Physiology (Immunology 2) Flashcards
History of adaptive immunity
Innate as evoloved over billions of years
Adaptive = not evolved until hagfish and sharks - TCRs and varaible like recombinant receptors showed up 5 millions YO
- Idetified prescence of TCR by the presence of RAG1/RAG2
- VLR = like TLRs but not as specific
- Prescence of RAG1/RAg2 = can have rearange,ent in TLR = allowed for strong specfitity and diveristy of the adaptive system
Specificity of Nuetrophils
Neutrophils are not specific (kill everything around them)
- As oppose to Adaptive that is more specific
Speed of Innate Vs. Adaptive
Innate is faster because it is not specific
Adaptive is slower because it is more specific
Where does the innate immune system end and the adaptive system begin
Adaptive kicks in when all barriers fail
- Responds to inlamation fails
Have transport of antigens to lymphoid organs = B and T cells = get clonal expansion of lymphocytes = remove the infection in a specific manner
NOT linear process – ALL happening at once
Image - at the arrow adaptive system comes in
Where does Innate end and Adaptive begin
Dentritic cells in skin –> DCs see a cut –> DCs see bacteria –> DC activates cells around them –> DCs go to the lymphatic vessels –> Landher hands (DC) - leaves the site of infcetion –> enters teh Lymph nodes -> DC transfers antigen to DCs that are resitndent in teh Lymph nodes –> come into contact with T cells and B cells –> T cell recognizes this and proliferates in response to infecton (NOW Adapative STarts)
Adaptive immunity Goals
Overall: To Specifically eliminate pathogens
- Without causing damage to surrounding tissue or cells
- While developing long lasting memory so that upon future challange it can rapidly respond - so that when you see antigen again you don’t need innate immune system and T and B cells can kill it
Memory response of Adaptive system
Response to antigen A is slow at the start -> then response to A decreases (Antigen A is cleared) –> then when you reintroduce antigen A and antigen B –> Antigen A response is fast and Antigen B response is slow
Shows the ability to see an infection for the second time and response immediatly (known as “memory”) = shows memory
Adaptive Immunity Time line
Adaptive = can take hours -days-weeks
memory = can take days to days-weeks
- Memory = can last for entire life (Example - some vaccies you will never need boosters for)
Key players in Adaptive immunity
Two major types of Lymphocytes (Major players are the Lymphocytes):
1. T lymphocytes (T cells) - mature in the thalymus
2. B Lymphocytes (B Cells) - mature in the bone marrow
T and B cells specifcally recognize pathogens using Major Histocompatibility complex (MHC)
- MHC - found on Antigen Presenting Cells
- MHC binds to T Cell receptor (TCR)
- MHC binds to B cell receptor (BCR)
- MHC binds to Antibodies (Immunoglobulins, Ig)
Overall - You need lymphocyte development and antigen presentatiionf or th adoative mmune system to work
images - Images = show structures of T cell receptor and AB ; B cell recepytor is antbobdy within the memebrane
Types of B cell receptors
BCR can be on surface of B cells OR can be secreted in the form of an AB
B cells have BCR and ANtibody Complex (IgG)
Major Histocompatibility Complex (MHC)
Function - Needed for antigen presentations - present peptides process from foreign proteins (Present the processed peptides to T cells)
There are two major classes - MHC I and MHC II
Coded for by chromosome 17 in mice ; coded for by chromosme 6 in humans
MHC Function
Overal: MHCs present antigens
- Called HLA in humans (HLA = human MHC)
- Goal of MHC = preent peptides that have been processed in the cell to a T cell
MHC I vs. MHC II
MHC Class I - product of K/D/L in mouse ; produc of B/C/A in humans
- Found on ALL nucleated cells (All cells but RBCs) –> because all says have MHC 1 they can always presen what is happning on the cell
MHC Class II - Product of I-A and I-E regions in mouse; produced by D region in humans
- Only found on Antige presenting cells –> Found on Macrophages + Dendritic cells + B cells (Also on thymic stromal cells and activated T cell
Expression of MHC
MHC expression is co-dominent (polygenic)
- Express BOTH of the alleles that you get from each parent (Get 3 MHC alleles from one parents and 3 MHC alleles from alleles from other parents = express 6 alelles)
- Have many alleles allows the immune system to have diverse presentation
- Once cel express multiple alleles of the gene
- recombination can occur differentley in difefrent children = causes difefrences between children
Means that every indiviuals have 6 different classes of MHC I (Hvae 2 allels for HLA-A, 2 alleles for HLA-B, and 2 allles from HLA-C - get 1 allele from each parent)
AND
Everyone has 6 different classes of MHC II alellles ( 2 alleles of DP, 2 alleles of DQ, and 2 allles of DR)
How does MHC Present Peptide
Overall: Peptide is brought into cell and broken down –> peices are loaded onto MHC comples –> Have peptides on the MHC comples –> MHC comples goes to the surfcae and expresses the peptide for the T cel to recognize via the TCR
- The epitopse recognized by the T cell receptors are often buried
- The antigen must first be broken dpwn into peptide fragemnts
- The epitode peptide binds to a MHC molecule
- The T cell recetopr bind to the comples of teh MHC+Epitode
T Cells (Overall)
Contain a T cell receptor (TCR) on the surface
Function - recognizes foreign petides presented by MHC complex molecules
Controls alsmot every aspect of the immune respinse:
1. Directleey kills infected cells
2. Eardicates cancer cells
3. Activates other cells
T cell activation in infection happens (later within days after infection) –> get activation and expansion of T cells –> get effector function –> Kill infectted cells
Image - shows when each step occurs
T cell receptor (Overall)
Made through somatic recombination of TCR genes –> this recombination causes all T cell receptors to be unique
- Somatic recombination also occurs with BCRs/ABs
- TCR is the counterpart to the MHC
- When born you do not have formed T cells - TCR needs to form throughout development of T cells
As TCR is being formed i omepletes combintorial and junctional diveristy
- Can have joining (addition or subraction of BP) = creates more diveristy
Result of recombination/combinitoral and juntional diversity = 10^11 possible combinations
TCR vs. MHC uniqness
Have set number of MHC that can express a set repitorior of peptides
Every TCY on new T cell is unique - 10^ possible combination
- Occurs because ocmbinatorial and junctional diveristy
- when combine genes it is intentially varaible to give as much varaety as possible to recoznie as much antigems as possible
TCR characteristics
ALL TCR is unique - every T cel has a different TCR unless it is form clonal expansion
- Have 10^11 possible combination of TCR genes = 10^11 possible TCR = can recognize 10^11 peptides
- Diversity can be seen in the stop of the TCR because that is where the TCR recognizes Peptides
Somatic recombination = responsble for fomration of TCR = causes al TCR to be unique
NOTE - TCR is always a trasnmemebrane protein it is never secreted
Image - see constant vs. variable region
TCR Recombination
Recombination = mediated by RAG1/2 (TCR forms via RAG1/2 Recombination)
Process - RAG1/2 omes into germine –> RAG1/2 brings Vchain and J chain some together need RAG 1/2 –> brings V and J together –> Cleave off repeats (cleave off excess germline DNA) = get one ended hair pin –> process to cleave open the hair pon –> combine hair pin and fill in gaps with random nucleotides (process of binding together) –> ligate –> forms impresice coding joint
- Ability to make imprecisily make coding joint = creates the diversity (needed fro uniqness of T cell)
- Coding joint = when bring the two genes together
- RAG1/2 KO mice and SCID mce lack function B and T cells due to impaired VDJ recombination
Maturation of T cells
Originate from precursor cells in the bone marrow and fetal liver –> Precusors will travel to the thymus for maturation
- thymus = above heart - bigger as child
In thylmus TCR has:
1. TCR gene rearangment
2. MHC-restriction development (get tested to see if they recognize MHC)
3. Positive and negative selection
Positive and negtive selection of T cells
Purpose: Want T cells to recognize foreign antigens but not self peptides
- Occurs when imature T cells are just forming TCRs
Overall: Want TCR to recognize MHC to function BUT you don’t want it to bind too stringly
- Death by negelct - fail to have sufficnet biding strength to self peptides -Self MHC complex on the thymic epithelium = receives no signals
- TCR fails to bind to MHC
- If TCR doesn’t bind to MHC = dies because it desn’t get survival signals
- Positive selection - T cell receptors bind with suffucnet strebngth to the self peptide-self MHC complex on the thymic epithelium –> genetrates T cell recetor survival signals –> survives in the thymus
- TCR can recognize MHC bu doesn’t bind stoo stronng that it kills cel expressing MHC
- Negative selection - Removes thymocytes whose receors have excessivly string reactivuty to self-peptides-MHC complex –> results in clonal deleation
- establishes self tolerance of the mature T ell population
- Bind too string = survival signals end up being death signals
- If cell that binds too strong exits the thymus it can cause autoimmunity
Chart - Want some ability to bind (Blue box = Positive selection - ells survivig)
T Cel development (End)
Once T cell development is complete AND decide if CD4 or CD8 Tcell –> T cells leave the thymus –> enter the blood stream –> T cells will populate the lymphoid tissues throughout the body until they encounter their cognate antigen (go in/out lymohonodes lymphatic vessels/blood until they find natigen)
- Cognate antigen = peptide T ell is meant to recognize
- CD4 vs. CD 8 = decided when TCR is formiing
Antigen presentation
Location - Occurs in secondary lymphoid tisses (Lymph node + Spleen + Peyer’s patch in gut)
Requires - Naive T cell + antigen presenting cell (APC) that has the cognate antigen that T cell was made to recognize (T cell and APC comes together) - APC = DC + macrophage + B cell
- Requires 2 signals for T cell to become activated (Usually 3 are given ; 3 is ideal)
- 2 signals = T cell with MHC and a secondary signal
- Antigen expressing cell needs to express the secondary signal to engage CD28
3rd signal = cytokines from PAC = tells signal which pathwya it needs t go after (pro or anti inflamtory or Treg) depening on context of activation
- If have T cell recignize MHC but no secondary signal = cell won’t kill cell because cell is not infcet BUT if cell epxressed co-still = T ell gets activation and the surviaval signal = needed for cell to be activated (no survival sgnal T cell won’t do antyhing)
End result - Clonal expansion of specific T cell
Clonal Selection
Start - Each lymphocyte bears a single type of receptor with unique specificity
- In Naive form each T cell is 1 in a million –> when they see an antigen they expand –> when the congate antigen is clearted the T cells contract
Iteraction between a foreign molecule and a lymphocyte receptor capable of bidning that molcule with high affinity leads to lymphocyte activation
The differentiated effector cells derived from an actaivte lymphocyte will have recetpros that are of idetical specificty to the receptors of the parental cell from which the lymphocyte was derived
***Lymphocytes bearing receptors specific for ubiqitous self molecules are detected at an early stage in lymphoid developmenbt and are therefore abset from the repitore of mature lymphoctes
Principles of clonal expansion
Start - Have many T cells with different receptors –> foreign antigen binds to T cells –> causes expansion of that specific T cell –> get diaghter cells with the same receptor as the parent T cell
End - Lymphocytes with enough specificty for the antigen will expand AND the Lymphocytes without affinity will be deleted (get clonal expansion of needed T cells)
done because you need 100s of T cells to clear and infection
Activating different types of T Cells
CD8 T cells - responds to MHC 1
CD4 T cels = responde to MHC 2
CD8 vs. CD4 T cells
CD8 = cytotoxic T cell - has speciifc and drastic functions
CD4 = Helper T cell - helps CD8 cells become activated/specific AND helps amke B cells more activated/more specifc/make better AB
CD8 Cytotoxic T cells
Overall - recignize foriegn peptides presneted by MHC I molecules –> When activated they kill infected/abnoraml cells by inducing apoptosis
When gets signal 1 and 2 (MHC 1 binding to TCR and CD28) –> cell exits the lymph nodes –> T cell proliferates (IL2 clonal expansion) –> T cell differentiates to a cytotoxic killer –> CD8 T cell will kill any cell that has MHC 1
- Needs second signal to be activated BUT not to kill = need to make sure the activation is secific so it does not kill random cells (once activated it will kill all cells with peptide)
CD8 T cell vs. NK cells
CD8 T cell = similar to NK cells(both release granzyme and forfrin) = both cause apoptosis BUT T cells does this with more specificity
CD T Helper Cells
Overall - recognize foreign peptides presneted by MHC II Molecules
Influnece otehr immune cells through cytokine secreation and cell-cell intercations (makes cells do certain things)
There are many subsets of CD4 T cells
Example - Have APC –> APC chews up bacteria –> Presnet bacteria on MHC II –> T helper cells sees that –> T help goes to IL2 pathway to difefrentiate –> Depeding on conetxt of signal (Pro or anti inlamatory) it goes down different helper cel pawtahy - dependong on helper cell pathway it goes down it will secerte cytokine to infleunce the CD8 T cells function or the way B cells function (Ex. help B cell make better AB) Vs. Th1 v. Th17 vs. Tregs
CD4 T Cell differentiation
T help cells - naive CD 4 cells that gets stimulation from DC or macrophage in contect on cytokine –> depedning on context of signal it will go off on certain oathways
Example - T foliclar helper cells = cell that lives in lymph nodes and eductes B cells (drive B cell down developmental pathways + make AB) Vs. Th2 cells goes out and antiinflamatory (parasitic actions)
CD4 T Helper T cell subsets
Exmaples:
T 1 - Kills intracelular bacteria or intrcellular viruses (help macorphages kil inraccular bacteria)
- Produce IFN gamma = allows macrophages to kill intraceular bacteria
TH2 - Parasitic or alergy imunity (affects basophils and eopshenophils and mast cells)
TH17 - Used in gut and activates nuetrophils to respond (Nuetrophils go on to kill exracellular bacteria)
Tregs = quiet the immune system (stops T cell functions)
Trn = affects B cells
Each express certain memebrane proteins or Transcriptio factors to differentiate them
Normal CD4:CD8 ratio
Normal ratio 2 (CD4) : 1 (CD8)
T Cell mediated Hypersensitivities
Clonal selection is not perfect - have T cell focused hypersensitivities that exhist even though we try to have T cells not recognize self peptides
Some autoimmune diseases = t cell Specific
Example - Contact demritutis = driven by T cell types
- Th1 = drives macrophages towards contact demrintutus
Th2 drives mast eospnophils + basophils + mast cells to allergic reactions
CTLs - Can kill cells that are not infected = often results in contact dermititus
B cells (Overall)
Posses B cell receptor on surface
- Can secrete the B cell receptor –> secreted B cell receptors are AB
Function - seceret highly specific antibodies (completes hummoral immunity)
- AB = go through VDJ recombination + Somatic hypermutation (After AB is made) + Class swicthing (After AB is made)
- Make AB = attach outside invaders
- After the AB is formd you have somatic hyoermutation –> have maturation to make sure Ab gets better/stronger/more specific
B cells can form long lived memory cells
B cells are Antigen presenting cells
Function in Humoral Immunity (Adpative arm of humoral)
B Cell receptor
Have Somatic recombination of BCR genes –> leads to all BCR genes being unique
- Goes through VDJ recombination similar to TCR
- Have combintorial and Junctional diversity at the top of AB that gives diversity –> Have 10^11 possibl combinations
- Cells make a PreBCR during development to make sure it is functional then have final BCR (look similar)
AB = solble BCRs –> occurs when AB goes througha. clas switch to a certain class then get secreted
- Certain BCRs are always membrane bound ; some are secreted
What are Antibodies (AB)
Anibodies are soluble BCRs
- BCR is membrane bound and AB is secreted (AB = solble BCR)
Antibodies = go through class switchinh
B Cell development
Naive B cells develope in the bone marrow
Immature B cells are tested in bone marrow) for ability to activate before they leave the bone marrow
B cells leave the bone marrow once a functional non-self reactive BCR has been formed –> go into circulation
B cells travel to the lymhoid tissues via the blood and lymphatic system
Once B cells encounter they cognate by Antigen presented by T folilcar heler cells they go through class swicthing and somatice hypermutation (furtehr development of AB)
- They can now form long lived memory cell OR becasome plasma cells OR become antigen presneting cells
Pre B cell
Pre B cell - rearanged
Pre B cell - recgonizes signlinhg on bone marrow –> BCR ges through rearangment –: After rearangmemt it s sepxress on the surgcae –> BCR ca bind to antigens on bone marrow cell
VDK recombination of BCR
Occurs in Bone marrow ; uses Rag1/2
Combination of V, D, and C chain in light chain of AB vs. Have V, D, J in heavy chain
- Juction and combintoral diveristy occirs in VDJ chain = amkes unique = can combine to different antigens
Light chain - joining of grminline of a V and J following by C
Heaving chain - have joining of D and J THEN V, D , J then eventually a conatnt region
AB = same proetin dubpliacted twoce to make a Y
Types of Cells B cells can become
Can form long lived memory cell
Can form plasma cell
can become an antigen presneting cell
What happens to B self that recognizes self antigen
Imature B cell that recognizes self antigen will die –> Means that any recognition of bound antigen to bone amrrow cell will kill B cell
B cells that respond to soluble agents can exit and suvive but they are innergic = they don’t ahve a strong ability to bind
Once the B cells exit the bone marrow they develope more - find cognate antigen –> go through class switching and hypermutation to make AB better –> form memory cells
B cell positive and negative selection
If have NO reaction = B cell is able to migrate to the periphery (normal maturation) and survive
- No reaction is prefered (immeditalty leave) ; don’t need survival signal
If react with multivalent self molecule they are deleted
- Ubiquitus ligand (MHC)
- Can go through recetpr editing ince BUt if it fails they are killed
- Multivalent = get cross linker = stringer signal = cell can’t exit
Soluble self molecule = migrate to the perifery
- Bind to self molecule not bound to cells –> IF they bound lightly they become innergic –> likley die in circulation because they won’t bond with peptode
- Cell will migrate but they are anergenic so they will likley die from the lack of cognate signal in the periphery
Low affinity/non-corsslinking = migrate to the periphery
- Clonally ignorant and may be self recative
- They will likley die because they won’ see cognate antigens
B cell vs. T cell selection
B cell = prefer no signal
T cell = needs signal to survive
B cell migration
After selection - B cells migrate –> B cell goes through circulation in lymph vessels –> B cells enter the Lymph nodes through the afferent vessels –> Creates B cell zones (germinal center) –> B cells hand oyt and wiat until they see congant antigen in T cells –> f B cell sees antigen on T folilcular cell –.>bind antigen –> if has good bind it will go to germinal centers –> it wil reconstruct its BCR –> B cell goes back out to T folicular helper cell –> if it binds string it will go back to germinal center –> recincysract BCR again –> does this multiple time suntil it gets such a string signla that it si a god AB and it wil leave and go into periphery > In the periphery they become APC or memery cell or plasma cell thats secretes AB
- Forms clones that are chnaging BCR to be stringer binders
- If cant make BCR better it will due (no postive signal from congrante antigen the cell dies)
- forms strong B cells because goes through ultiple rounds of editting
- This process is the reason why you have different AB responses
Direction of somatic hypermutation
Editting is not directional positive or nagativ
When have better editting you have better binding = more survival signals = they will survive
If have worse edittings = has less survival signals = clone dies
Gemrinal center
Cluster of cells that all recognize a particular antigen to make a stronger bond
B cell recognition
First - BCR recognizes cognate Antigen presnetd to b cell by T follicla helper cell and comes in close contact with Tolicular cells that expresses the aantigen –> T folliclar helper cel that expresses antige feeds signals to the B cell that it is time to start activating
- T cell actiavtes the B cell further to mkae better AB (activate sto start Ab generation and somatic hypermutations)
AT the same time - B cell presnets antigens to teh T cel whcih stiulat T cell to produce more cytokines atoavting teh B cell to go down different paths
What happens once B cells proliferate
Once B cell proliferation happens and string antibody is formed - B cell cn go down diferent oaths
- B cell can stay in germinal center B cell and keep editing adn educate B cells aound it
- B cell can beocme. apalsma cell (terminally difefretaited and seerted AB)
- B cell can become memebory cell - has the same AB or BCR as plasma cell but not scereted it instead it hodls onto it untl see natigen again and goe sto lmphy nodes and mkaes more clones = more plsma cells + more AB
Resting B cell
Have rsting B cells - have high levels of BCRs + High levels of MHC2 BUT not scerting AB
- Need somatic hypermuation + gowth + need class wicthing to make better AB
- Can stay as resting or develope into a plasma cell
PlasmaBlasts
High levels of BCR and MHC2 AND can secrete AB
Not lkiley going through somatic hypermutation
Plasma cells
AB factory - atkes AB that have been developed and secretes them as much as possible into circulation
- Doesn’t need additional antigen stimulation
- Temrinal point for B cell
Antibody (Overal)
Antibody = proetins made in resonse to a froeign antigen taht can bind to the antigen in a very specific fashion
Fab region - has light (constant) and heavy (Varible) chains
- Fab = AB binding region
Fc Region - Cell binding region (binds t innate cells ae any cell with Fc receptor)
- Constant region
Antibody function
Goal of AB - Develop an AB potent enough to nuertilize any apthogen (make it incapable for pathogen to infect cell and caise damage)
- Nuertolize micobes and toxins
- Opsinization and phagocytosis of microbes (Allows macrophages and nuetrophiles to phagocytose cells)
- Antibody dependent ceullar cytotoxity
- Compliment activation - helps proteins bind to compliment = get more phagocytosis + inflamation + death of microbes
- Imporant for NK cells - brings antigen closer to NK cell = NK can kill
Can have complement activations which leads to:
1. Phagocytosis of micrboes opsonized with complement fragments
2. Inflamation
3. Lysis of microbes
Macrophages and AB
Macrophages have Fc receptor to bind to Fc of AB ; AB is also bound to the antigen –> MAcriphage is able to bind to Fc regio of AB and pill in antigen and detsroy antigen
Antibody Class switching
There are 5 different classes of AB
Different AB classes have different function
- Have different types of Antibodies
Constant region determines the type of AB - formed by looping out of gene
Antibody Isotypes
- IgG
- IgM
- IgA
- IgE
- IgD
IgG
Best studies
Found in circulation - most abundent serum AB (has specilizd subclasses)
Functions:
1. Opsinizatiion
2. ADCC by NK cells
3 Activation of clasical pathay of complement
4. Feedback inhibition of Bc ell activation
5. Neonatal immunity (Crosses the womb to placenta - placental and colostral transer)
IgG
Most abudent serum antibody
Specilized usbclasses
Function:
1. Opsinization
2. ADCC by N cells
3. Activation of the classical pathway of compliment
4. Feedback inhibition of B cell activation
5. Neonatal immmunity (placental and colostral ransfer of IgG1)
IgA
Function:
1. Nuertralization
2. Mucosal immunity (in gut)
Secreted as a Dimer
Most abunden AB
IgE
Function:
1. Mast cell degranualtion
Affects parasitic inefction + Allergy
Antibody Meidtaed hypersensativities
Have AB mediated hypersensitivities
IgE is most common 9most are dirven by IgE - mast cell repsonse to something
- Example - penecilin - repsonds to IgE = get histamines
- driven by IgE = allergies + Asthma + rjhynuits
Some driven by igG - Antibiotic allergic responses - invloved macrophages going crazy becase AB and compliment activation
IgG = Solble antigen reponse
IgE
Function:
1. mast cell degranulation –> Affect parasitic inefctons and allergy
- Binds to mast cels –> leads to mast cell degranulation –> get histaomine in system –> get alergic reaction
Review of Innate Vs. Adaptive Immunity
Innate immunity – have physical barriers + moleculaar barriers + cellular barriers
Adaptive – Have APC +. cell immmunity + B cell immunity
Putting it all together
Example - Get a cut
get a cut –> Mast cells secret histamins that casie nearby capilaries to dialte –> nuertophils and moocytes leave capilaries –> Mnocytes will mature to macrophages –> Nuertophils + DCs + Macrophages will release chemicals that stimualte inflamatory response AND Nuetraphils and macrophages will consume invading bacteria via phagocytosis
Putting all together (MINE)
have cut –> bacteria gets into cut –> Intial response is AMst cels in area make histamines that cause capilaeries to dialter = alows nuertrhis and monocytes to get to site –> Monocytes because macroohages in tissues + Nuertals + DCs will release things in reponse to infectoon –> get inlanattion and draws more cells to come in and attch bacteria ; mac wil pagnosytse bacteria –> DCs wil take bacteria to lyhode node –> Actiavte D4 or CD8 t cells –> t cells go to site of infcation –> CD8 T cells kill cells in area that are inefcted –> CD 4 tells cell shelp mac kill bvayceria and induce more pro inflamatory response in area ; At the same time B cells are activated by antgen and folicular cels = go to germinal centers = make AB –> once have good Ab the cells exit and make Ab and some cells stay to imporve Ab (Stops when antigen is gone) –> then clear cut
Look at IgM and IGD
