Adaptive Immunity

Question 1

Which T-Cells bind to MHC 1 vs 2?

Answer 1

Cytotoxic T cells bind to MHC 1 at tissue

T helper cells bind to MHC 2 in lymph node

Question 2

T Cell development

Answer 2

Produced in bone marrow and migrate to thymus where they mature. Differentiate into CD4 (T helper) and CD8 (Cytotoxic T cells). At this point they are naive (not yet exposed to an antigen). They develop a specific TCR completely randomly. They then undergo 3 checkpoints, during which 98% die.

1. Checkpoint to confirm that they have a TCR. At this point they are not differentiated and have bot CD4 and CD8 coreceptors.
2. Immature T-cells bind to epithelial or dendritic cells in the thymus, which both have high expression of self MHC. The recognition of self MHC involves the participation of either CD4 or CD8. Whichever does not participate in this recognition is downgraded, resulting in a T cell that expressed only CD4 or CD8. Positive selection.
3. In binding of a TCR and a self MHC, it must be confirmed that the binding is not too tight. If the binding to too tight, apoptosis occurs.
4. T cell then moves to lymph nodes where it awaits activation by an antigen.

Question 3

CD4

Answer 3

A naive T-helper Cell, not yet exposed to antigen. Cluster of differentiation 4. A surface binding molecule on T helper cells that will help attach the T helper cell bind to MHC2 upon contact.

Question 4

CD8

Answer 4

A naive cytotoxic T-cell, not yet exposed to antigen. Cluster of differentiation 8. A surface binding molecule on cytotoxic T cells that will help attach the cytotoxic T cell to MHC1 upon contact.

Question 5

Thymocyte

Answer 5

Immature T-Cell

Question 6

TCR

Answer 6

T-cell receptor is a molecule found on the surface of T cells that is responsible for recognizing fragments of antigens that are bound as peptides to MHC. TCRs exhibit self recognition and are highly specific towards antigens. There are 10^14 TCR possibilities as the result of random gene rearrangement.

Question 7

T cell activation

Answer 7

Naive, differentiated T cells awaits interaction with antigen presenting cell in lymph node. Diversity of T Cells is immense, each with a unique TCR specific to a single antigen. Upon contact with the appropriate MHC (class 1 or 2) on an APC, CD 4 or 8 interacts with the MHC, sparking a kinase that activates gene expression. The cell is primed but requires a 2nd signal before it is fully activated.

Then a CD28 on T cell interacts with B7 molecules on the APC, fully activating T cell.

T cells the release IL2, which allows the clonal proliferation of T cells, some of which become effector cells while others become memory cells.

The T cell then enter the systemic circulation via efferent lymphatics.

Question 8

IL2

Answer 8

Interleukin 2 is produced by the activated T cell. This cytokine acts as a growth factor to proliferate cloned T cells.

The drug Tacrolimus suppresses IL2 as an immunosuppressant. A defect in IL2 results in no T cell and immunodeficiency (eg. Severe Combined Immunodeficiency).

Question 9

Tacrolimus

Answer 9

Tacrolimus is an immunosuppressant drug that suppresses IL2 (a cytokine growth factor to proliferates T cells).

Question 10

T helper cell

Answer 10

Differentiated by CD4. Binds to MHC2 on APC. Activated effector cell acts to activate B Cells and macrophages. It also produces cytokines to drive the immune response.

Note: After activation the T helper cell proliferates. The offspring vary slightly in their specialization. They will release different Interleukin cytokines, each of which activate different immune responses.

Question 11

Cytotoxic T cells

Answer 11

Differentiated by CD8. Packed full of vesicles with toxic enzymes. Binds to MHC1 on infected cell to directly kill virally infected or tumor cells. ‘Performin’ forms pores in the membrane and the vesicles release proteolytic enzymes (granzymes).

Question 12

Severe Combined Immunodeficiency

Answer 12

A disorder with IL2, so no T cell proliferation and therefore serious immune deficiency.

Question 13

T Cell immunodeficiencies

Answer 13

• Primary Immunodeficiency-hereditory
• DiGeorge Syndrome-deletion on chromosome 22. Neuromuscular and heart defects, immune compromised, and hypothyroidism.
• Severe Combined Immunodeficiency-IL2 defect. T cells can’t proliferate. Severe immune deficiency. (Boy in the bubble).

Question 14

BCR

Answer 14

The B-cell receptor transmembrane receptor protein is located on the outer surface of B cells. The receptor is composed of an antibody that, like all antibodies, has a unique and randomly determined antigen-binding site. When a B cell is activated by its first encounter with an antigen that binds to its receptor, the cell proliferates and differentiates to generate a population of antibody-secreting plasma B cells and memory B cells.

Note, the BCR does not nee MHC, although it has some for recognition of APCs.

Question 15

B cell activation

Answer 15

Antigen binds to BCR (B cell antigen receptor) which triggers phagocytosis. The B Cell then presents the antigen on its MHC2 molecule. The cell then finds a T helper cell in a lymph node. B cell’s MHC2 presenting antigen binds to the TCR and the B cells CD40L (L for ligand) binds to the T cell’s CD40. The T cell, now activated itself, emits cytokine IL2, which in addition to stimulating T cell replication also stimulates the B cell to produce antibodies.

Question 16

B Cells

Answer 16

B cell are produced and matured in the bone marrow. They have a B cell antigen receptor on their membrane, which can bind to antigen in peptide, lipid, protein, carbohydrate form.

Make antibodies and memory cells matching one specific antigen.

Question 17

Antibody structure and duties.

Answer 17

A Y shaped protein held together by disulfide bonds. It is produced by activated B cells. At the tip of the Y is the antigen binding surface (aka epitope) that binds very tightly to antigens. They also have cites for the binding of compliment proteins. Additionally, they have a Fixed cite, which is not variable and binds to macrophages, basophils and mast cells.

When antibodies are bound to an antigen, they promote phagocytosis (opsonisation), pathogen neutralization, activate classical complement cascade, promote agglutination.

Question 18

Epitope

Answer 18

The tip of an antibody that recognizes antigens.

Question 19

Antibody neutralization

Answer 19

Antibodies surround and bind to pathogen or toxins, preventing it from entering cells.

Question 20

Antibody opsonisation

Answer 20

Antibody Fc region binds to FcR on phagocytes, tagging the antigen for phagocytosis.

Note: These are IgG antibodies in particular.

Question 21

Fc and Fc receptor

Answer 21

Fc is a site on antibodies that bind to innate immune cells. FcR is the receptor on the innate immune cells that receive the antibody.

Question 22

Antibody complement activation

Answer 22

Antigen binds to pathogen. C1 binds to the complement region on the antibody, activating the classical complement pathway.

Question 23

How do T cells get their diversity?

Answer 23

There are 10^14 possible TCRs on T cells. They get their diversity from random gene variation. This is why so many of the are killed during the checkpoints.

Question 24

Granzymes

Answer 24

Upon binding of a cytotoxic T cell to the MHC1 of a virally infected or tumor cell, proteolytic enzymes called granzymes are released into the target target cell to degrade it.

Question 25

Performin

Answer 25

A tool of cytotoxic T cells; Performin form pores in virally or tumor infected cells.

Question 26

B Cell / Antibody deficiency

Answer 26

• Adenosine deaminase deficiency: transcription blocked. B cells are mitotically active, so they suffer.
• X linked agammaglobulemia: A mutation causing the improper development of mature immune cells. Treat with intravenous immunoglobulin.

Question 27

Antibody classes (5):

Answer 27

IgG, IgM, IgA, IgD, IgE (think g-made.)

The antigen binding sites are the same, but they have different Fc regions,

Question 28

IgG:

Answer 28

The king of antibodies. 75%

Can carry out all functions of antibodies (opsonisation, agglutination, neutralizing, compliment cascade).

Question 29

IgM:

Answer 29

This is the antibody that makes up the BCR on naive B cells. When bound, it activates the signal to activate the B cell.

They are also secreted as pentamers (five of them around a common point, so they are very good at agglutination.

Question 30

IgE:

Answer 30

The allergy antibody. IgG Fc region will bind to mast cells, eosophils, and basophils even before binding with an antigen. When the antigen does bind, the cells are triggered to release histamine.

IgE will also bind to worms. Allergy theory is that because we don’t have parasites anymore, our IgE is free to work elsewhere.

Question 31

IgD:

Answer 31

Very little in serum. Role unclear.

Question 32

IgA:

Answer 32

Secreted across mucosal epithelium. Found in tears, saliva, GI, lungs.

Question 33

IgA deficiency

Answer 33

Most common Ig deficiency.

Cause increased pulmonary and GI infections and allergies (recurrent ulcerative colitis, Crone’s).

Question 34

B cell diversity?

Answer 34

10^11 possibilites. Due to random gene rearrangement. Occurs in early development.

Question 35

B cell negative selection

Answer 35

Many B cell antigens will react to self molecules. Negative selection removes the antibodies that recognize self in the bone marrow during early development.

Question 36

B cell development

Answer 36

Bone marrow:
     Antibody gene arrangment
     Negative selection
     Migrate to secondary lymphoid tissue
     Naive
     6 day life span

Question 37

Class switching

Answer 37

When a B cell switches to producing a different antibody. Changes occur in the Fc region, at the DNA level, induced by cytokines.