TOPIC 12 - immunology Flashcards
what does the immune system provide protection against?
- microbial pathogens including bacteria, viruses, parasites, fungi
- tumor cells
what is innate immunty
- First line of defence- deal with pathogen before adaptive immunity kicks in
- Non-specific response
- all animals have it
what is adaptive immunity
- Second line of defence
- Highly specific with memory= faster and greater response in future infection
what is active immunity
-Antigens enter body and trigger
Innate and adaptive immune systems
-Provides long term protection
what is passive immunty
-Antibodies pass from mother to
Foetus across the placenta
-Infant in breast milk
-Provides short term protection
what is the common stem cell which immune cells originate from?
common pluripotent hematopoietic stem cell
in bone marrow
what are the linages of pluripotent hematopoietic stem cell
Myeloid lineage generates
Lymphoid lineage
what cells are in the myeloid lineage
Polymorphonuclear leukocytes (neutrophil, eosinophil, basophil) Monocyte/macrophages, dendritic cells, mast cells
what cells are in the lymphoid lineage
- B- and T-
- natural killer (NK)
- lymphocytes
what are Polymorphonuclear leukocytes or granulocytes
characterised by multilobed (2 to 5) nuclei and cytoplasmic granules
what are neutrophils
- Principal phagocytic cell of innate immunity
- Rapidly migrate to sites of infection
- ingest microbes by phagocytosis
- release oxygen free radicals
- degranulate releasing proteins with microbicidal properties e.g. lysozyme
what are eosinophils
Important defender against multicellular parasites and have a role in allergy and asthma
what are basophils
Involved in inflammatory allergic reactions. Releases the potent vasodilator, histamine.
what are monocytes
-Circulate in blood, bean shaped nuclei, precursors of
tissue macrophages.
- Effectors of the inflammatory response to microbes.
- Kills pathogens via phagocytosis, free radical production, myeloperoxidase and inflammatory cytokines.
what are macrophages
- Derived from blood monocytes
- Participate in innate and adaptive immunity
- Phagocytosis, microbicidal mechanisms, antigen presentation to other cells
what are dendritic cells
Process and present antigens (antigen presenting cell {APC}) on their cell surface to T-lymphocytes to initiate specific immune responses.
what are mast cells
Similarities with basophils, release histamine, close association with allergy and inflammation
what kind of immunity are small lymphocytes involved in immunity
specific immunity
what do b lymphocytes do?
B-cell
- produce antibodies
- present antigens to other cells (APC)
- can produce long lived memory cells- rapid and faster production of antibody on second exposure/ subsequent viral infection
what do t lymphocytes do?
T cell
- plays critical role in development and regulation of cell mediated immunity
- Influences the activities of other cells (e.g. B-cells)
- able to kill virally infected and tumour cells
- generate long lived memory cells
what is a natural killer cell/NK cell and what do they do?
Large granular lymphocyte
- generally considered part of the innate immune response.
- Release perforins and granzymes
- trigger apoptosis in target cell.
- Kill infected cells which do not express foreign surface antigen, respond rapidly, involved in tumour immunosurveillance
what are the 2 key immunological sites in the body
primary lymphoid tissue
secondary lympoid tissue
what is 1’ lymphoid tissue
Development and maturation of lymphocytes: bone marrow (B lymphocytes) and thymus gland (T lymphocytes)
what is 2’ lymphoid tissue
Mature lymphocytes encounter antigens/pathogens:
Includes: lymph nodes, spleen and lymphoid tissue at other sites e.g. tonsils, appendix, adenoids, Peyer’s patches (in ileum),bronchial associated lymphoid tissue (BALT).
where are lymph nodes found
Found at specific sites in the body:
- armpits
- jaw
- neck
- axilla
- elbow crease
- groin
- behind the knee
where do ‘virgin’ B and T lymphocytes come from?
home from bone marrow and thymus to specific
sites in lymph nodes.- swelling around areas with lymph nodes
what happnes to size of lymph nodes
During infection, architecture and size of nodes change in response to activation and proliferation of lymphocytes
what is the spleen
- Lymphoid organ in the abdomen
- Removes damaged or old erythrocytes
- Key site of activation of lymphocytes from blood borne pathogens
what is the architecture of spleen?
Red pulp:
Erythrocytes removed
White pulp:
Lymphocytes stimulated
what are the mechanical barriers in the innate immune system
- Provided by skin and mucous membranes
- competition with normal flora/microbiota
- mucous entraps
- cilia propel microbes out of body.
what are physiological barriers in the innate immune system
- stomach acid kills some pathogens
- fever response inhibits pathogen growth
what are chemical mediators in the innate immune system
- Lysozyme cleaves bacterial cell wall
- Interferon induces antiviral defenses in uninfected cells
- Complement lyses microbes directly or facilitates phagocytosis
what are phagocytic leukocytes involved in the innate immune system
Phagocytes - Cells specialized in the process of phagocytosis
Macrophages: Reside in tissues and recruit neutrophils, become activated release cytokines (TNF, IL1)
Neutrophils: Enter infected tissues in large numbers, become activated , release cytokines (TNF), phagocytose bacteria
what NK cells invovloed in the innate immune system
- Summoned from the blood
- Release cytokines (IFN-γ, IL2)
- Kill infected cells (trigger apoptosis)
what is the adaptive immune system and what does it do
- called into action against pathogens that overcome innate immune defences
- system “adapts” to the presence of an infectious agent by activating, proliferating, and creating specific responses to eliminate the microbe
what are the 2 types of adaptive immune responses?
- humoral immunity
- cell-meidated immuniuty
what is humoral immunity
mediated by antibodies produced by B lymphocytes
what is cell mediated immunity
effected by T lymphocytes
in what state are cells in in a non-infected tissue?
- resident macrophages : eating up dead and dying cells in the tissue. general ‘gardening’ duties.
- dendritic cells: on sentry duty waiting for the first sign of a pathogen
- most monocytes and neutrophils in the blood stream pass the healthy tissue
what happens during the first wave in an infected tissue?
- dendritic cells exit the infected tissue to from lymphocytes in the lymph nodes about the invading pathogen
- neutrophils from the blood stream into the infected tissue to kill the pathogen
what happens during the second wave in an infected tissue?
- neutrophils have killed pathogen but they have destroyed themselves in the effort: ‘pus’
- monocytes flood in from the blood stream and become inflammatory macrophages
- macrophages clear away debris, while some may also migrate to lymph nodes to inform lymphocytes about infection by presenting antigen to lymph nodes and so getting production of antibodies
what happens in the resolution stage of an infected tissue?
inflammatory macrophages change properties as the infection resolves and help to repair damage to the tissue
what kind of cells do macropahges phagocytose?
- dying cells
- opsonized cells and pathogens
how do macrophages recognise if a cell is dying ?
membrane plasma lipid profile changes when cell dies and macrophages can recognise this
how do macrophages recognise opsonized cells and pathogens?
the surface is coated either with complement proteins
what is the oponization?
- term that refers to an immune process where particles such as bacteria are targeted for destruction by an immune cell known as a phagocyte
- oponization process is the means of identifying the invading particle to the phagocyte
what happens to an opsonized cell?
- If the cell or pathogen is coated with antibodies it can be efficiently taken up by the Fc receptor on macrophages
- the Fc receptor on the macrophages binds with an Sc receptor and facilitates the uptake of opnized cells/pathogens
what do dendritic cells do in infection?
migrate to lymph nodes to recruit lymphocytes to fight
- dendritic cell presents antigen to niave t cell
what specialisation do dendritic cells have?
- has specialised receptors on its surface that allow it to recognise patterns of foreign molecules (eg.clusters of sugars that are present on surface of many pathogens
= kick start immune response
what does the niave t cell do after being presented with dendritic cell?
proliferate and the daughter t cells can help b cells
what do the b cells do following help from the t cells?
- b cells proliferate and produce antibodies
- antibodies coat pathogens so that macrophages phagocytose them
how does the body produce antibodies following phagocytosis
-Although macrophages can’t present to naïve T-cells they can present to the primed daughter cells of a T-cell activated by a dendritic cell.
=The body can produce lots more antibody now if the infection continues
what is the name of the cell that confers immunity in us?
antibodies
they recognise antigens
what type of antigen causes an immune response to be raised?
immunogen
antibodies are called immunoglobulins
what are the 5 different classes of immunoglobulins?
IgA, IgD, IgE, IgG, and IgM
what is the structure of IgG
- IgG is made up of two pairs of two different proteins/ 4 bits:
- heavy chain (Hc)
- light chain (Lc).
- two identical antigen binding regions (Fab)/ variable region on heavy and light where antigens and molecules recognised as forgein- antigen binding sites there.
- Variable region on heavy and light = highly polymorphioc areas(occuring in several froms)- form grove between 2 variable regions of chains= little pocket antibody can get into.
- In IgG = 2 antigen binding sites both identical
- The specificity of the antibody binding to its antigen is due to the folding of the Fab region, which matches the shape of the antigen molecule very precisely.
- The tail region (Fc) can bind to Fc receptors on the surface of immune system cells such as macrophages.
- Constant regions on heavy and light chains – joined by disulphide bridges
how specific are B cells?
exist as clone of cells that produce one specific antibody with variable region to detect antigen
what happens to the specific antibodies produced by b cells?
transported to the surface of the cell, to become B cell receptors (initially IgD).
Each B cell will have thousands of these BCRs, but all of them on that cell are identical
what happens when B cells bind to variable antigen binding site on immunoglobin(antibodies)?
triggers and stimulates B cells to divide its cognate antigen the cell proliferates
- After about a week of proliferation, there will be a clone of around 20,000 identical B cells in the blood all recogising that specific antigen
what 2 types of cell do B cells produce?
- plasma cells
- memory cells
what do plasma cells do?
- produce the antibody to fight the infection
- memory cells that survive in the blood stream so that if the antigen is encountered in the future
what happens if an inactive B cell is exposed to an antigen?
- first exposes igD and IgM as they are in the transmembrane membrane
- activates cell = poliferation = clones
- some clones turn into plasma cells
- mature plasma cells = secrete antibody
- some B cells into memory cells
what is IgD?
B cell receptor
what is IgM?
- B cell receptor
- pen-emetic (5 of them linked together)= has potential to bind 5 times normal amount
- has 2 binding sites
- main antibody responsible for fixing complement molecules
- main antibody formed in 1’ antibody response
what is IgA
- b cell receptor
- has 4 antigen binding sites
- associated in mucus membranes
- in tears
- in saliva
what is IgG
can cross placenta and can fix complemts
- involved in phagocytosis
what is IgE?
associated with allergy
how does the gene recombination work: what are the building blocks for variable regions?
the variable, diversity and joining segments
how does gene recombination from heavy chains?
- gene segments link together
- 48 variable regions an 5 constant regions : at random selected and put into heavy chain
NB- constant regions not part of the actual antigen binding site
what are the segments to the heavy chain genome?
V gene
D gene
J gene
C gene
what is special about the C gene?
C-segment lets you only choose from alpha, delta, epsilon, gamma and mu and are therefore called the constant genes
(…….IgA-D-E-G and M)
how do we get diversity in B cells?
rearrangement of immunoglobulin gene segments
- followed by somatic hypermutation in gene
what is somatic hypermutation?
- mutation rate high in antibody genome = change variable region of gene
- one mutation may increase affinity of variable region for particular antigen = antigen binds stronger = more selection for that clone = higher affinity for antigen
- If randomly hypermutation increases affinity, then antigen clone expressing the better antibody will receive more stimulation than other clones so it will divide more and more of the high affinity antibody will be produced.
how do antibodies function?
label invading organisms so that they can be destroyed by other parts of the immune system
1) antibodies bind to bacteria and viruses = opsonization :
- fab region of the antibody binds to the antigen on the surface of the microorganism and Fc regions are available to bind to Fc receptors on the surface of cells such as macrophages
- binding of Fc also helps activate the macrophage
- this enhances phagocytosis due to linkage
2) bound antibody also triggers complement activation and lysis of bacteria by the classical pathway
what does opsomisation mean?
to prepare for eating
how cab antibodies stop viruses entering cells?
Antibodies can also bind to viruses to prevent them from entering into cells, and target them for destruction
what is the 1’ antibody resposnse?
exposure to an antigen, there is a slow rise in IgM followed by a slow rise in IgG
what is the 2’ antibody response?
- rapid and greater rise in Specific IgG
- limited rise in IgM
- much quicker and greater response
- higher affinity antibody produced = protection against disease
- much stronger and faster immune response: memory/ anamnestic response
what kind of receptors do T cells display on their surface?
TCRs
what is the structure of T cells?
- alpha and beta chain
- constant and variable region
- variable region for antigen recognition
how do T cells arise?
Like antibodies, they are also very diverse and arise from
recombination of gene segments in a similar fashion.
are T cells receptors released from cells?
no,
remain on the surface of the T cell and exhibit clonal expansion, in response to peptides that they recognise
how do T cells recognise an antigen?
only recognise an antigen when it has been properly presented via the Major Histocompatibility Complex (MHC) of another cell
what id MHC?
Major Histocompatibility complex
- molecules important in recognising self
antigens that discriminate us from forgein bodies
if 2 individuals are histocompatible what does this mean?
- tissues can be transplanted from one to another without rejection = can get transplantation from that person
how do MHC’s vary?
MHC don’t vary as a result of VDJ- recombination as with antibodies or TCR
- we inherit genes that are very polymorphic from our parents
why are MHC complexes important?
T cells only recoginse antigens as complexes with MHC molecuels
how are peptides presented on the surface of APCs
in association with MHCs
what is MHC presentation?
allows immune cells to discriminate between normal antigens on the surface of all cells, and those that are foreign and potentially dangerous.
what are MHC class 1?
- MHC class I proteins are present on almost every cell in the body
- They present endogenous antigens that are synthesised in the cytoplasm
how do antigens bind to MHC class 1 proteins?
- Samples of all proteins made on ribosomes, whether normal host proteins are chopped up into short peptides the proteasome.
- The resulting peptide fragments are transported into the endoplasmic reticulum, where peptides of ~10 amino acids can bind to MHC I proteins
- These peptide MHC complexes are transported via the Golgi apparatus to the cell surface.
- Once at the cell surface, the membrane-bound MHC I protein displays the antigen for recognition to cytotoxic T cell lymphocytes. (CD8+)
- If foreign (viral) protein fragments are detected as forgien , t lymphocyte the cell is killed otherwise the cell is spared.
what are MHC class 2 proteins?
MHC II proteins are only present on specialised antigen-presenting immune cells - macrophages, dendritic cells and B cells .
MHC II proteins present exogenous antigens that originate extracellularly from foreign bodies such as bacteria
how do antigens bind to MHC class 2 proteins?
- Following phagocytosis, foreign peptide fragments are bound to MHC II proteins in the endosome, before being transported to the cell surface.
- Once at the cell surface, the membrane-bound MHC II protein displays the antigen.
- It is recognised by a different type of T cell, namely the helper T cell lymphocyte (CD4+)
- The binding of helper T cells to B cell MHC II-antigen stimulates the development of antibody-producing B-cells against that antigen (T-cell help)
what is the best way to eliminate viral infection
to destroy the cells which that virus has infected before that cell can release new virus particles.
Class I presents viral proteins to CD8+ve cytotoxic T-cells.
whats the best way to kill bacteria/yeast
generate antibodies that will clump the pathogens and mark them for ingestion or for further attack by the complement system.
Class II presents bacterial/yeast proteins to CD4 +ve helper T-cells to promote the expansion of B cells.
how do we prevent B and T lymphocytes attacking self cells?
- they are so diverse so can have the potential to attack own cells
- carefully selected and educated during development to not responds to ‘self’
- if system goes wrong: auto immune disease- type 1 diabetes
what are autoimmunity disorders?
Misdirected adaptive immune response
Results from a loss of self-tolerance
(e.g. type I diabetes, rheumatoid arthritis, Crohn’s disease,
vitiligo, thyroiditis, multiple sclerosis)
what are disorders of hypersensitivity reactions?
Over-reaction of adaptive immune response (types I-IV ) (examples: peanut allergy, asthma)
what are disorders of immunodeficiencies?
- Components of immune system either absent or defective
- Genetic or acquired etiology
(e. g. AIDS, congenital complement deficiencies)
what does innate immunity cause?
local redness and swelling associated with other infections
what is the innate immunity composed of?
- Complement activation (blood plasma)
- Phagocytosis by macrophages and neutrophils
- Natural killer (NK) cells
NB: involves humoral (fluid phase) and cellular responses
does innate immunity involve memory cells?
has no memory and responds in same way every time to repeated infection
- slower than adaptive immunity
what are the effectors of the complement system?
1- MAC
2- Anaphylatoxins
3-Opsoniastion
4- Activate and atttract Neutrophils
what is Mac
membrane attack complex
-“stabs” invading pathogens- protein complex that makes pores/perforates cell membrane of pathogen or virus and so kills it
what is anaphylatoxins
- byproducts from activated complement factors which play a role in allergic reactions and anaphylactic shock
- controlled through key in fighting infection
what is opsonisation
priming/ labelling of pathogens to get recognised by phagocyte for phagocytosis
what is the role of the complement system?
role in priming the removal of pathogens by macrophages and neutrophils
what are the 3 complement activation pathways?
Classical
Lectin or mannose-binding
Alternative
what do all complement activation pathways inc the activation of
complement factors C3 and C5
what is the classical pathway activated by?
antigen-antibody complexes
so requires activation of adaptive immune system first
what are the main complement factors in the classical pathway?
serine proteases (similar to trypsin but only cleave on particular factor)
NB- complement activation involves limited proteolysis-cleave only one (or few) other protein(s) in only one place- to activate the next factor
wha does the classical pathway produce?
Limited proteolysis leads to the activated complement factor and a byproduct:
Produces anaphylatoxins, opsonins and MAC
what are the 5 steps the classical pathway
- activated when C1 binds to antibody/antigen complexes (generated by adaptive immunity)
- C1 cleaves complement factor C2 into C2a and C2b by proteolysis
- C1 also cleaves factor C4 into C4a and C4b
- C2a and C4b form a complex which cleaves factor C3 into C3a and C3b
- C3b joins the C2a/C4b complex forming a C2a/C4b/C3b complex which cleaves C5 into C5a and C5b
- C5b finally forms a complex with C6, C7, C8 and C9 producing the Membrane-attack complex (MAC) which perforates the cell membrane of pathogens or virus-infected host cells- produces pore
what complement factors play role in anaphylaxtoxins?
C3a
C4a
C5a
what complment factors play role in opsonisation
C3b
binds to pathogens to prime phagocytosis by macrophages
Complement factors are from the same enzyme family as trypsin, but act with much higher substrate specificity
true or false?
true
what does the mannose binding lectin (MBL) bind to?
mannose found on the surface of pathogens
what two things does MBL bind?
MBL Associated Serine Protease (MASP) 1 & 2 which activate C2 and C4
Rest of pathway (C3-9) identical to the Classical pathway
which pathogens activate Lectin pathway
Yeast (Candida albicans)
Viruses (HIV and influenza A)
Bacteria (Salmonella and Streptococci)
Parasites (Leishmania)
what 2 pathways have direct contact with the pathogens?
The alternative pathway,
the lectin path
what happens in the alternative pathway?
Spontaneous low-rate auto-activation of C3: that ot can be negligible
Auto-activated C3b binds to proteins factor B and properdin on pathogen surface which activates more C3 and activates C5
Rest of pathway the same as classical (C6-9)
what can uncontrolled anaphylatoxins lead to?
anaphalactic shock as large conc involved in allergic reactions
what do anaphylatoxins trigger?
- Trigger degranulation of endothelial cells, mast cells (histamine) and phagocytes
- Cause smooth muscle contraction and enhance vascular permeability= easier for neutrophils and NK cells to infiltrate infected tissue
- C3a and C5a are chemoattractants for neutrophils- activate and attract neutrophiles to site of infection
how does the process of opsonisation by C3b work?
C3b binds pathogen
C3b is cleaved to iC3b/ inhibited C3b
Macrophages contain receptors for iC3b, facilitating phagocytosis
what cells have phagocytosis has main function
professional phagocytes:
Macrophages
Dendritic cells
Neutrophils
NB-NK cells function differently
how does phagocytosis work?
- chemotaxis and adherence of microbe to phagocyte
- ingestion of microbe by phagocyte : macrophage, dendritic cell or neutrophil
- formation of a phagosome
- fusion of the phagosome with a lysosome to form a phagolysome
- digestion of ingested microbe by enzymes in phagolysome
- formation of residual body containing indigestible material - creates APC
- discharge of waste materials
where are macrophages located?
skin
lungs
intestines
are macrophages part of the first or second line of defence?
first defence against pathogens
what are the 3 main activation states of a macrophage ?
resting
primed
hyper-active
what does a resting macrophage do?
- collects tissue debris
- eliminates apoptotic cells
- low MHC class 2 expression
- class
what are MHC class 2 molecules?
cell membrane proteins that are specific for antigen-presenting cells such as macrophages and dendritic cells and that present antigens from ingested pathogens onto the cell surface for antigen recognition by helper T cells
what kind of cells present MHC class 2 molecules?
professional macrophages
class 1 is presented by all of the cells
what is a primed microphage?
Primed by interferon gamma (IFN-g) produced by NK cells and helper T cells
Increased expression of MHC II
Increasingly phagocytotic
what is a hyperactive macrophage and what does it do?
Stimulated with IFN-g and lipopolysaccharide (LPS)(molecule produced by bacteria) produced by Gram-negative bacteria
Stop proliferating, become larger and very phagocytotic
Produce cytokines: tumour necrosis factor (TNF) and interleukin-1 (IL-1)
TNF in reinforcement recruit more natural killer cells and white cells
where do we fins neutrophils
Reside in the blood (cf. macrophages)
where are neutrophils activated?
Activated and attracted to site of infection
are neutrophils short lived or long lived?
short lived - 5 days
recruit more and more when there’s an infection to the site
what do neutrophils do?
” sniff out” infection
what is the mechanism by which neutrophils “sniff out” infection and what key molecules are involved?
“Double-key” mechanism to infiltrate inflamed tissue from the blood:
Selectin Ligand (SLG)– (present on neutrophils and SELECTIN expressed on inflamed vascular endothelium)
ICAM – Intercellular adhesion molecule on endothelium of tissue/blood vessel
Integrin: INT- on surface of neutrophil : bind to ICAM
Selectin and integrin are expressed and activated in response to IL-1, TNF, LPS and C5a
under normal conditions what is expressed in a neutrophil cell?
neutrophil expresses Selectin ligand on its cell membrane and the endothelial cell expresses Intercellular Adhesion Molecule, which are incompatible and the neutrophil circulates freely.
what happens with neutrophils when the tissue is inflamed and activated?
IL-1 and TNF is secreted by hyperactive macrophages
= TNF stimulate the expression of Selectin on the endothelial cell membrane to which SLG on the neutrophil binds.
-Selectin-SLG interaction not strong enough to stop the neutrophil completely= cells bind and start “rolling” on the endothelium
-C5a accumulates in the inflamed tissue due to increased complement activation, and the bacteria secrete significant amounts of lipopolysaccharide (LPS), LPS and C5a activate integrin on the neutrophil
-INT binds ICAM on endothelial cells: interaction is so strong, that the cells stop rolling and stick to the vascular wall close to the site of infection
what is the role of F-Met peptides
Human proteins: N-terminal Methionine (Met)
Bacterial proteins: N-terminal Formyl methionine (F-Met)
Neutrophils “track” F-Met peptides
F-Met peptides are secreted by macrophages after phagocytosis of bacteria
what stimulates neutrophils infiltrating infecting tissue?
C5a and F-Met peptides
= vascular permeability
what other molecules do neutrophils secrete?
- TNF to activate NK cells and neutrophils
- Very phagocytotic upon activation and infiltration of infected tissue
what is pus?
Short-lived neutrophils : pus at sites of injury/inflammation
what is an NK cell?
The assisted suicide cell
Stops every cell it encounters and checks it out
Like bouncer in night club
Lymphoid (cf. macrophage and neutrophil)
where is the NK cell found
Blood, liver and spleen
what is the mechanisms by which an NK cell operates?
“Roll, stop, exit” mechanism to infiltrate infected tissues
what is the function of an NK cell?
IFN-g & IL-2 production- helps activate further WBC
Apoptosis of infected cells:
- Fas on NK cell binds Fas ligand on target cell
- Saves healthy host cells by recognising MHC-I on host cells
- If meets virus or pathogen binds fas ligand and no MHC class 1 – will release:
- Perforin(makes cell leaky) and granzyme B (“suicide” enzyme/apoptotic): molecular messengers inducing apoptosis of infected cell.
how does the innate system act with virus infections?
- Complement opsonises viruses with C3b
- Complement produces MAC on enveloped viruses
- Virus-infected host cells
- NK cells induce apoptosis
- TNF and IFN reduce viral reproduction
what are the 3 things specific immunity is characterised by?
Learning
Adaptability
Memory
what are the components of specific immunity?
Cellular:
- B cells (bone marrow derived)
- T cells (thymus derived)
Soluble:
- Immunoglobulins/antibodies in circulation (produced by B cells)
- Cytokines (many produced by T cells) to activate and enhance other parts of immune system
what are cytokines?
messenger molecules that are released by T cells to signal other cells in the immune system that they need to respond to an invading microorganism.
many different cytokines.
what do B cells do?
-present immuogloblin on surface produce a vast array of antibodies that recognise specific antigen
Each B cell produces a specific antibody that recognises a specific antigen
what happens when an antigen binds to the antibody?
Antibodies act as B cell receptors- if antigen binds through b cell receptor = stimulate cell proliferation
release lots of the same antibody into the plasma
does only one B cell recognise one antibody?
one or more b cells which are capable of recognising and binding that antigen to stimulate an immune response
is antibody-antigen interaction enough to activate B cells to proliferate and mature into plasma cells?
no
second signal is needed
explain the second signal needed for B cell activation
- provided by T cell help
T-dependent antigen:
- B cell requires: 1) interaction with T cell and T cell receptor and MHC- T cell interaction
- T cell releases cytokines and IL-2 and 4 = stimulates B cell further and activates it
T-independent antigen:
cell generates antibodies independently
e.g. bacterial lipopolysacharride, polysaccharide,
Antibodies generated= lower affinity- IgM type memory cells not the same
what are the 2 steps in B cell maturation?
i) Clonal expansion
ii) Production of large amounts of the antibody
what is clonal expansion?
Each specific B cell proliferates to produce a clone of identical cells (ie producing the same specific antibody
can produce plasma or memory cells
what are memory cells and what do they do?
B cells remember an antigen
If B cells are confronted by an antigen on a second occasion, the Ab response is much quicker (memory) and larger= pathogen quickly dealt with
This forms the basis for immunity and vaccination
explain the 1’ response
- Following exposure to an antigen B cells responsible for that antigen proliferate and divide and release
- slow rise in IgM followed by a slow rise in IgG
- Sub population of IgM cells undergo class swithcing and produce IgG
- Also have population of cells that produce memory B cells and not plasma cells
explain the 2’ exposure
-After primary exposure levels decline so if we add boost ect.
Following exposure to previously encountered antigen, there is a rapid and greater rise in specific IgG (and limited rise in IgM)
Memory or anamnestic response
Basis for vaccination
do B cells only generate the antibody or can they also be APC?
can act as APC
= can stimulate T cell arm of the immune system- so can trigger immune system aswell
interaction between B and T cells is crucial for a healthy immune response
does vaccination require a cellular response or does it mainly target the complement system?
no
requires interaction between B and T cells to generate antibody
what do the 2 recognition sites on an antigen allow for?
that antibodies can cross link pathogens, which is one way to stop them invading cells (viruses) or multiplying (bacteria).
what family of proteins do antibodies belong to?
immunoglobulins (Ig)
what are the 5 types of immuniglobins ?
IgG IgD IgE IgA IgM
where is IgG found and what does it do?
Major Ig in the blood
Enters tissue space
Prepares bacteria to be killed
where is IgD found and what does it do?
Found in B cell membrane
Helps cell division
where is IgE found and what does it do?
Trace amount
Allergic reactions
where is IgA found and what does it do?
- Protects entrance of pathogens
- Saliva, tears, GI & respiratory tract
where is IgM found and what does it do?
Mainly bloodstream
Kills bacteria
what are the levels of immunoglobin rsposnse to an antigen?
Early Ig response is low affinity IgM
mainly blood stream
Later immune response is of high affinity IgG type
Blood and interstitial tissue
B cells can change the type of antibody they produce (not the specificity). This is called class-switching and will be explained later
how do vaccinations work?
Prime immune response with killed/part of bacteria ect. So we lay memory cells down This relies on the introduction of: Live attenuated virus Killed virus Part of a virus Killed Bacteria Part of bacteria
Immune response develops and provides long-lasting immunity- memory B cells
Booster injections may be required
what 2 antigens does the Hepatitis B infection have?
serious condition and relatively common
-Hepatitis surface antigen (HBsAg): detected in active disease.
-Hepatitis core antigen:
not tested for but antibodies can be detected (HBcAb) indicating current or previous infection
if aptient has HBs surface antibodies but nor for core antibodies what does this mean
vaccination to HepB is performed using surface antigen of the virus only
NB: If exposed to antigen itself we would nave antibodies for both surface antigen and core antigen = been exposed to hepatitis in past
what diseases involve B cell over activation?
Graves’ disease (autoimmune hyperthyroidism) is production of antibodies that mimic the action of TSH
This leads to uncontrolled hyperthyroidism as previously discussed
Detection of high levels of a particular antibody is frequently used in the diagnosis of autoimmune disease
do B cell kill bacteria?
b cells do produce antibodies but usually coat bacteria – other parts of immune response effect killing system
B cells do play key role in activating t cells
what are the 3 main types of t cell?
- T helper cells (Th) cells
- T killer cells
- T regulatory cells (Tregs)
what do T helper/ Th cells do?
- CD4 +ve
- Help one another
- Activate B cells
- Activate phagocytes by releasing gamma interferon = activate macrophages and stimulate phagocyes and phagocytosis
what do T killer cells do?
- Cytotoxic T lymphocytes (Tc) (CD8 +ve)
- Effective at attacking viruses (virually effected cells)
what do T regulatory cells do/ Treggs
not fully understood
- regulate or suppress other cells in the immune system - protect against autoimmune disease
how do t cells recognise cells?
need antigens “presented”, otherwise can’t recognise or respond to them
which cells present the antigen
Monocytes and macrophages
B cells
Dendritic cells
what happens once T cells presented with antigen?
- T helper cells Boost the immune response –e.g. release IFNg activating macrophages
- Kill directly (CD8 +ve)
do t cells express receptors on their surface?
yes
express receptors on their surface that are specific for a specific antigen. However, the TCR only recognises the antigen when it is presented together with an MHC molecule
what molecules are t cells associated with?
-CD3 molecule (CD3/TCR complex)
-
what are CD4 associated with
t helper cells
what are CD8 associated with
cytotoxic t cells
how is an antigen presented to t cells?
- Antigen is processed
- Antigen is presented in conjunction (MHC)
- MHC is present on all cells and they are individual-specific
MHC I for CD8 +ve cytotoxic cells (Tc)-result is that the Tc cell will kill the infected cell.
MHC II for CD4 +ve Helper cells (Th)- release cytokines to trigger an immune response.
how are t cells activated?
antigen is processed and presented in conjunction with MHC class I or II to T cells
A second signal is needed, otherwise T cell fails to be activated and becomes “anergic” / not respond to antigen
why is a second signal needed to activate the t cell?
prevent T cells being activated by the body’s own (host) antigens, which would lead to an autoimmune response
comes from the recognition of a CD28 molecule on the T cell by a CD80 molecule on the APC cell
Only when the presentation is made by an APC, with the necessary CD80 molecule as well, will the Th cell be activated
what does the activation of t helper cells result in
cytokine production leaing to:
- Chemoattraction of other cells
- Autoactivation of themselves
- Augmentation of inflammation (increased level)
- Stimulation of Ab production by B cells
what does the activation of t cytotoxic cells lead to?
cell death
can b cells activate t cells?
b cells antigen presenting cells and activate t cells which can activate b cells to produce antibodies
where are cytokines mainly produced?
lymphocytes- mainly T cells
what do cytokines do?
Draw more cells to site of injury
Activate T cells
Activate B cells and cause Ab production
Activate macrophages
what do Th1 cytokines do?
Th1 activate cell mediated immunity
IL-2, IL-15, IFN-g
what do Th2 cytokines do?
Th2 are responsible for antibody production
IL-4, IL-10, IL-13
is the balance between Th1 and Th2 important?
affect autoimmune diseases that can developImmune treatment of multiple sclerosis (Th1 disease) can result in the development of Graves’ disease (Th2 condition)
how does HIV attack the cell?
HIV virus has an antigen on the surface called gp120- binds to cd4 on cd4 positive t helper cells
CD4 forms the receptor for this antigen (virus is attached to CD4 cells)
Virus injects its RNA and reverse transcriptase into the cell (transforms RNA to DNA) and forces the cell to make viral genes and forget about its own function, with the net result of HIV replication
Virus replicates in cd4 helper t cells and bursts open
how is central tolerance miantained in bone marrow/ B cells
Clonal deletion when cells encountering self are recognised
Further B cell receptor gene editing-Ig gene rearrangement- early development
how is clonal selection mainatined in thymus/T cells?
Positive selection: only cells recognising MHC survive
Negative selection: cells recognising self antigen die (clonal deletion)
what is centeral tolernce?
stop immune system mounting response against self antigens
what is peripheral tolernce
Once the lymphocytes have developed and entered the periphery, they can be eliminated by regulatory T cells if they recognise self antigens.
Regulatory T cells (Tregs) that eliminate immune cells directed against self antigens
Absence of second signal when lymphocytes are activated / antigen presentation (immune cell anergy)
Anatomical barriers and immune privileged areas:
Inside the eyes (injury to one eye can cause immune destruction to the other eye causing blindness – complete tragedy)
what are autoimmune diseases?
AD occur when self tolerance against a body antigen is broken
give examples of organ specific autoimmune conditions
Thyroid disease
Type 1 diabetes
Pernicious anaemia
Some skin conditions
give examples of non specific autoimmune conditions
Systemic lupus erythematosus (SLE)
explain the process of B cells interacting with T cells
- Antibodies are triggerd when a B cell encounters its matching antigen
- the B cell takes in the antigen and digests it
- then it displays antigen fragments bound to its own distinctive MHC molecules
- the combo of antigen fragment and MHC molecule attracts the help of a mature, matching T cell
- lymphokines secreted by the T cell allow the B cell to multiply and mature into antibody-producing plasma cells
- released into the bloodstream - antibodies lock onto matching antigens - antigen antibody complexes are soon eliminated either by complement cascade or by the liver and spleen
why is the interaction between a B cell and a T cell described as a 2 way process
The B cell that has recognised its specific antigen will only proliferate and mature after it has interacted with a Th cell (by presenting the antigen with the MHC class II molecule to the Th cell).
whats the innate process is in B cells in comparison to T cells?
B cells:
cellular- neutrophils
soluble- complement
T cells:
cellular - NK cells
soluble- cytokines
what is the acquired process in B cells in comparison to T cells?
B cells:
humoral immunity
extracellular organisms
T cells:
cell-mediated immunity
intracellular organisms
where are endogenous antigens derived from?
degradation/waste products produced in the proteasome
where are exogenous antigens derived from?
degradation of phagocytosed material in endosomes
what is needed in addition to MHC, CD8/4 and a T cell receptor?
co stimulator
what happens in the absence of a co-stimulator?
anergy - no T cell activation, cell temporarily unresponsive to all signals
what is positive lymphocyte selection?
need to recognise pathogenic antigens (non self)
what is negative lymphocyte selection?
need to ignore self antigens to prevent auto-immune response
what is tolerance lymphocyte selection?
need to tolerate harmless non-self antigens to prevent damage/disease
what happens to T cells that bind and recognise self antigens in the thymus?
apoptosis (negative selection)
what do T cells express after proliferation in the cortex?
both CD4 and CD8
what determines which co-stimulator stays on the surface of the T cell?
MHCI or II plus antigen
what are self antigens produced by?
medullar thymic epithelial cells
what prevents self recognition?
expression, breakdown and MHCI/II presentation of organ-specific proteins
what is acquired tolerance in the reproductive system?
eutherian fetoembryonic defence system
- foetal material (gametes) lack MHC molecules so are invisible to lymphocytes
- overproduction of glycoproteins buries antigens and suppresses immune response
how is tolerance built over time?
presence of growing concentrations of environmental antigens that increasingly get presented by the antigen presenting cells and therefore considered as self antigens
what is class switching?
swapping of constant (Fc) region so Ig can change type (5 types with identical recognition sites)
what Ig are circulating as first defence?
IgM (main and low affinity) and IgD
what are polyclonal antibodies?
antibodies from 2 or more different B cells that target the same pathogen but via a different antigen
what are monoclonal antibodies?
every lymphocyte creates a unique antigen binding site - by activation B cell clones are formed - their antibodies are identical
what is somatic hypermutation?
in the vdj gene segments mutation frequencies are very high - occurs after first B cell activation
what is the benefit of hypermutations in the variable region?
- a mutation can cause a worse, equal or better binding to the antigen
- mature B cells continuously need to be activated to proliferate so there is ongoing positive selection leading to higher antigen affinity
how does class switching occur?
somatic hypermutations - switches to higher affinity
what happens if negative T cell selection fails?
anergy —> self recognising CD8+ cells start attacking cells
- self recognising CD4+ could cause positive selection of a maturing B cell in lymph node —> makes self recognising antibodies
AUTO-IMMUNE DISEASE
what is antigenic shift?
genetic shuffling - different types of a virus blend and a new subtype is formed
what is antigenic drift?
random mutation change antigenic profiles to evade immune system
