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Flashcards in Adaptive Immunity Deck (37):
1

Which T-Cells bind to MHC 1 vs 2?

Cytotoxic T cells bind to MHC 1 at tissue
T helper cells bind to MHC 2 in lymph node

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T Cell development

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.

3

CD4

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.

4

CD8

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.

5

Thymocyte

Immature T-Cell

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TCR

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.

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T cell activation

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.

8

IL2

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).

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Tacrolimus

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

10

T helper cell

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.

11

Cytotoxic T cells

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).

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Severe Combined Immunodeficiency

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

13

T Cell immunodeficiencies

-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).

14

BCR

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.

15

B cell activation

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.

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B Cells

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.

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Antibody structure and duties.

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.

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Epitope

The tip of an antibody that recognizes antigens.

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Antibody neutralization

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

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Antibody opsonisation

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

Note: These are IgG antibodies in particular.

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Fc and Fc receptor

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.

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Antibody complement activation

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

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How do T cells get their diversity?

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.

24

Granzymes

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.

25

Performin

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

26

B Cell / Antibody deficiency

-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.

27

Antibody classes (5):

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

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

28

IgG:

The king of antibodies. 75%

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

29

IgM:

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.

30

IgE:

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.

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IgD:

Very little in serum. Role unclear.

32

IgA:

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

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IgA deficiency

Most common Ig deficiency.

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

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B cell diversity?

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

35

B cell negative selection

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

36

B cell development

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

37

Class switching

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