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FMS Week 8 (also some 7) Immunology > Humoral Immunity > Flashcards

Humoral Immunity Flashcards

1
Q

Immunoglobulin (antibody) molecules functions in the humoral immune response

A

1) antigen recognition
Membrane assocated antibody IgM is the receptor that B cells use to repscifically recognise antigens. The antibodies that B cells produce have the same specificities as the receptors on that B cell

2) Effector function
Soluable antobodies are secreted by antigen-activated B cells and plasma cells. Antibodies are the major effector molecules of humoral immunity. Different antibody types are specialized for different locations and functions

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2
Q

Antibodies are defined by what

A

Isotype and idiotype

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3
Q

Isotype

A

defined by the constant domain (ie IgG, IgM, IgE, ect) This domain determines the effector function of Ig molecule

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4
Q

What domain determines the effector function of the Ig molecule

A

The constant domeain

ie isotype

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5
Q

Idiotype

A

determined by the variable and hypervariable domains of the Ig molecule. The idiotype determines the specificity of the anitobody molecule

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6
Q

What determines the specificity of the antibody molecule

A

hypervsariable and variable domains

ie idiotype

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7
Q

B cell development occurs in two destinct stages

A

Antigen intependent phase

Antigen dependent phase

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8
Q

Antigen independent phase of B cell development

A

occurs in bone marrow

Diverse B cell receptors generated (>10^9 specificities)

Test for. functional BCR (b cell receptor)

Select out self reactive cells

not dependent on specific interactions with other immune cells

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9
Q

Antigen dependent phase of B cell development

A

Occurs in peripheral lymphoid tissues

Selecting and amplifying responses

avoid responding to peripheral selft antigen

increase affinity to antigen

select Ig subclass, which influcences effector function

generate memory cells for recell responses

critical role of CD4+ T helper cells

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10
Q
A

Review of B lymphocyte maturation

Pro B cell expands. THen has pre B cell heavy chain. If failed receptor goes to apoptosis. If immature B cell IgM+ reacts to self antigen it will either receptor edit or apoptosis

Then goes to periphery

MAture B cell IgM+, IgD+ responds to antigen

it secretes antibody and establishes memory

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11
Q
A

Overview of B cell responses in the periphery

Naive B cell recognises microbial antigen

T cell helps with antigen presentation and B cell is activated

Clonal expansion

Differentiation
You can wither have class switch or affinity maturation
Also make memory B cells IgG+

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12
Q

Role of peripheral lymphoid organs in B cell development

A

1) Where B cells encounter concentrated antigen

2) Where B cells interact with othet immune cells
- T helper cells: critical for clonal B cell ploliferation and maturation
- Folicular dendritic calls and Tfh: mediate affinity maturation

3) Provides the appropriate microenvironment to influence effector function (through class switching)

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13
Q
A

Peripheral lymphoid organ

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14
Q

Parts of peripheral lymphoid organ

A

Primary follicles (B cell zone)- Where B cells encounter antigen

Paracortex (T cell zone)- Where T cells encounter antigen presenting cells (APCs)
(dendritic cells travel here when they have found antigen)

Secondary follicle (germinal center)- consequence of the interaction between B and CD4+ T cells

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15
Q

How do B cells find antigen?

A

Antigen enters the nodes via the afferent lymphatics and is either trapped in the subcapsular sinus by specialized macrophages or is delivered to the follicles via conduits

Recirculating B cells migrate from the blood into the follicles of the lymph node

Upon Ag engagement via the B cell receptor, the B cells move towards ther paracortex (where the T cells hang out)

Without Ag engagement, the B cell leaves the node through the efferent lymph and recirculate between and through secondary lymphoid tissues

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16
Q

How do B cells find antigen in my words and in picture

A

Antigen enters node in afferent lymph

Ag trapping cells in subcapsular sinus trap antigen

B cell follicle- Recirculatnig B cell migrates from blood to follicular mantle

Engages Ag via BCR, inducing interaction with primed T cells

Engages Ag via +CR2 and trandports it to FDC

If no Ag involvement, B cell leaves node in lymph

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17
Q
A

Microbial Antigen Recognition

Microbe binds to antigen receptor (which has no signaling capability) However, Igalpha and Igbeta have ITAM which is a signaling pathway ans helps them to form signal cascade ultimately leading to transcroption

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18
Q

Features of antigens that promote B cell responses

1) bound complement

A

B cell signaling is enhances by complement bound to antigen

When a pathogen is coated with C3d, engagement of the CD21/CD19 complex by C3d synergizes with signaling through the B cell receptor

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19
Q

Features of antigens that promote B cell responses

2) pathogen multivalency

A

Highly multivalent antigens induce stronger B cell responses

Some highly multivalent angigens can induce T-cell independent responses

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20
Q

Features of antigens that promote B cell responses

3) pathogen-associated molecular patterns (PAMPs)

A

Most pathogens contain PAMP that can activate PRR receptors (such as TLRs) expressed by B cells

Signaling through toll-like (and other) receptors synergizes with BCR signaling

These lignds acan also induce polyclonal activation of B cells

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21
Q

What are the functional cconsequences of antigen binding to the B cell receptor ?

A

1) entry into the cell cycle
2) Low level IgM secretion (short lived Plasma cells)

3) Expression of molecules that are important in subsequent interactions with T helper cells
These include:
Co-stimulatory molecules
Cytokine receptors
Presentation og Ag on MHC II

4) Migration out of the follicle toward the T rich zone (CCR7 up arrow)

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22
Q

What happens when CD4+ T cells respons to antigen

A

Antigen presentatio by DC to helper T cell

Activation of CD40 ligand, cytokine secretion

Entry into cell cycle (proliferation)

differentiation into effector T cells

  • Secretion of cytokines and expression of surface molecules
  • Migration towards B cell zone (lymphoid follicle)
  • Enter circulation and migrate to the site of infection
23
Q

Overview of B and T cell interaction in the Lymph Node

A

B cells amd T cells are segregated in the lymph node

B cells encounter antigen in primary follicles
T cells encounter antigen presenting ccells in the T rich zone

Upon antigen recognition, both cell types modulate CCR7 expression and migrate towards eachother

STEPS
Antigen presentation:T cell activation
CCR7 down and CXCR5 up and migration of activated T cekks to edge of follicle
B cell presents antigen to activated helper T cells
Antigen uptake and precessing; B cell activation
B cells increase CCR7 and migration of activated B cells into folicle

24
Q

The specificity of the B/T cell interaction in mediated by MHC class II presentation of internalized antigen

A

B cell interacts with microbial protein antigen

Receptor mediated endocytosis of antigen happens

antigen processing and presentation happens on class II MHC peptide complex

T cell recognition of antigen (activted CD4+ T cell)

25
Q

B cell antigen presentation and the concept of linked T helper epitopes

A

MHC can only display proteins

If you have a sigar specific B cell will do receptor-mediated antigen internalization, proteolysis, and presentation of peptides

Will then display protein on cell and present it ot a protein specific T cell

26
Q

Conjugate vaccines

A

A technique for proviting T helper responses to antigens that do not have T cell epitopes

Polysaccharide (PS): contains B cell epitopes but lacks T cell epitopes

Tetanus Toxoid (TT): contains both B and T cell epitopes

Immunize with PS
B cells PS specific
Th cells: NONE
IgG response: NONE

Immunize with TT-PS conjugate
B cells: PS-specific and TT specific
TH cells: TT specific
IgG response: anti PS IgG and anti-TT IgG

27
Q

Key components of T cell help

A

Activation of T cell; expression of CD40 ligand, cytokine secretion

Activation of B cell and by cytokines and CD40 ligation

B cell proliferation and differentiation

The specificity of this interaction is maintained by:

1) Cognate interaction mediated by cell-cell contacts
2) Interaction occurs in a specific location at the boundary of the T-rich zone and the primary B cell follicle

X-linked Hyper IgM syndrome is due to a mutation in CD40L; B cells in these patients do not class switch

28
Q

What are the consequences of the T:B cell interaction

A

1) Clonal expansion of B cells
2) Establishment of germinal centers
3) Class switching
4) Affinity maturation
5) Differentiation to memory cells

In general, all of these events are predicted on B cells recieving help from CD4+ T cells

29
Q

The germinal center reaction

A

Upon activation by CD4+ T cells, B cells begin to proliferate and enter what is known as secondary follicles

Secondary follicles are home to germinal center

Each follicle is mainly clonal, and the germinal center contains two regions, the light zone and the dark zone

In the dark zone, B cells undergo rapid cell division and turn on the machinery that leads to:

1) somatic hypermutation of the variable regions of the B cell receptor
2) Class switching

The light zone of the germinal center is rich with follicular dendritic cells (FDCs) and CD4+ T cells (TFH cells). B cell survival is dependent on interaction with FDC-bound Ag and presentaion of Ag to T cells

30
Q

Antibody affinity selection

A

Affinity selection is the process that leads to increqased affinity of antibodies for a particular antigen as a T cell dependent humoral immune response progress

Mutations and affinities were measured after vaccinations. Shaded regions are CDRs (complementary determining regions) The mutations are found here
This shows that the antibodies are getting mutations to increase binding

31
Q

Affinity selection is mediated by 3 factors

(affinity maturation)

A

1) Rapid division
After interacting with CD4+ T cells, B cells rapidly proliferate (divide every 6-12 hours)

2) high mutation rate
Expression of the protein AID ( activation induces deaminase) leads to hypermutation of the V domain of the BCR (1 error per 1000 bases per cell division)

3) Selection
B cells compete for binding of limiting amounts of antigen displayed by folicular dendritic cells. Only cells taht successfully bund to antigen and then recieve help from Tfh are selected sa

32
Q

Affinity selection: Evolution in a germinal center

A

Antigen is taken up by FDCs in the form of immune complexes and held in a non-degraded form for month after an infection. FDCs + antigen + Tfh + CD40L provide survival signal to B cells

Taken together, this process selects for mutations that lead to stronger binding of antibody to antigen

33
Q

B cell class switching

A

Class switching- a biological mechanism that changes a B Cells production of antibody from one class (isotype) to another

Different antibody types have different effector functions

Class switching is mediated by cytokine environment

cytokines are largely produced by Th cells. Different Th subsets produce different cytokines and promote switching to different isotypes

Th1 produces INF-gamma which mediates class swithcing to IgG

Th2 produces IL-4, IL-5, IL-13 which mediates class switching to IgE

34
Q

Th1 produces ____ which mediates class switching to ___

A

INF-gamma

IgG

35
Q

Th2 produces ____ which mediates class switching to ___

A

IL-4, IL-5, IL-13

36
Q

There are 5 different antibody classes based on different

A

heavy chains

37
Q

IgM and IgD

A

Expressed on naive B cells. Both are expressed as membrane receptors, but only IgM is expressed as soluable antibody

38
Q

IgG, IgE, and IgA

A

Expressed on ACTIVATED or MEMORY B CELLS that have undergone class switching. All 3 molecules can be expressed as membrane receptors or as soluable antibody

39
Q

How do cytokines mediate class switching?

A

1) Cytokines induce transcription from specific promoters. (For example, IL-4 induces transcription from Ie)
2) Transcription triggers a recombination events that result in the deletion of intervening constant (C) genes
3) The resulting DNA can be transcribed and translated
4) This process results in an antibody with the same specificity, but a switched constant domain

40
Q

IgM effector function

A

produced early upon B cell activation

activates the classical complement pathway

41
Q

IgG effector function

A

the major Ig isotype in the blood

Transferred across the placenta

Activated the classical complement pathway

mediated neutralization and opsonization of pathogens

mediated antibody-dependent cellular cytotoxicity

42
Q

IgA isotype

A

Produced in mucosal tissues and secreted into the lumens of the GI and respiratory tracts

Mediates pathogen neutralization

Can be transferred to infants via breast milk

43
Q

IgE effector function

A

defense against helminths

involved in allergic responses

44
Q

Effector function os antibodies

A

Some of them are mediated by Fc receptors

45
Q

Memory B cells

A

Generated in germinal centers
therefore we only have humoral memory to T dependent antigens

Circulate through lymphoid organs

Express the affinity matured BCR on their surface

Typically isotype switched (eg IgG+ or IgA+)

Very long lived
persistence of memory B cells after an immune response ensures that we have increased numbers of B cells specific for the antigen and ready to rapidly expand and differentiate into plasma cells and secrete antibody upon reexposure to antigen
Provide the basis for secondary GC reactions

46
Q

Plasma cells

A

arise predominantly from germinal ceners (in primary responses) or from memory B cells (in secondary responses)

Are very long lived (several months or longer)

Often home to bone marrow, gut, lactating mammary gland

Are predominantly isotype switched

47
Q

Features of primary and secondary antibody responses to a T DEPENDENT ANTIGEN

A

Notice that hte first response takes much longer

Antibody levels at peak are also much higher in second exposure

In primary response, you make IgM and IgG and in secondary response we only see IgG

48
Q

Do you have IgM respsonse with a polysaccharide T independent response?

A

YES

49
Q

Some antigens can provoke B cells responses without the requirement for T help

A
50
Q

With T independent antigen first and second response

A

ARE THE SAME

51
Q

Which of the following events does NOT occur in the germinal centers

somatic mutation of Ig V genes

Ig gene V(D)G recombination

B cell proliferation

T folicular helper cell iteractions with B cells

generation of memory B cells

A

Ig gene V(D)J recombination

this is an early event that happens in the bone marrow

52
Q

Previously healthy young european woman who had not been immunized against measels virus became infected with the virus while traveling to disneyland developed a rash, high fever, cough, and runny nose, and then fully recovered after 4 days. A blood test performed 2 months later, after her return to europe, showed the presence of high affinity IgG antibodies specific for measels virus antigens. Which of the following proteins was NOT necessary for the production of these high affinity IgG antibodies?

CD40 ligand

Activation induced deaminase

Class II MHC

CXCR5

Fc gamma receptor

A

Fc Gamma receptor- helps regulate but not produce

CD40 ligand- expressed on T cells. important for class switching

activation induced deaminase (AID) - important in class switch and affinity maturation

Class II MHC- B and T cells come together

CXCR5- chemokine to go to zone

53
Q

Distinct B cell subsets mediate different types of antibody responses

A

FMS Week 8 (also some 7) Immunology (9 decks)

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