Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Immunology > Exam 2 > Flashcards

Exam 2 Flashcards

1
Q

The life of a B cell

A
  • repertoire assemsbly
  • negative selection
  • positive selection
  • searching for infection
  • finding infection
  • attacking infection
  • first three happen in bone marrow, second three happen in secondary lymphoid tissues
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Rearrangement of Ig genes markers successive stages of B cell differentiation

A

Heavy chain assembled first. Expressed with the Cµ chain (Cd not expressed until later)

k light chain genes rearrange next. If attempts to make k light chain are unsuccessful, l chains rearrange

IgM expressed on cell surface

Development is guided by stromal cells (fibroblasts, adipocytes, osteoblasts, endothelial cells) in bone marrow through cell-cell interactions and cytokines like IL-7

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Ig gene rearrangement results in productive and nonproductive rearrangements in pro-B cells

A

D-J on both chromosomes rearranges (efficient)

V splicing to D/J occurs on one chromosome at a time

1/3 chance of maintaining the reading frame for each chromosomal rearrangement

Successful rearrangement is tested by ability to express the m heavy chain

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

The pre-B cell receptor monitors the quality of the Ig heavy chain

A

Second test: Rearranged heavy chain is interrogated for ability to assemble with light chain PRIOR to light chain expression

VpreB and l5 are made by pre-B cells and act as a light chain surrogate. They are conventional proteins (not made by gene rearrangement, not variable). Pre-B cell receptor is expressed in intracellular vesicles

If assembly of the pre-B-cell receptor is successful, signals through Igb turn off gene rearrangements at heavy chain locus and pro-B cell receives survival and proliferation signals

In the absence of functional pre-B-cell receptor, cell dies by apoptosis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Rearrangement of light chain genes in pre-B cells

A

Unlike at the heavy chain locus, multiple V to J recombinations can occur

Rearrangement occurs on one chromosome at a time beginning with the k locus

At each V-J recombination event, there is a 1/3 chance of success

Up to 5 attempts per chromosome possible (5 Jk segments)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Light chain rearrangement

A
  • k gene rearrangement happens first, one chromosome at a time.
  • if successful then cell expresses mu and k
  • then lambda locus rearranges
  • if successful cell expresses mu and lambda
  • once it travels to the surface, rearrangement stops
  • if no success, apoptosis
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Expression of heavy and light chains during B cell development

A
  • pro b cell
  • HC rearrangement
  • proliferation
  • successful HC rearrangement pass the surrogacy test
  • approximately 100 cells each cell expresses same HC
  • LC rearrangement in each cell
  • population of cells with same HC but different LC
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Ig gene rearrangement generates random specificities – many will be directed against self Ag

A
  • No reaction with self ag; immature b cell moves to the blood and expresses IgD and IgM
  • reaction with self ag; immature b cells is retained in bone marrow
  • multivalent self Ag in bone marrow (on stromal cells, hematopoeitic cells, plasma proteins)
  • negative signal delivered to immature B cell by multivalen ag
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Autoreactive receptors on immature B cells can be modified by receptor editing

A
  • receptor editing only occurs on light chain genes
  • self antigen ligates immature B cells IgM
  • cell receives signal to maintain expression of RAG proteins
  • immature B cell continues to rearrange light chains
  • further rearrangement generates a new VJ and simultaneously removes the old one
  • immature B cell makes a new light chain and thus an IgM with a different specificity
  • if the new receptor is self reactive, light chain genes continue rearranging
  • if the new receptor is not self reactive the b cell leaves the bone marrow
  • if the cell runs out of V genes to try, the celldies
  • this is called clonal deletion
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Immature B cells reactive with monovalent self Ag are made nonresponsive to Ag

A
  • IgM of immature B cell binds soluable univalent self antigen
  • B cell is signaled to make IgD and to become unresponsive to ag
  • enters the peripheral circulation but does not survive for long
  • soluble proteins tend to be monovalent
  • binding of monovalent self Ag in bone marrow to immature B cells induces anergy
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

B cell tolerance to self Ag

A

Three mechanisms operate on immature B cells to deviate away from self-reactive Ab:

  1. Successful receptor editing away from self-reactivity
  2. Death by apoptosis
  3. Induction of anergy

This is called central tolerance because it occurs in primary lymphoid organ

Some immature B cells leave bone marrow and encounter self Ag not found in bone marrow.

These cells become tolerant by induction of anergy or induction of apoptosis

This is called peripheral tolerance

Some B cells remain that are reactive to self Ab normally inaccessible to B cells (e.g., interior of cells)

Systemic lupus erythematosis: autoimmune disease in which patient makes Ab to DNA

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Transition from immature to mature B cells requires entry into secondary lymphoid tissues

A

Enter lymph node from blood through the high endothelial venules (HEV)

In primary lymphoid follicle, they encounter follicular dendritic cells that provide final maturation signals (immature to mature B cell transition)

B cell retained if encounter with specific Ag occurs

If not, cell leaves via efferent lymphatic vessel

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

T cell development; general consideration

A

Same lymphoid precursor in bone marrow gives rise to B cells and T cells

T cell precursors leave bone marrow and travel to thymus. This is where TCR gene rearrangement occurs. CD4 and CD8 T cells are generated here. abTCR and gdTCR are generated here. T cells in thymus are called thymocytes

TCR gene rearrangement occurs in thymus

Positive selection enables survival of T cells with TCR reactivity to self MHC. Cells with no self MHC reactivity die

This is followed by negative selection, which induces death of T cells with TCR that are too strongly MHC reactive (mechanism to avoid autoimmunity)

After these selection events, mature T cells leave thymus to populate the periphery

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Thymus slowly degenerates after one year

A

This phenomenon is called thymic involution

A long-lived repertoire of mature peripheral T cells established at birth. They may also be self renewing

Note this differs from B cells, which are continually differentiating from bone marrow precursors throughout the host lifetime

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

general course of t cell development

A
  • Thymic cortex: double negative precursor
  • thymic medualla; double positive cell
  • become single postive and then exit to blood
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

cell death in thymus due to unsuccessful rearrangement of TCR

A

2% of thymocytes successfully rearrange their TCR. 98% undergo apoptosis

Apoptotic cells are phagocytosed and cleared by thymic macrophages

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

TCR rearrangements in DN thymocytes

A
  • DN start to rearrange their B, y and d loci
  • y and d genes rearrange and commit; assemble with CD3 on cell surface; leave and migrate to tissues, do not undergo positive selection in the thymys
  • B chain gene rearrangement, pre TCR and arrangement stops and expression of CD4 and CD8; pre T cell rearrangement of a y a d
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

Structure of pre t cell receptor

A

Successful assembly of a functional pre-TCR is a checkpoint in T cell development

pTa is the functional equivalent of the surrogate light chain

Pre-TCR forms a superdimer with CD3 molecules. The pre-T cell receptor serves as both receptor and ligand, delivering a signal to stop b, g, d rearrangement and start making CD4 and CD8

Cell reaching this stage are called pre-T cells

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

TCR B locus rearrangements

A

-two attempts can be made to acheive a productive rearrangement

Two attempts because there are 2 D gene segments

Note: if rearrangement involves first splicing to Cb2, rescue of nonproductive event not possible because Db1, Jb1 and Cb1 has been spliced out!

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

Events immediately following successful TCR b chain rearrangement

A

RAG1 and RAG2 turned off – allelic exclusion at the b locus

Pre-T-cell undergoes proliferation creating a clone of cells expressing the same Vb chain

Proliferating cells express CD4 and CD8 (most thymocytes are DP)

After cessation of proliferation, RAG1 and RAG2 and associated enzymes re-expressed and a, g and d undergo rearrangement

Successful expression of a chain and b chain (and assembly in to TCR) marks the second checkpoint in T cell development

The result is a T cell expressing functional TCR and both CD4 and CD8. This cell can become either a class I-restricted CD8 T cells or a class II-restricted CD4 cell

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

The strange situation of the d-chain locus

A

-rearrangement of an a chain gene always elimates the linked d chain locus

Any Va to Ja rearrangement (productive or not) deletes the whole d-chain locus

So a cell committed to the ab lineage cannot aberrantly express a gdTCR simultaneously

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

Positive and negative selection of T cells

A

In the thymus a population of T cells co-expressing CD4 and CD8 with random ab TCR specificities are generated

TCR recognize peptide Ag and self MHC, so T cells with TCR that can recognize MHC must be selected for survival - positive selection

Of the positively selected T cells, those expressing specificity for MHC + self peptides must be eliminated to avoid autoimmunity – negative selection

Selection occurs in the thymus

Because of receptor editing at the Va locus, a pre-T cell can try out several TCR specificities in the positive selection screen

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

Positive selection

A

Thymic cortical epithelial cells express both MHC1 and MHC2, and therefore present self peptides on both

These cells interrogate newly formed T cell receptor (TCR) positive, DP T cells

Recognition of either MHC1 or MHC2 = survival. Progeny of the T cell are restricted by that particular MHC1 or MHC2

2% of DP cells survive this test

whatever it interacts with is what it becomes (MHC1=CD8, MHC2=CD4)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

Negative selection

A

-eliminates strongly autoreactive T cells

Dendritic cells and macrophages in the thymus interact with DP cells through self MHC + self peptide

Occurs mostly at the cortical/medullary junction

When the interaction is too strong, cell receives a DEATH signal (apoptosis)

Negative selection is a mechanism of central tolerance in T cells

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

What about self antigens NOT found in the thymus?

A

Autoimmune regulator (AIRE)

Transcription factor in thymic medulla epithelial cells

Induces transcription of low amount of various tissue specific self antigens

These can be tested in combination with MHC and used to select against T cell autoreactivity

Another mechanism of self tolerance

Some people lack functional AIRE, resulting in autoimmune polyendocrinopathy-candidiasis ectodermal dystrophy (APECED). Wide spectrum autoimmune disease affecting several tissues

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

Regulatory T (Treg) cells – A distinct CD4 lineage

A

Treg recognize self MHC2 + self Ag

Suppress activation of autoreactive CD4 cells that escape negative selection in the thymus

Operate outside the thymus. A peripheral tolerance mechanism

Suppression involves direct cell-cell contact and cytokines but mechanism not well understood at present

Suppression of autoreactive T cells by Treg requires them to interact with the same APC

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

T cell mediated immunity

A

Three important phases to consider:

Activation of naïve T cell by Ag + MHC

Differentiation of activated T cell to an effector cell

Effector function of the T cell – how it fights infection

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
28
Q

When DC takes up Ag

A
  • transport it to secondary lymphoid organs to activate T cells
  • DC take up ag in the skin and move to enter draining lymphatic vessel
  • DC cells bearing ag enter the draining lymph node where they settle in T cell areas
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
29
Q

Immature DC characteristics

A
  • highly phagocytic
  • low MHC expressiodn
  • Low expression of costim molecules
  • Chemokine receptor CCR 6 expression (response to MIP3alpha in tissue)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
30
Q

Mature DC characteristic

A
  • low phagocytic activity
  • high MHC expression
  • high expression of costim molecules
  • CCR7 expresion (respond to MIP3Beta in lymph node)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
31
Q

DC cell presentation to T cells

A
  • receptor mediated endocytosis of bacteria, presentation via MHC2
  • Macropinocytosis of bacteria or virus, MHC2
  • Viral infection, MHC1
  • Cross presentation of exogenous viral ag, MHC1
  • Transfer of viral ag from infected DC to resident DC, MHC1
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
32
Q

Naïve T cells encounter Ag-bearing DC in the lymph node

A
  • T cells that do not recognize Ag/MHC leave via the lymph and continue recirculation
  • T cells that recognize Ag/MHC on DC are retatined in the lymph node where they undergo activation and proliferation
  • After T cell activation and acquisition of effector function, T cells leave lymph node and home to the site of infection
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
33
Q

T cell: DC interaction

A
  • T cell initially binds DC through low affinity LFA-1 ICAM 1 interactions
  • Subsequent bind of T cell receptors sends signal to LFA1
  • Conformational change in LFA1 increases affinity and prolongs cell-cell contact
  • interaction of T cells with DC involves low affinity transient interaction followed by stable binding if TCR/MHC pep contact is established
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
34
Q

The two signal model for T cell activation

A
  • the combo of an antigen specific signal and a costim signal is required to activate a naive T cell
  • Professional antigen-presenting cells express B7
  • These include DC macs and B cells
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
35
Q

Costimulation

A

Costimulatory molecules like B7 are only expressed on activated B cells, macrophages and most importantly DC

DC in tissue normally do not express B7

Activation of DC by infection stimulates B7 expression and therefore cells become licensed to deliver signal 2 for T cell activation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
36
Q

Infection factors causing DC activation:

A
  • Microbial molecules recognized by TLR and other pattern recognition receptors
  • Inflammatory cytokines (most important: TNF-a and IFN-g)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
37
Q

T cell activation

A
  • TCR/MHC pep and CD28/B7

- causes activation, proliferation and aquisition of effector function

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
38
Q

IL-2 drives early expansion of Ag-specific CD4 T cells

A
  • activated T cells have high affinity T cell receptor
  • naive t cells express low affinity IL2 receptor
  • autocrine signaling because induces production of IL2 from the T cell
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
39
Q

T cells that encounter Ag MHC without B7

A
  • become anergic

- cell remains non responsive even if costim occurs later on

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
40
Q

Why costim?

A
  • T cell selction in the thymus is not 100%
  • some autoreactive cells escape into periphery
  • Once a t cell has been activated, does not need costim
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
41
Q

T Cell Activation Leads to Increased Expression of CTLA-4

A
  • This is an inhibitory receptor for B7 molecules
  • initiation of response: cross linking of CD28 delivers the co stimulation signal during activation of naive t cells and induces expression of CTLA4
  • Later in response: CTLA4 binds B7 more avidly than does CD28 and delivers inhibitory signals to activated T cells
  • Important to turn the response off
  • CTLA4 engagement stops T cells from proliferation, they eventually die from apop
42
Q

CD4 T cell fates

A
  • Th1
  • Th2
  • Th17
  • TFH
  • Treg
  • Th effector cells are fully differentiated and do not require costim
43
Q

TH1

A
  • induced by IL12 and IFNy
  • T bet txn factor
  • secretes IL2 and IFNy
  • activate macrophages
44
Q

TH17

A
  • induced by IL6 and TGF B and IL23
  • RORyT txn factor
  • secrete IL17 and IL6
  • enhance neutrophil response
45
Q

TH2

A
  • induced by IL4
  • GATA 3 txn factor
  • secrete IL4 and IL5
  • activate cellular and ab response to parasites
46
Q

TFH

A
  • induced by IL6 and IL21
  • Bd6 txn factor
  • secrete IL21
  • activate b cells and maturation of ab response
47
Q

Treg

A
  • induced by TGF B
  • foxP3 txn factor
  • secrete TGF B and IL 10
  • suppress other effector T cells
48
Q

Most cytokines exert their function by binding to receptor on target cell and triggering JAK/STAT signaling

A
  • cytokine recptor su and JAK are separate
  • cytokine receptors bind JAK
  • cytokines binding assembles the receptor which is then P
  • STATs bind to P receptor and are then P
  • P STAT dimers go to the nuclue and initiate gene signaling
  • Different JAK and STAT triggered by different cytokine
49
Q

Th subsets are often counter regulatory

A
  • patients that control Tb form of leprae make strong Th1 response, patients with lepromatous form make a strong Th2
  • cytokines produced by Th1 promote production of more Th1 and down regulate Th2 and vice versa
  • results in polarization of the immune response
50
Q

Activation of CD8 T cells

A

Follows same principles as activation of CD4 cells (although it requires Ag presentation on MHC1

Dendritic cells carry Ag in to lymph node activate CD8 cells

Requires same two signals

Autocrine IL-2 drives proliferation

Effector CD8 cells are called cytolytic T lymphocytes (CTL)

51
Q

It is harder to activate naïve CD8 cells!

A
  • Requires more potent DC activation signals (and therefore greater surface density of costimulatory molecules)
  • then can make their own IL2 to drive proliferation
  • Or: Requires help from activated CD4 Th1 cells that provide additional IL-2
52
Q

Cross presentation enables exogenously derived peptides to enter the class I presentation pathway

A

A mechanism for peptides to cross from the MHC2 to the MHC1 presentation pathway

Important: This is necessary for CD8 T cell activation against viruses that do not infect DC!

Exogenous ag usually presented by MHC2

53
Q

Once a T cell (CD4 or CD8) is activated, costimulation is no longer required for Ag-specific effector function!

A
  • The requirement for signal 2 is relaxed in T effector cells
  • This is especially important for CD8 cells that must recognize and kill virus infected cells
  • Also applies to CD4 cells that may encounter tissue macrophages or B cells in lymph node that are expressing Ag+MHC2 but little or no B7
54
Q

Cytotoxic T cells killing

A
  • form an immmunlogical synapse and destroy the target cell by triggering apoptosis
  • have granules containing cytolytic molecules
  • specific recognition redistributes cytoskeleton and cytoplampic components of T cell
  • Release of granules at the site of cell contact
  • contents of granules enters host and triggers apoptosis
  • also release IFN y
  • Are “serial killers”
55
Q

activation of macrophages via Th1

A
  • Macs need 2 signals
  • IFNy and ligation of CD40 ligand (on the T cell) and CD40 (on the macrophage)
  • Th1 cell and infected macrophage come together
  • T cell binds and activates
  • Killing of intravesicular bacteria occurs
56
Q

TFH cells act in lymph nodes to help the B cell response

A
  • TFH cell recognizes a peptide derived from the B cell’s antigen- MHC2
  • Naive B cell and TFH cell exchange signals that begin the process of B cell activation
  • Mutual stimulation: T cell recognizes MHC2, Express CD40L, T cell secretes cytokine, induces B cell activation
57
Q

TH2 function

A
  • Promote basophil, mast cell and eosinophil degranulation
  • Important in control of parasitic worms
  • Same responses form the basis for allergies
58
Q

TH17 function

A
  • Release of IL-17 induces cells in infected tissues to release chemokines and cytokines that mobilize neutrophils in bone marrow and recruit them to site of infection
  • Neutrophils phagocytose and degrade microbes
  • Therefore Th17 cells are specialized in killing extracellular pathogens
59
Q

Treg function

A
  • Down regulate T cell responses
  • Secrete down regulatory cytokines (IL-10, TGF-b)
  • Important in preventing autoimmunity and cytokine-mediated pathology
60
Q

Structure of B cell co receptor

A
  • CD81, CD19, and CR2
  • CR2 is a complement receptor
  • Binding of CR1 to C3b bound to pathogen facilitates its cleavage by factor I to iC3b and C3d
  • CR2 component of B cell co receptor can then bind to C3d
61
Q

The B cell co-receptor enhances signaling mediated by surface IgM

A
  • b cell receptor and co receptor cooperate in B cell activation by a pathogen
  • bacterial cell binds to IgM via Ag
  • OR b cell and co receptor cooperate in B cell activation by a soluable Ag
  • C3d binds Ag and brings it to IgM
62
Q

Thymus-independent antigens

A

Most B cell responses to Ag also require T cell help
Thymus-dependent Ag

Highly repetitive and densely packed Ag (especially carbohydrate Ag) stimulate B cells strongly enough to get by without T cell help

However, the antibodies produced are low affinity IgM and not very effective
Thymus-independent Ag

63
Q

Follicular dendritic cells (FDC )

A
  • serve as repositories for B cell antigens in secondary lymphoid organs
  • Extensive system of dendrites promotes accumulation of antigen
  • Expression of CR2 (receptor for C3d) promotes binding of complement-opsonized Ag
  • Zero phagocytic activity in FDC retains Ag on the cell surface
  • Warning! FDC are NOT the DC we encountered in the context of T cell activation. They are NOT professional APC!
64
Q

Activated B cells and Ag-specific T cells meet at boundary between T cell and B cell region of lymph nodes

A
  • naive B cells search for specific Ag displayed by FDC in the b cell area, naive t cells search for specific ag presented by DC cells in the T cell area
  • Ag activated t cells proliferate and differentiate; ag activated b cells move to boundary region
  • ag activated b cells present ag to effector TFH cells, forming cognate interactions and cognate pairs
65
Q

Cognate interaction at the B cell/T cell boundary

A
  • helper t cell conjugates with the b cell and begins to synthesize cytokines and CD40L
  • the helper TFH cell reoritents its cytoskeleton and secretory apparatus toward the B cell
  • cytokines are secreted into the narrow space between TFH cell and the B cell
  • B cells are acting as APC for the TFH
  • Adhesive contact promoted by LFA-1/ICAM1 interactions
  • TFH cytokines targeted to B cell
66
Q

Back-and-forth behavior of B cell/TFH pairs in the lymph node

A
  • Dividing B/TFH cells
  • B cells secrete IgM; IgM leaves LN and goes into circulation
  • Some B cells stay here and differentiate into plasma cells under the influence of TFH
  • Other B/TFH pairs go to the primary follicle
  • Rapid B cell proliferation mediated by FDC cytokines results in formation of a germinal center
  • TFH continue to proliferate providing further help

-Large, rapidly dividing B cells are called centroblasts
Interaction of germinal center B cells with TFH induces AID (activation-induced cytidine deaminase) required for somatic hypermutation and isotype switching

67
Q

Germinal center

A
  • Composed of naïve B cells that are passing through the LN
  • Some centroblasts leave dark zone and become slowly dividing centrocytes
  • Centrocytes interact with FDC (red) and TFH (blue)
  • Rapidly dividing closely packed centroblasts (green
68
Q

Somatic hypermutation and affinity maturation selects for B cells making high affinity Ab

A
  • Centrocytes receiving strong signals from FDC survive.
  • Migration to outer regions of light zone allows contact and further help from Ag-specific TFH
  • Some plasma cells stay in lymph node
  • Other travel to bone marrow and are long-lived
69
Q

Isotype switching occurs mainly in germinal center B cells

A

Driven by interactions with TFH and the cytokine mix they produce

TFH cytokines in turn determined by interactions with DC and early cytokines during TFH generation

DC responses and early cytokines in turn determined by nature of infection

70
Q

B cells must decide whether to become a plasma cell or a memory cell

A

TFH cells help them decide

During the height of an immune response, generation of plasma cells is favored

As the immune response subsides, TFH preferentially induce memory B cells

71
Q

IgG

A
  • targete out of blood and into tissue by FcRn
  • fluid phase endocytosis of IgG from the blood by endothelial cells of the blood vessels
  • acidic pH of endocytic vesicle causes associateion of IgG with FcRn protectin it from proteolysis
  • on reaching the basolateral face of the endothelial cell the basic pH of the extracellular fluid dissociates IgG from FcRn
72
Q

IgA

A
  • dimers cross the intestinal barrier and provide protection in the gut lumen
  • binding to IgA to receptor on basolateral face of epithelial cell
  • Receptor mediated endo of IgA
  • transport of IgA to apical face of epithelial cell
  • Receptor is cleaved, IgA is bound to mucus through secretory piece
73
Q

mothers provide Ab to their young before and after birth

A
  • during pregnancy: Iga,G,M,E in the mother
  • IgG can cross the placenta
  • IgA can be acquired orally through breast feeding
  • first year of life, baby has really low levels of IgG
74
Q

IgE

A
  • triggers mast cell degranulation
  • mast cell has FCeRI to recognize IgE
  • Release of histamine and other bioactive molecules
  • Important in anti-worm defense
  • Cause of allergy and anaphylactic shock!
  • eosinophils also degranulate in response to FCeR1 crosslinking
75
Q

neutralizing function of Ab

A
  • prevention of inctracellular infection
  • virus normally enters cells by receptor mediated endocytosis dependent upon HA interact with cell surface carb
  • Ab can bind HA before it can interact with the cell and be taken up
76
Q

Bacterial infections on mucosal surfaces can be prevented by neutralizing Ab response

A
  • F-protein is a bacterial adhesin. Binds to epithelial-associated fibronectin facilitating tissue colonization
  • can be bound and neutralized by IgA
77
Q

Bacterial toxins can be neutralized the same way

A
  • toxin binds to cell surface receptor
  • endocytosis of toxin receptor complex
  • dissociation of toxin to release active chain which posions the cell
  • however, Ab blocks bind of toxin to cell surface
78
Q

Neutralizing functions of Ab

A

Prevent viral entry
Prevent bacterial colonization
Prevent toxins from acting

79
Q

IgM bound to the pathogen surface triggers the classical pathway of complement activation

A

-IgM conformation changes upon binding, allowing for C1q binding to Fc region of IgM
-C1r and C1s activated by binding
Cleaves C2 and C4 generating classical C3 convertase
-Assembly of the alternative C3 convertase (C3bBb):
Amplification of the response
-IgM highly efficient at complement activation because it has 5 binding sites for C1q
-However, its large size restricts easy entry into tissues

80
Q

Complement activation by IgG requires binding by at least two Ig molecules

A
  • IgG molecules bind to ag on bacterial surface
  • C1q binds to two or more IgG molecules and initiates complement activation
  • OR IgG molecules bind to soluble multivalent ag because IgG generally has higher affinity than IgM. It can bind to soluble ag
  • C1q binds to soluble immune complex and initiates complement activation
  • phago and digestion of immune complexes mediate by complement receptors and Fc receptors
81
Q

Red blood cells play a role in clearing immune-complexes

A

Binding of immune complexes via CR1 in erythrocytes

Transport to spleen and liver for degradation by macrophages

Vast majority of cells in blood are erythrocytes, so this is an important mechanism of dealing with immune-complexes

Failure to eliminate immune complexes can result in deposition in tissues resulting in pathology and disease

82
Q

Antibodies exert effects through Fc receptors on hematopoeitic cells

A
  • FcyRI is the high affinity receptor for IgG1 and IgG3
  • FcyRI binds the lower hinge and CH2 of IgG3
  • IgG3 bound to FcyRI binds ag
  • Cells expressing FcgR1 bind Ab even without Ag. No signaling, no response
  • Cross-linking by Ag triggers a response
  • Expressed by macrophages, DC. Inducible on neutrophils and eosinophils
83
Q

Fc signaling stimulates receptor mediated uptake and destruction of pathogen

A
  • Ab binds to bacterium
  • Ab coated bacteriumbinds to FC receptors on the cell surface
  • macrophage membrane surrounds bacterium
  • macrophage membranes fuse, creating a membrane enclosed vesicle; the pahagosome
  • lysosome fuse with phagosome creating phagolysosome
84
Q

The family of Fc receptors on hematopoeitic cells

A
  • These receptors are structurally distinct from FcRn (which mediates transcytosis)
  • They have different isotype specificities and different binding affinities
  • Activating receptors mediate phagocytosis response
  • Inhibitory receptors mediate downregulatory signals
85
Q

Fc receptors are important in NK cell function

A

NK cells express FcgRIII

Cross linking by Ab/Ag signals NK cell to kill the target

This is called antibody-dependent cell-mediated cytoxicity (ADCC)

CD20 monoclonal antibody (Rituximab) used to treat B cell lymphoma by exploiting ADCC

ADCC can also function against virally infected cells

86
Q

Features of mucosal immune system

A

Located at sites where material is passed between the body and the environment

Must protect the vast surfaces that contact the outside world (200 times the surface area of skin)

99% of pathogens gain access through mucosal surfaces

Mucosal tissues are inhabited by vast numbers of harmless or beneficial microbes (estimated that there are 10 times more bacteria in the gut than cells in the body! 1000’s of species!)

Composed of both innate and adaptive components

Must “know” not to respond to food and harmless microbes, but still be ready to fight against harmful pathogens

87
Q

Challenge of mucosa

A
  • These are sites where we exchange materials with the outside world, but we must keep microbial pathogens out
  • These are barrier tissues
  • Bacteria, fungi, viruses normally in the gut are called microbiota
88
Q

The structure of mucins gives mucus its characteristic protective properties

A

Epithelial cell in mucosal tissues secrete a mucus layer

Acts as a physical barrier impeding movement and entry

Composed of large molecular weight mucins rich in heavily glycosylated serine and threonine residues

Mucins linked by disulfide bonds at N and C-termini

Rich in sialic acid giving mucins a polyanionic surface that binds antimicrobial molecules (e.g., defensins, IgA)

Mucus retains water, preventing dehydration of epithelium

89
Q

Five ways that the commensal gut microbiota benefit their human hosts

A
  • synthesize essential metabolites
  • break down plant fibers in food
  • inactive toxic substances in food or made by pathogens
  • prevent pathogens from benefits from the resources of the human gut
  • interact with epithelium to trigger development of secondary lymphoid tissue
90
Q

Gut-associated lymphoid tissues and lymphocytes

A
  • organized lymphoid tissue and single lymphoid follicles are present in the gut wall
  • DC, macs, lymph, and mast cells in the lamina propria
  • peyer’s patch: secondary lymphoid organ in the small intestin
  • isolated lymphoid follicle
  • and M cells
91
Q

Sytemic immune system

A

Occasional interaction with microbes

Short episodes of violence followed by peace

A reactive response

92
Q

Mucosal immune system

A

Close and continual contact with microbes

Ongoing low intensity skirmishes

Proactive response

93
Q

Strategies to keep inflammation under control in the intestine

A

Presence of Treg cells secreting IL-10 downregulates inflammatory cytokine responses

Macrophages differentiating in the intestine acquire a specialized “inflammation anergic” phenotype

Inflammation anergic: Intestinal macrophages are phagocytic but have little or no cytokine responses or respiratory burst activity

Secretion of down-regulatory cytokine TGF-b by epithelial cells

There are other mechanisms

94
Q

Uptake and transport of antigens by M cells

A

M (microfold) cells are specialized epithelial cells that overlie gut lymphoid tissue (e.g. Peyer’s patch). Their role is to sample contents of gut

Extensive invaginations in M cells form an intraepithelial pocket

Strategically located to permit microbes and Ag to enter secondary lymphoid tissue of gut through transcytosis. This process delivers Ag and microbes intact to cells in Peyer’s patch

Some pathogens exploit M cells as a port-of-entry: Shigella bacteria, poliovirus

95
Q

Gut dendritic cells taking up antigens have three distinct challenges

A
  • Food Ag: introduction of Treg and induction of anergic T cells (oral tolerance)
  • Commensals: induction of Tfh in draining lymph node; induction of ag spec b cells to control translocating commensals
  • Pathogens: danger signals: induction of T effectors in draining lymph node
96
Q

Capture of antigens from the intestine by dendritic cells

A

DC cells can extend processes across the epithelial layer to capture Ag from the lumen of the gut

97
Q

Lymphocytes activated in mucosal tissues return to those tissues as effector cells

A

Naïve lymphocytes recirculate through mucosal and nonmucosal lymphoid tissue

Naïve T and B cells express CCR7 which responds to CCL21 and CCL19 in secondary lymph nodes

CCR7 down-regulated after activation

After activation, lymphocytes leave lymph nodes and home to mucosal tissues (not just intestinal mucosa, also respiratory tract etc.)

98
Q

Lymphocyte trafficking in the gut

A
  • naive b and t cells expressing CCR7
  • enter HEV; encounter CCL19 and CCL21
  • activated lymphocytes are CCR7 negative and have ligands for MADCAM1
  • MADCAM1 on mucosal endothelial cells lining blood vessels
99
Q

Secretory immunoglobulins become attached to the mucus, where they stand ready to bind commensal and pathogenic organisms

A

Poly IgR binds to J chain of IgA and IgM mediating epithelial translocation

Ab tethered to mucin through disulfide bonding

Ab binding to bacteria in intestinal lumen impedes mobility and access to host

100
Q

Secretory IgA can be used to remove pathogens and their products from the lamina propria

A

Cholera toxin inactivated by IgA

Ab binds toxin in lamina propria. Complexes are disposed of in the lumen

Reverse transcytosis

101
Q

Helminths are major human pathogens that parasitize the intestines: Th2 responses protect

A
  • Caused by parasites that live in gut
  • Cause disease by competing for nutrients and damaging host tissue
  • Worms avoid being cast into the flowing fluid of the gut lumen
  • Immune response directed towards driving worms into the fecal stream (Th2 dominant)
102
Q

Human responses to helminth infection can either confer protection (Th2) or cause chronic parasitic disease (Th1)

A

Protection:

  • Increased epithelial cell turnover; increased mucus
  • Increased production and recruitment of eosinophils
  • Production of IgE
  • Mast cell recruitment to intestine

Chronic:

  • Intestinal tissue inflammation and damage
  • Production of ineffective antibody isotypes (IgG)

Immunology (4 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions