate in blood and lymph
found in large numbers in lymph organs (geminal centres)
B Cell Recepters (BCR) recognise antigens
BCR are IgM/IgG antibodies
BCR have diversity
when activated B cells change into plasma cells
What are the five types of immunoglobulins produced by B cells
1)IgG - 80% (Monomer)
4 types (1-4 66%, 23%, 7%, 4%)
resistance against virus, bacteria, toxins
2 binding sites
2)IgE (Monomer)
2 binding sites
worms + allegens
attaches to basophils and mast cells
3) IgD (monomer)
2 binding sites
B cell receptor (on surface)
4) IgM (Pentamer) 10 binding sites - bind multiple B cell receptor early response conc. declines as igG production accelerates
5) IgA (Dimer)
antimicrobial component in epithelial tissue.
2 types (1+2)
Structure of B cell receptor
1) Variable region
2) constant region
light + heavy chains
What are the three main functions of antibodies in the human body?
prevent microbial activity and aid removal of threat from host:
1) Neutralization
2) Opsonization -> coating with protein -> phagocytosis
3) Initiation of complement
What is opsonisation in B cells/antibodies
Coating of pathogens by antibodies or complement proteins.
This causes:
- Phagocytosis
- Antibody dependent cellular cytotoxicity (ADCC)
antibodies bind antigens on surface of target cell
NK cell CD16Fc receptor recognise cell-bound antibody
Cross-linking of CD-16 triggering degranulation into lytic synapse
Tumour cell dies by apoptosis
- Mast cell degranulation
What occurs in complement initiation in antibodies
Classical pathway
Binding of complement protein to antibody
antibody coating on antigen/allergen
e.g IgE attached to allergen can drive mast cell degranulation
IgG or IgM
B cell development
each stage: defined by rearrangement of the immunoglobulin heavy and light chain genes
immature B cell receptor mainly IgM
Mature B cell express both IgM and IgD on surface
once in periphery B cells migrate to secondary lymphoid organs (in germinal centres in lymph waiting for t cells)
In bone marrow: stem cell lymphoid progenitor pro b cell D-J/V-DJ early b cell late b cell immature b cell VDJ
Periphery:
Mature b cell VDJ (antigen Naive - need to react to T cell or specific antigen to change)
plasma/memory cell
B cell receptor diversity
Heavy chain: V, D, J
Light chain: V J
What is negative selection in B cells
occurs in bone marrow
Macrophages will engulf and remove self reacting B cells
No reaction to self antigen ->
immature B cell moves to the blood and expressed IgG an igD.
reaction to self antigen -> Immature retained in the bone marrow.
B cell activation
1) Thymus dependent antigen - antigen requires T cell
2) Thymus independent antigen -
occurs in lymph node
activation of naive B cell -> plasma cell
multiple signals required as with t cells activation by APC
1) interaction with T helper cell
2) co stimulation
3) cytokines tell B cell what to do
What occurs in antigen dependent B cell activation?
1) T cell and BCR interact
2) need cobinding: CD40 (on B cell) to CD40L (on T cell)
3) Cytokine signal released from T help cell ->
proliferation of B cell
-> plasma cells (IgM before class switching) -> antibodies
-> memory B cells
What occurs in antigen independent B cell activation?
Antigens e.g bacterial LPS can activate B cells directly
- > B cell differentiation
- > plasma cells (IgM -> antibody response weaken than antigen dependent B cell activation)
- > NO memory B cells
B cell activation and class switching
activation leads to class switching
IgM response is weak -> switch to IgG (or a/e)
occurs by gene rearrangement
antigen binding site remains same
repeated exposure to antigen causes affinity maturation
avidity important
What is affinity
strength of binding of single antibody to antigen
IgG usually have a high affinity for their antigen target
IgG, IgM, IgE has high affinity, low avidity
IgM has low affinity but high avidity
IgA intermediate affinity - avidity
What is avidity
Ability of antibody to form complexes
give a measure of the overall strength of an antibody - antigen complex
avidity taken in to account valency (amount of antibody binding sites) of an antigen interaction (have 1, 2 or 10 binding sites)
Class (isotype) switching in B cells - 5 types and 5 functions ? COME BACK TO
?
IgG IgM IgA IgD IgE
What are germinal centres?
Hubs for T cell and B cell cross talk about
1) proliferation and differentiation
2) Somatic hypermutation (e.g. class switching)
In lymphoid organs, cross talk leads to generation of both arms of the adaptive immune response
- humoral immunity
- cellular immunity
Vaccinations and their relation to b cells and T cells
Antigen exposure leads to immunological memory
1st:
