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Flashcards in Immuno 10 Deck (72)
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1

What must T cells supply to a B cell to become fully activated?

The 2nd signal of activation other than MHC binding.

Once that has occurred, the B cell proliferates and differentiates, and the final effector cells that are produced are plasma cells (antibody “factories”) and memory cells (a clonally expanded population of daughter B cells that occupy secondary lymphoid tissues of the body for long periods of time).

2

What is the first signal to B cell for activation?

The 1st signal of B cell activation is crosslinking of the B cell receptor by binding of the immunoglobulin component of that BCR with its cognate antigen. ***Sufficient signaling will not occur unless multiple copies of the BCR are crosslinked with antigen***

3

How do B cells signal to the nucleus of the cell so that the cell will know that the BCR has encountered its cognate antigenic determinant?.

The signal transduction unit of the BCR is known as the Ig-alpha/Ig-beta complex. Once this signal has been transmitted, the B cell has now received its first signal of activation.

4

Besides the signals that are transmitted via the Ig-alpha/Ig-beta complex, that are some other signals that can increase the intensity of the 1st activation signal. What are they?

The B cell co-receptor, complement receptor 2, or CR2, has affinity for complement component C3b, and when it binds to C3b, additional signals are transmitted as part of the 1st signal of activation. This should seem logical to you because if an antigen that is recognized by a B cell has been opsonized by labeling with C3b, that is a pretty good sign that the antigen is not a self determinant and is likely to be pathogen-derived. This indicates to the immune system that an immune response is needed to clear an infection.

There are also CD19 and CD81

Even all of these mechanisms together isn't usually enough to cause B cell activation and require T cell help

5

What do CD19 and CD81 do?

surface markers of B cells that are also part of the B cell receptor complex. CD19 is an important component of the signaling apparatus of the B cell receptor because it amplifies the signals that are transmitted via the Igα/Igβ complex. The function of CD81 has not been clearly established.

6

Some non-protein antigens can elicit B cell activation in the absence of T cell help (albeit, a partial activation, really). How?

T-independent antigens

Some non- protein antigens can also activate B cells in the absence of T cell help. In this case, the antigen crosslinks multiple BCRs on the surface of the cell, in addition to another determinant of the antigen that binds to an unlabeled receptor on the cell surface. This receptor is what is known as a pattern recognition receptor, or PRR. PRRs are receptors that recognize structures that are common to large numbers of bacteria. These structures are known as pathogen-associated molecular patterns (PAMPs). A good example would be the LPS receptor that binds to bacterial LPS, which is found on all gram-negative bacteria. The combination of BCR and PRR engagement is sufficient to partially activate the B cell.

NOTE: that B cells that are activated by T- independent antigens do not initiate germinal center reactions, and they do not result in immunological memory (no memory cells are generated).

7

T or F. T-independnent antigens can activate B cells in the absence of T cell help

T

8

There are two types of T-independent antigens: What are they?

TI-1 and TI-2 antigens

9

What are TI-1 antigens?

T-independent 1 (or TI-1 antigens): this type of TI antigen has PAMPs, and can crosslink BCRs, and therefore has an intrinsic ability to initiate partial activation of B cells.

These types of antigens are known as mitogens. Interestingly, if these types of antigens are supplied in high enough concentrations (much higher than would ever be seen naturally in a host), they can activate B cells in a non-specific fashion.

10

There are multiple ways that TI-1 antigens can activate B cells. Name them.

This graphic shows how mitogens can activate B cells. In the top panel a high concentration of mitogen results in polyclonal (meaning that multiple antibody types are produced) activation of B cells that results from engagement of large numbers of PRRs on the B cells by the PAMP component of the mitogen.

The bottom panel shows what happens when the mitogen is supplied in low concentrations. In this case, the activation of a specific B cell occurs due to crosslinking of BCRs that bind specifically to some component of the mitogen, with simultaneous engagement of the PRR by the PAMP component of the mitogen.

Both of these result in production of antibodies that are almost all of the IgM isotype. There is some programmed class switching to IgG, but because there is no germinal center reaction, no other class switching will occur. In addition, there will be no immunological memory generated.

11

How do TI-2 antigens work?

T-independent type-2 (TI-2) antigens can cause B cell activation by heavily crosslinking BCRs on the surface of the B cell. These antigens are typically highly repetitive structures that have many copies of the antigenic determinant that is recognized by a B cell. A good example of such an antigen is a cell wall polysaccharide.

There is a subset of B cells that have a restricted BCR repertoire that account for most of this type of immune response. These cells are known as B1 B cells

12

Which type of antigens: T-dependent, TI-1, or TI-2- will result in: Antibody response in the absence of cognate T cells or in the absence of a thymus (no T cells)?

There will be no antibody response made in response to a T-dependent antigen, but because no T cell help is required for antibody responses against T-independent antigen, both TI-1 and TI-2 antigens will elicit a response.

13

Which type of antigens: T-dependent, TI-1, or TI-2- will result in antibody response in infants?

infants can produce effector T cells, and therefore can make antibody responses to T-dependent antigens. Infants can also make antibodies in response to TI-1 antigens. However, because the B1 B cell population is not formed until about 5 years of age, infants cannot respond to TI-2 antigens.

14

Which type of antigens: T-dependent, TI-1, or TI-2 will activate T cells?

this only occurs in response to T-dependent antigens because (at least for the purposes of this course), T cells can only recognize protein determinants.

15

Which type of antigens: T-dependent, TI-1, or TI-2- will cause induction of immunological memory?

T-dependent antigens can elicit memory B cells, but TI-1 and TI-2 antigens cannot.

16

Which type of antigens: T-dependent, TI-1, or TI-2- will cause activation of B cell in an antigen-independent fashion?

this only occurs in the case of mitogens (TI-1 antigens).

17

Which type of antigens: T-dependent, TI-1, or TI-2- requires repeated epitopes?

TI-2 only

18

What are 3 examples of TD antigens?

1) Diphtheria toxin

2) Viral hemagglutinin

3) Purified protein derivative (PPD) of Mycobacterium tuberculosis

19

What are 2 examples of TI-1 antigens?

1) Bacterial LPS

2) Brucella abortus- I have no idea why Brucella abortus (a bacterium) is listed under TI-1 antigen, and I take some issue with that because all bacteria make a large array of protein determinants that would all be listed in the T-dependent column. It is probably listed because it is a gram negative pathogen (so it has LPS).

20

What are 2 examples of TI-2 antigens?

1) Pneumococcalpolysaccharide

2) Polymerized flagellin (Salmonella)

Capsular polysaccharides and flagellin are both highly repetitive structures that are produced by an array of different bacterial pathogens, and both are good examples of TI-2 antigens.

21

Where do germinal centers form?

form in the lymphoid follicles within the B cell zone of secondary lymphoid tissues.

22

What occurs in a germinal center reaction?

The reaction is formed by the daughter cells of rapidly dividing B cells (all derived from a single B cell that was activated) and T cells (all descendent from the helper T cell that supplied the secondary activation stimuli to that B cell).

As the proliferating B cells mature, they undergo somatic hypermutation (which results in affinity maturation) and isotype switching (driven by the cytokines produced by the helper T cells.

The positively selected high-affinity isotype-switched B cells differentiate into either plasma cells or memory cells.

23

B cell activation (mostly) requires T cell help. How does this work?

Once a naïve B cell receives its 1st activation signal (binding to its cognate antigen), it will move into the T cell zone of the secondary lymphoid tissue. In the T cell zone, the B cell will interact with many T cells. If an effector CD4 T cell recognizes its cognate determinant bound to an MHC class II molecule on the B cell, it will supply the second signal of activation. The B cell and the T cell will then begin to proliferate rapidly, forming a primary focus in the T cell zone.

Please note that either a TH1 or TH2 cell can supply the second signal of activation to any B cell.

As the B and T cell proliferate, some of the B cells will differentiate into plasma cells (and will produce IgM antibodies because they have not yet class switched).

At least one pair of the daughter B and T cells will eventually migrate into the lyphoid follicle of the B cell zone and continue proliferating. This will become a germinal center.

24

Describe a germinal center.

The helper T cells are found around the periphery of the germinal center. There is a region that is filled with large B cell precursors that are at the early stage of development, known as centroblasts. These cells are rapidly dividing and are beginning to undergo somatic hypermutation. As they develop and become smaller (now called centrocytes) they move into an area that is filled with follicular dendritic cells.

25

How are follicular dendritic cells distinct from the dendritic cells?

FDCs do not present peptide antigens to naïve T cells. Instead, these cells express a high density of Fc receptors and complement receptors on their surface. They use these receptors to trap immune complexes (antigens that have been bound by C3b, antibody, or both) on their surface. The developing centrocytes compete for binding to immune complexes that are trapped on the FDCs. Those that have the highest affinity for antigen will receive survival signals from the FDCs, and they will process the antigen and present it to the effector CD4 T cells that will, in turn, produce cytokines that drive isotype switching in the developing B cell.

B cells that cannot complete effectively for binding to antigen trapped on the FDCs will not receive survival signals and will become anergic and die. Therefore, B cells bearing receptors that received somatic mutations that resulted in lower or similar affinity for the antigen will typically die, while those bearing receptors that received mutations that increased the affinity of the BCR for antigen will be positively selected to continue developing. Over time, this results in what is called affinity maturation.

26

In summary, during a germinal center reaction, the following important things occur:

1) B and helper T cell proliferation

2) Somatic hypermutation and affinity maturation

3) Isotype switching (driven by the helper T cell cytokine array)

4) B cell differentiation into plasma cells and memory cells.

27

IL-4 induces antibody switching to?

most importantly, it induces class switching to IgE. It also promotes switching to IgG isotypes that are weakly opsonizing (IgG2 and IgG4 in humans).

28

IL-5 induces antibody switching to?

augments class switching to IgA (both subtypes in humans)

29

IFN-gamma induces antibody switching to?

Promotes class switching to strongly opsonizing isotypes of IgG (IgG1 and
IgG3 in humans)

30

TGF-beta induces antibody switching to?

to weakly opsonizing subtypes of IgG (2 and 4)

Note: each of these cytokines inhibit class switching to their opposing isotypes (TH1 cytokines inhibit class switching to weakly opsonizing IgGs (2 and 4), IgA, and IgE, while TH2 cytokines inhibit class switching to strongly opsonizing IgG (1 and 3) subtypes.