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CP reviewer 1 > MHC and Transplant Rejection > Flashcards

MHC and Transplant Rejection Flashcards

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1
Q

What is an isograft?

A

A graft between two individuals that are genetically identical (monozygotic twins)

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2
Q

What is an allograft?

A

Transplant of organ/tissue from one individual to another of the same species with a different genotype (i.e. not identical twins)

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3
Q

What is a xenograft?

A

a tissue graft or organ transplant between different species

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4
Q

What is HLA?

A

The human leukocyte antigen (HLA) system or complex is a group of related proteins that are encoded by the major histocompatibility complex (MHC) gene complex in humans.

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5
Q

How does the adaptive immune system become activate after the first few foreign cells have been phagocytosed?

A

Lymphocytes mount a specific immune response by recognising antigens on the surface on antigen-presenting cells such as macrophages:

  • Pathogen is phagocytosed
  • The macrophage or dendritic cell digests the pathogen and presents a small peptide (the antigen) on its surface
  • The antigen is presented as part of a receptor that is located on the surface of antigen-presenting cells (MHC)
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6
Q

In humans, what are MHCs called?

A

Human Leukocyte Antigens (HLAs).

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7
Q

What are the 2 classes of antigens found on cell surfaces?

A

Class I and class II

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8
Q

On which cells are Class I antigens found?

A

All nucleated cells (except RBC’s)

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9
Q

Describe type I antigens (MHC class I molecules)

A
  • Heterodimers
  • Heavy chain
  • β2-microglobulin (β2M)
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10
Q

On which cells are Class II antigens found?

A

APCs

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11
Q

Cytosolic pathogens:

  1. Where are they degraded?
  2. What MHC class do the peptides bind to?
  3. What cells are they presented to?
  4. What is the effect on presenting cells?
A
  1. Degraded in the cytosol
  2. Peptides bind to MHC Class I
  3. Presented to effector CD8 T cells (cytotoxic T cells)
  4. Causes cell death of presenting cell
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12
Q

Intravesicular pathogens:

  1. Where are they degraded?
  2. What MHC class do the peptides bind to?
  3. What cells are they presented to?
  4. What is the effect on presenting cells?
A
  1. Degraded in endocytic vesicles (low pH)
  2. Peptides bind to MHC class II
  3. Presented to CD4 T cells
  4. Activate presenting cell to kill intravesicular bacteria and parasites
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13
Q

Extracellular pathogens and toxins:

  1. Where are they degraded?
  2. What MHC class do the peptides bind to?
  3. What cells are they presented to?
  4. What is the effect on presenting cells?
A
  1. Degraded in endocytic vesicles (low pH)
  2. Peptides bind to MHC class II
  3. Presented to CD4 T cells
  4. Activate B cells to secrete Ig to eliminate extracellular bacteria/toxins
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14
Q

On which chromosome does the MHC region occur on?

A

Chromosome 6

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15
Q

HLA genes are highly polymorphic. What does this mean?

A

HLA genes are highly polymorphic, which means that they have many different alleles –> allowing them to fine-tune the adaptive immune system and bind different peptides

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16
Q

Where do T cells originate from?

A

from haematopoietic stem cells which are produced in the bone marrow

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17
Q

After leaving the bone marrow, where do progenitor T cells travel?

A

travel to the thymus via the blood

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18
Q

Where do T cells mature?

A

Thymus

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19
Q

How are T cells positively/negatively selected in the thymus?

A
  • Thymocytes (immature T cells) that recognise self-MHC molecules receive positive signals for survival
  • Thymocytes that have receptors to self-antigen molecules receive negative signals and are removed
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20
Q

How can HLA variability be linked to disease?

A

People with certain HLA antigens are more likely to develop certain autoimmune diseases, such as type I diabetes, rheumatoid arthritis, celiac disease, SLE

E.g. DR3 confers susceptibility to SLE

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21
Q

After transplantation, where do donor-derived APCs migrate to?

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A

Migrate to the graft-draining lymphoid tissues –> recognised as foreign by T cell receptors on recipients lymphocytes

22
Q

Autologous vs allogeneic?

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A

Autologous: Auto means self. The stem cells in autologous transplants come from the same person who will get the transplant, so the patient is their own donor.

Allogeneic: Allo means other. The stem cells in allogeneic transplants are from a person other than the patient, either a matched related or unrelated donor.

23
Q

Why is a strong immune response caused during transplantation of allogeneic cells?

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A

As peptides are completely different

24
Q

What is the immunological synapse?

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A

The interface between an antigen-presenting cell or target cell and a lymphocyte such as a T/B cell or Natural Killer cell.

25
What is **indirect alloantigen recognition?** Describe in terms of transplantation
Normal antigen mechanism of T lymphocytes: * Alloantigens derived from graft are internalised, processed and presented in form of peptides by **recipient’s APCs** on their MHC II molecules * Presented to T lymphocytes --\> rejection of transplant
26
What is direct alloantigen recognition? Describe in terms of transplantation
* Population of APCs is localised **inside donor’s tissues** and is co-transferred from donor to recipient via transplant procedure --\> 'passenger cells' * Shortly after transplantation, these cells migrate through lymphatic system to regional **lymphatic nodes**. * Inside the lymphatic nodes, these cells are confronted with **recipient’s naïve T lymphocytes** and their contact culminate in recognition of allogenic MHC displayed on the surface of the passenger cells. * This phenomenon is called **direct recognition** and leads to acute rejection of allografts In this case, alloreactive T cells are stimulated by donor APCs
27
Difference between direct and indirect alloantigen recognition?
Stems from the **origin of the macrophages** (APCs): * Direct: the involved APCs are **donor derived**. * Indirect: the APCs involved are **recipient APCs**
28
Once the CD4+ T cell have recognised a foreign antigen, they can generate many types of responses.
1. Antibody production (B cells) 2. Cytotoxicity (CD8+ cells) 3. DTH (delayed-type hypersensitivity response)
29
What is HLA typing?
* A kind of genetic test used to identify certain individual variations in a person's immune system. * The process is critical for identifying which people can safely donate bone marrow, cord blood, or an organ to a person who needs a transplant.
30
What is a haplotype?
A haplotype is a group of genes within an organism that was inherited together from a single parent.
31
What are the 3 general groups of HLA?
HLA-A, HLA-B and HLA-DR There are many different specific HLA proteins within each of these three groups. (For example, there are 59 different HLA-A proteins, 118 different HLA-B and 124 different HLA-DR
32
Example of two children inheriting the very same HLA from their parents, they are an HLA **"identical match".** While another child in the same family can inherit a different combination of HLA:
33
How is HLA inherited?
HLA is inherited as a "set" of the three HLA groups, A, B, DR. This set is known as a "haplotype". You inherit one haplotype from each parent. Therefore, there are a total of four different haplotype combinations from 2 parents: * You have a 25% chance of inheriting all of the same HLA (same 2 haplotypes) as any one of your siblings * You have a 25% chance of not inheriting any of the same HLA (none of the same haplotypes) * You have a 50% chance of sharing 1 haplotype with your siblings. * You have a 1 in 4 chance of being an identical match with your siblings.
34
What type of a mismatch is this?
1,1,1 mismatch as 1 mismatch per HLA
35
How is HLA typing carried out?
* Extraction of DNA * Amplification * Detection of sequence polymorphisms (i.e. tissue type) * Hybridisation to probes * Sequencing
36
Renal transplant pathway
37
What is purpose of antibody testing?
This test checks your blood for antibodies against a cell marker called a human leukocyte antigen (HLA). The test is done if you need an organ transplant, to help find a donor organ that will work in your body. General antibodies --\> against many HLA types Specific antibodies --\> against donor
38
What are sensitising events?
* Previous transplant * Pregnancy * Blood transfusion Sensitisation is a process by which the immune system will produce an antibody in response to any substance it considers abnormal.
39
How is flow cytometry used for antibody detection?
Flow Cytometry uses fluorescent markers on antibodies or other proteins in order to quantifiably detect changes in protein expression via excitation of the various fluorescent markers. Flow cytometry can be used for detecting numerous targets either on the surface or within cells in the same sample.
40
What is Luminex screening?
Luminex-based single antigen bead (L-SAB) technology, which uses recombinant single HLA molecules, allows detection and characterisation of HLA antibodies at greater sensitivity
41
What is solid phase testing?
A method of testing for incompatibility between plasma antibodies and target RBC antigens.
42
Detection of antibodies methods comparison
43
What is danger of a really sensitivity antibody detection test?
Pick up lots of low level antibodies that actually won't cause rejection --\> depriving people of chance to have transplant
44
What are the 3 types of rejection?
1. Hyperacute 2. Acute rejection 3. Chronic antibody mediated rejection
45
What is hyperacute rejection?
* Occurs within minutes or hours after a transplantation --\> when you let go of clamps, organ can go black * Is caused by the presence of **pre-existing antibodies** of the recipient that match the foreign antigens of the donor, triggering an immune response against the transplant. * These antibodies could have been generated as a result of **prior blood transfusions**, **prior transplantations** or **multiple pregnancies.**
46
Where can pre-exisiting antibodies in hyperacute rejections come from?
* Prior blood transfusions * Prior transplantations * Multiple pregnancies.
47
What is acute rejection?
* This occurs within the first 6 months after transplantation. * Some degree of acute rejection will occur in all transplantations, except between identical twins. * Acute rejection is caused by the formation of **antibodies following the detection of non-self antigens** in the donated graft. * Directed agaist foreign HLA molecules (effect of HLA mismatch)
48
What is chronic rejection?
* Repeated episodes of acute rejection can ultimately lead to chronic rejection of the graft and failure of the transplant. * Chronic rejection commonly manifests as scarring of the tissue or organ which can occur months to years after acute rejection has subsided.
49
What causes hyperacute rejection?
* Preformed antibodies * Xenograft rejection * ABO incompatible transplantation (ABO antibodies) * HLA incompatible transplantation (Anti-HLA)
50
What are anti-HLA antibodies?
Anti-HLA antibodies are formed by the immune system when you are exposed to proteins that appear similar to tissue types. This most commonly occurs in the setting of previous transplantation, pregnancy, or blood transfusion.
51
What can post transplant anti-HLA Abs be used as?
Biomarker of poor outcome --\> no known treatment

CP reviewer 1 (59 decks)

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