Immune System Physiology: Adaptive System

Question 1

where does innate end and adaptive begin?

Answer 1

antigen uptake by langerhan cells in the skin —> langerhans cells leave the skin and enter the lymphatic system —> mature dendritic cells enter the lymph node from infected tissues and can transfer antigens to the resident dendritic cells —> B7-positive dendritic cells stimulate naive T cells

Question 2

what are the goals of adaptive immunity?

Answer 2

to specifically eliminate pathogens:
1. without causing damage to surrounding tissue or cells
2. while developing long lasting memory so that upon future challenge they can rapidly respond

Question 3

when does the adaptive system respond?

Answer 3

within hours to weeks and the duration of the response can last days to lifetime

Question 4

what are the two major types of lymphocytes?

Answer 4

1. T lymphocytes (T cells)- mature in the thalamus
2. B lymphocytes (B cells)- mature in the bone marrow

Question 5

how do T cells and B cells recognize pathogens specifically?

Answer 5

-major histocompatibility complex (MHC)
-T cell receptors (TCR)
-B cell receptors (BCR), which can also be secreted as antibodies (immunoglobulins, Ig)

Question 6

what do you need for the adaptive immune system to work?

Answer 6

you need lymphocyte development and antigen presentation to happen simultaneously

Question 7

major histocompatibility complex (MHC)

Answer 7

-needed for antigen presentation
-2 major classes: MHC Class I and II
-they are found on chromosome 17 in the mouse and chromosome 6 in humans
-referred to as human leukocytes antigens (HLAs) in humans
-present peptides to T cells

Question 8

MHC Class I

Answer 8

-product of K/D/L in mouse and B/C/A in humans
-on all nucleated cells (just not RBCs)

Question 9

MHC Class II

Answer 9

-products of I-A and I-E regions in the mouse and D region in humans
-on macrophages, dendritic cells, B cells, thymic stomal cells, and (activated) T cells

Question 10

MHC expression is co-dominant (polygenic)

Answer 10

-alleles you get from both parents are expressed on cells
-you get 3 MHC Class I alleles (A, B, C) from mom and you get 3 MHC Class I alleles (A,B,C) from dad
-you also get 6 different Class II alleles (DP, DQ, and DR) from each parent
-different combos occur in different children of the same family
-allows for diversity in antigen presentation

Question 11

how does an MHC present peptide?

Answer 11

-peptide is generated from a protein that is generally intercellular (often buried)
-brought into cell —> broken down —> loaded onto MHC complex —> MHC complex goes to the surface and expresses the peptide for T cells

Question 12

T lymphocytes (T cells)

Answer 12

-possess a T cell receptor (TCR) on the surface
-recognize foreign peptides
-kill cells, eradicate cancer cells, and activate other cells
-their activation occurs within days

Question 13

T cell receptor (TCRs)

Answer 13

-somatic recombination of TCR genes —> ALL T cell receptors are unique so every T cell has its own receptor assuming it’s not from an original parent cell
-10^11 possible combinations
-combinatorial and junctional diversity where genes are joined
-add/subtract base pairs to create even more diversity in variable region —> this is where you recognize peptides

Question 14

how does a TCR form?

Answer 14

-RAG1/2 mediated recombination
-V chain and J chain come together —> cleave off 23 and 12 repeats —> this leaves open-ended hair pins —> hair pins cleave open and DNA-PK comes in with Artemis to combine hair pins
-fill in the empty gap with random nucleotides and ligand it to make it imprecise coding joint (diversity)

Question 15

maturation of T cells

Answer 15

-originate from precursor cells in the bone marrow and fetal liver
-precursors travel to the thymus for maturation —> this is why you have a large thymus when you are younger then it shrinks as you get older
-precursors go through TCR gene unification and tested to see if they can recognize MHCs in thymus

Question 16

what are the three types of positive and negative selection?

Answer 16

1. death by neglect
2. positive selection
3. negative selection

Question 17

death by neglect

Answer 17

TCR fails to bind to MHC and cannot recognize MHC Class I/II —> dies from not receiving signaling
(fails to have sufficient binding strength to the self peptide:self MHC complexes on thymic epithelium)

Question 18

positive selection

Answer 18

T cells bind with sufficient strength to MHC self peptide —> functionally recognize but not so strong that it kills cell expressing the MHC complex

Question 19

negative selection

Answer 19

TCR has incredible strength in binding to MHC complex self peptide —> induces autoimmunity (removes thymocytes whose receptors have excessively strong reactivity to self peptides complexed with self MHC molecules)

Question 20

goldilocks concept for TCRs + selection

Answer 20

you want just enough affinity so that the TCR binds to the MHC complex but not too little since it will die and not too much that it kills the cell

Question 21

T Cell Development Complete

Answer 21

-T cells leave the thymus
-stay in the lymph nodes (cervix, armpits, legs, arms) until they encounter their cognate antigen
-develop most of the T cells as a child and stop producing past puberty —> thymus shrinks
-experience a lot of unknown exposure as a child and when an adult, no longer anything new —> naive cells can be specific to antigens
-vaccines can induce a T cell response to COVID

Question 22

cognate antigen

Answer 22

-an antigen that B or T binds to
-when professional antigen presenting cells in the lymphoid tissue present cognate antigen, it initiates a T cell response

Question 23

antigen presentation

Answer 23

-occurs in the secondary lymphoid tisssues (lymph nodes, spleen, Peyer’s patches)
-naive T cell and antigen presenting cells are needed
-2 signals are needed for activation
-results in clonal expansion of specific T cell

Question 24

principals of clonal expansion

Answer 24

-every lymphocyte bears a single type of receptor with a unique specificity
-interaction between the foreign molecule and the lymphocyte receptor will induce the cell to expand
-differentiated effector T cells will expand and are derived from original parent T cell
-daughter T cells have receptors identical to parents —> expand and clear infection
-allows for mature lymphocytes that can respond to different antigens

Question 25

2 types of T cells can be activated

Answer 25

-CD8 T cells- respond to MHC I complex
-CD4 T cells- respond to MHC II complex

Question 26

CD8+ cytotoxic T cells

Answer 26

-recognize foreign peptides on MHC Class I molecules
-kill any cell in the body with a foreign peptide
-naive CD8 is activated by APC —> receives 1 and 2 signals —> proliferates and expands —> differentiates to killer —> goes after any cell in the body
-requires secondary signal to activate but not to kill so the activation has to be very specific

Question 27

CD4+ helper T cells

Answer 27

-recognize foreign peptides presented by MHC Class II molecules —> produces cytokines to act on B cells
-help CD8+ become activated and B cells to become activated

Question 28

different flavors of CD4+

Answer 28

-Tfh- follicular helper cell that lives in the lymph node
-Th2- live in the extracellular pathways (target eosinophils, mast cells, and basophils)
-Th1- involved in the inflammatory response and viruses (target dead intracellular bacteria)
-Th17- present in the gut (target neutrophils to help with recruitment)
-Treg- regulatory T cells that tell other T cells to relax with anti-inflammatory cytokines

Question 29

T cell-mediated hypersensitivities

Answer 29

-these are rare and typically see hypersensitivities with antibodies
-the most common type are the type IV
-Th1 cells result in contact dermatitis- instead of killing macrophgaes you activate them
-Th2 cells increase IgE production —> induce allergiesand you see it in chronic asthma
-CTL cells go after cells accidentally and can also cause contact dermatitis

Question 30

B lymphocytes (B cells)

Answer 30

-possess B cell receptors (BCRs) on the surface
-secrete highly specific antibodies or humoral immunity
-BCRs are like antibodies but they are membrane-bound
-antibodies go through VDJ recombination- similar to TCR
-once antibodies form you go through many mutations to become better and stronger
-go through class switching

Question 31

class switching

Answer 31

B cells change the type of antibody molecules they produce without changing their antibody specificity

Question 32

B cell receptors (BCRs)

Answer 32

-all BCRs are unique like TCRs
-10^11 combos
-RDJ recombination like TCRs
-soluble BCRS = antibodies, which can also go through class switching

Question 33

VDJ recombination of BCR in bone marrow

Answer 33

-combo of V, J, and C in light chain and V, D, J, and C in heavy chain
-all junctional diversity occurs in the heavy chain —> this also happens with the RAG1/2 gene

Question 34

B cell development

Answer 34

-naive B cells develop in the bone marrow
-tested for autoreactivity before they leave the bone marrow and enter the bloodstream
Ex. pre B cells are rearranged and recognize things on bone marrow —> rearranged it is expressed as IgM on the surface —> must respond to self antigen presented on bone marrow cells
-immature B cell that recognizes self antigen will die whereas no recognition will help it survive
-B cells that bind to soluble antigens are allowed to exit and survive —> don’t have strong ability to bind

Question 35

positive and negative selection of B cells

Answer 35

-no reaction is preferred and don’t need survival signals to leave
-combine to self molecule not bound to cell- bind lightly they likely die in circulation anyway
-low affinity/non-cross-linking- allowed to exit and become mature B cells but tend to die since they don’t recognize antigens
-B cells then migrate after leaving the bone marrow

Question 36

B cell migration

Answer 36

-naive B cells travel through circulation in lymphatic vessels to lymph nodes via efferent lymphs
-B cell zones wait for antigen from T cells —> can exit and go to new lymph nodes
-once they see cognate antigen they form germinal centers that recognize a particular antigen —> go through somatic hypermutation process where the antibody is constantly mutated
-better binding sends in better signals

Question 37

B cell Ag recognition

Answer 37

-B cell recognizes cognate antigen
-comes in close contact with Tfh cell which a) binds antigen and b) activates the B cell
-B expresses the peptides from antigen to the TCR of Tfh —> if Tfh recognizes it will help B cell response
-antigen recognition from Tfh cells induces signals that activate B cells —> B cell proliferation generates plasmablasts that form the primary focus —> further differentiation can proceed to the germinal center, resting memory cells, or antibody-secreting plasma cells

Question 38

B cell lineages

Answer 38

resting B cells, plasmablasts, and plasma cells

Question 39

resting B cells

Answer 39

-high levels of BCR and high levels of MHC Class II
-do not secrete antibodies
-need additional growth, somatic hypermutation, and class switch

Question 40

plasmablasts

Answer 40

-high levels of BCRs and MHC Class II
-secretes antibodies
-not likely going through somatic hypermutation

Question 41

plasma cells

Answer 41

-antibody factories
-no need for Ag stimulation

Question 42

antibody

Answer 42

-Fab is composed of variable light and heavy chains as well as constant light and heavy chains —> Ag binding region
-Fc is the constant region binding to innate cells

Question 43

what are antibodies?

Answer 43

proteins made in response to a foreign antigen to that can bind to that antigen in a very specific fashion

Question 44

antibody function

Answer 44

-develop one potent enough to neutralize (make incapable) for pathogen to infect cell
-allow macrophages and neutrophils to phagocytose
-key in NK cell functionality and complement —> pathogen bound up by antibody so the complement can better recognize it

Question 45

class switching

Answer 45

constant regions determine the flavors of antibodies

Question 46

antibody isotopes + their functions

Answer 46

-IgM- secretes as a pentamer- helps with complement pathway and receptor on naive B cell
-IgD- B cell bound receptor and is always cell-bound- cannot be secreted
-IgG- circulation and activates NK cells and complement pathway
-IgE- involved in mast cell degranulation and parasitic infections plus allergies
-IgA- found in the gut and mucosal immunity
-can be formed from looping out of gene- IgM loops out of the rest of the genes and becomes IgD

Question 47

antibody-mediated hypersensitivities

Answer 47

-type I is IgE, type II is IgG as cell- or matrix-associated antigen or cell-surface receptor, and type III is IgG as soluble antigen
-IgE is the most common- with penicillin, the IgE response produces mass cell degranulation

Question 48

example of cut highlighting immune system

Answer 48

bacteria gets into cut —> mast cells release histamines that cause nearby capillaries to dilate —> neutrophils and monocytes rush to scene —> monocytes mature to macrophages once they enter the tissues —> neutrophils, macrophages, dendritic cells all release cytokines and chemokines to draw in more cells —> dendritic cells take the bacteria back to the lymph node where it activates naive T cells and they leave the lymph node to go to the site of infection
for B cell immunity:
B cells become activated and go to germinal center to produce antibodies

Question 49

when does adaptive immunity end?

Answer 49

when the antigen is gone and the cut is clear