Major Histocompatibility Complex & Immunological Tolerance

What is the major histocompatibility complex (MHC), where is it located, and what does it encode?

A cluster of genes on the short arm of chromosome 6 at band 2 that encodes proteins involved in immune recognition, including the human leukocyte antigens (HLAs).

Three classes of MHC protiens

Two classes function in antigen presentation

-MHC I on virtually all tissue cells

MHC II only on PM some immune system cells

I-nteracts with two major types of T cells

-MHC I ± CD8 (Cytotoxic)

-MHC II - CD4 (Helper T cells)

-MHC III genes code for products that include secreted proteins that have immune functions eg. complement components, and inflammatory cytokines

Why are MHC proteins important in immune recognition and transplantation?

MHC proteins allow T cells to discriminate self from nonself

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transplanted tissue can be recognized as foreign because of differences in MHC proteins contributing to transplant rejection.

What are the six main HLA markers used by the immune system to target foreign cells?

Class I: HLA-A, HLA-B, HLA-C.

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Class II: HLA-DR, HLA-DP, and HLA-DQ.

Which HLA antigens are considered most important in organ transplantation?

HLA-A and HLA-B.

What is HLA matching, what is the best possible match, and what is the worst possible match?

HLA matching compares important HLA markers between donor and recipient to assess compatibility. The best possible match is 6/6 and the worst is 0/6.

How are HLA markers primarily tested according to the lecture?

Primarily by PCR.

What is immunological tolerance?

Immunological tolerance is a state of unresponsiveness of T and B lymphocytes to a particular antigen.

Why does the immune system need mechanisms of immunological tolerance?

Random recombination of antigen-receptor genes creates a very large receptor repertoire that can include receptors capable of recognizing self-antigens.

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-Tolerance prevents these cells from attacking the body's own tissues.

What is the consequence of a breakdown in immunological tolerance to self-antigens?

It can result in autoimmune disease because immune cells become reactive against the body's own antigens.

What are the two major requirements that the immune system must balance when generating antigen receptors?

It must maintain a large enough receptor repertoire to recognize many possible pathogens while preventing receptors from attacking the host's own tissues.

What is the difference between natural (self) tolerance and induced tolerance?

Natural or self-tolerance:

is the failure to attack the body's own proteins and antigens

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Induced tolerance:

Tolerance to external antigens and can be deliberately manipulated to reduce reactions such as allergies.

What are the two levels at which T-cell tolerance is established?

Central tolerance:

which occurs during T-cell development in the thymus,immature thymocytes undergo harsh

selection processes in the thymus resulting in the deletion of

most T cells with high affinity for self antigens.

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- Peripheral tolerance:

Maintains tolerance in mature T cells outside the thymus.

What happens during central T-cell tolerance in the thymus?

1. Self-antigen presentation: Thymic epithelial cells and dendritic cells present self-antigens to immature T-cell precursors in the thymus.

2. Self-antigen recognition: T-cell precursors use their T-cell receptors (TCRs) to recognize self-peptide–MHC complexes.

3. Positive selection: T cells that recognize self-peptide–MHC complexes with an appropriate level of binding receive survival signals and continue developing.

4. Negative selection: T cells that bind too strongly to self-antigens undergo apoptosis (programmed cell death) to prevent them from attacking the body’s own tissues.

5. Maturation and release: Fewer than 5% of the original T-cell precursors survive selection and leave the thymus as mature, naive T cells.

What proportion of T-cell precursors survive central selection according to the lecture?

Less than 5% survive the selection events and leave the thymus as mature naive T cells.

What is peripheral T-cell tolerance and why is it necessary?

It consists of mechanisms that maintain T-cell tolerance outside the thymus because some autoreactive T cells escape central deletion and enter the periphery.

What are the four mechanisms of peripheral T-cell tolerance described in the lecture?

-Immunological ignorance,

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-anergy

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-peripheral deletion of autoreactive T cells by activation-induced

cell death or cytokine withdrawal

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- suppression of immune responses by regulatory T cells.

How do immunological ignorance and anergy prevent autoreactive T-cell responses?

-Immunological ignorance prevents contact between autoreactive T cells and their target antigens

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- while anergy is the inability of T cells to mount an effector response after recognizing their target antigen.

What mechanisms establish B-cell tolerance?

-Clonal deletion of autoreactive B cells, mainly in the bone marrow

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- receptor editing, which rearranges autoreactive B-cell receptors;

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- B-cell anergy, in which B cells cannot mount responses after recognizing their target antigen.

How does T-cell tolerance help maintain B-cell tolerance?

If T-cell tolerance to an antigen is firmly established, B cells recognizing that antigen will usually remain tolerant because B-cell tolerance is maintained by tolerant T cells.