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Terms in this set (40)
What are HLA,what are they involved in and what encodes these antigens?
-HLA= human leukocyte antigens
-They are involved in graft (tissue) rejection or compatibility as so they are also called histocompatibility antigens
-MHC genes encode the antigens and are expressed in all tissues
What HLA antigens are in Class 1 MHC genes/Ag?
HLA- A, B, C, F, E, G
(cell membrane proteins)
What HLA antigens are in Class 2 MHC genes/Ag?
HLA- D: DR, DQ, DO, DN, DP
(cell membrane proteins)
What HLA antigens are in Class 3 MHC genes/Ag?
HLA- C2, C4 and BF (factor)
(secreted complement components)
Tissue typing involves what MHC molecules?
MHC Class 1 HLA-A and HLA-B
MHC Class 2 HLA-DR
What two purposes do MHC tissue typing antigens serve?
1. MHC binds to and present, processed foreign antigenic peptides to T cells, thereby initiating the immune response
2.MHC antigens distinguish the membrane antigens on a transplanted donor organ to tissue from those of the recipient, initiating tissue rejection
How does a child inherit HLA?
A child inherits one allele in each group as a set (haplotype) for each of their parents. Look at page 4 in Module 11 for example
What is a phenotype?
A listing of allthe alleles identified in an individual
What is polymorphism?
The existence of two or more alternative forms of a gene. Each variant is called an allele. It happens so MHC molecules can recognize foreign antigens from ourselves.
What does tissue typing involve?
(Also called histocompatibility testing)
Involves determining HLA antigens present on both the donor and recipient tissues as well as determining if the recipient may have HLA antibodies in their serum
Why is a tissue crossmatch performed?
To help predict compatibility of the transplant.
What are the two HLA antigen Detection Techniques?
1.Serological (reacting antigen with an antibody)
Describe serological antigen detection.
-Antisera containing a known antibody is used to detect HLA antigens on patient's cells.
-Lymphocytoxicity (complement dependent) involves mixing patient lymphocytes with known antisera and incubated. Complement is added and further incubated. The mixture is examined and will look for cells damaged (because they bound the HLA antibody and complement damaged them). Damaged cells take up dye (trypan blue or eosin) and can be quantitated.
What are the two molecular techniques for antigen detection and describe them?
1. Sequence Specific Oligonucleotide (SSO) typing
-DNA for a whole chromosomal region is amplified by PCR
-The amplified DNA is then tested by adding radio-labeled oligonucleotide probes, that are complementary for DNA sequence characteristic on certain HLA antigens.
-The probes will then type for the presence of specific DNA sequences
2.Sequence Specific Priming (SSP)
-higher resolution than SSO typing
-Oligonucleotide primers are used to start the PCR, and have sequences complimentary to known sequences that are known of certain HLA specificities
Both SSO and SSP typing use a PCR (polymerase chain reaction). Describe the automated process of PCR that we use.
1.obtain DNA from person of interest
2.double stranded DNA is denatured (split) into single stranded DNA
3.Oligonucleotide primer sequences are then chosen to identify area of interes
4.If a primer is chosen that is close to a region of special interest, then only that part of the DNA will by duplicated when DNA polyermase enzyme and deoxyribnucleotide triphosphates are added.
5. This process can be repeated with denatured and putting the DNA back together until there is sufficient amount of the selected portion to type.
Name the 3 antibody detection techniques and describe them.
1.Microlymphocytotoxicity ( patient's serum is tested agaisnt a panel of cells with known HLA antigens, then complement is added and cell damage is indicative of antigen/antibody binding)
2. ELISA (enzyme-linked immunosorbent assay; purified HLA antigens bound to microtiter wells and binding of antibody from patient's serum is detected by using a 2nd anti-IgG/IgM labelled with alkaline phosphatase. Enzyme substrate allows for detection)
3.Flow cyometry (detects antibodys from the patient binding to reagent T and B lymphocytes or purified HLA antigens; advantage is no complement)
What is mixed lymphocytes culture (MLC) tests/ mixed lymphocyte reaction (MLR) tests?
-Is an in vitro tissue crossmatch using the biological response of lymphocytes to foreign HLA to measure histocompatibility.
What is the principle behing MLC/MLR tests?
-When you mix lymphocytes of two people together, each cell population will recognize any foreign HLA Class 2 (D) antigens of the other
-Lymphocytes will respond by blast transformation and synthesizing new DNA
-Radio labeled thymidine is added to culture and will be incorporated into the new DNA
-The uptake of thymidine is measured and tells us the difference between the HLA Class 2 types of the person (↑ thymidine uptake=↑ DNA created= ↑ difference in HLA types of the two people)
-Thymidine uptake is quantitated in a liquid scintillation device
-A low MLC is associated with excellent transplant survival
How long does it take to perform an MLC/MLR test and when do you use it?
-4 to 5 days to perform
-Use it only for living donors because organs from deceased donors only survive 24 to 48 hours
Name the six things that are of clinical relevance with the HLA system
4.Platelet (and Granulocyte) Transfusions
5.HLA and Disease susceptibility
6.Organ,Bone Marrow and Stem Cell Transplant
Describe natural function clinical relevance.
-most important function of the MHC molecules is participation in recognition of immunogens and regulation of immune responses.
-T lymphocyts recognize foreign antigen in combination with HLA (MHC) molecules
Describe anthroplology clinical relevance.
-there is an associatoon between certain HLA genes and racial orgin ex.) HLA-A1 European
Describe paternity testing clinical relevance
-excluding by doing first order exclusion (like paternity testing). This is when you look at a child and then at a possible parent. If the child doesn't have at least one of the haplotypes from the possible parent, then that person would not be the child's parent.
-In labs we combine red cells with HLA testing of the mother, child and possible father, with further genetic analysis (RFLP method= direct comparsion of DNA fragments)
Describe platelet (and granulocyte) transfusions clinical relevance
-HLA class 1 antigens are carried in high concentration on leukocytes and platelets but low concentration of RBCs
-Patients with an intact immune system that require multiple transfusions will develop antibodies to the HLA antigens on the transfused cells
-To avoid making antibodies with just RBCs tranfused, the cells are washed and filtered to reduce leukocyte contamination
-HLA antibodies can lead to two problems
1.patients become refractory to platelet transfusions= platelets are sensitized and removed rapidly
2.Non-hemolytic transfusion reactions may occur in response to the HLA antigens
Describe HLA and disease susceptibility clinical relevance
-The HLA antigen can play an important role in disease (all of its mechanisms are probably involved in varying degrees with different diseases)
-In multiple sclerosis and ankylosing spondylitis with high association with HLA-B7 and HLA-B27 respectively, cell mediated immunity is depressed.
-More than 500 diseases have documented HLA associations but many are low frequency and may be due to chance
Describe Organ, bone marrow and stem cell transplant clinical relevance
-Tissue transplants (other than blood) may require HLA typing
-Kidney= ABO and HLA (A,B,DR) typing, check for existing HLA antibodies
-Heart & Liver= ABO and then physical size is considered. HLA matched and check for HLA antibodies
-Bone Marrow/HPC/Stem cells= HLA matched (HLA- A,B,DR,DQ) ABO not required
-Cornea/sclera= cornea most frequent and successful transplant
transfer of cells, tissues or whole organs from one site of body to another or from one individual to another
transfer of tissue from one area to another on the same individual
transfer of tissue from one individual to a genetically identical individual
transfer of tissue between two genetically different individuals from same species
transfer of tissue between individuals of different species
What is graft rejection and who does the rejecting?
-Graft rejection= due to incompatibility between donor and recipient (MHC antigens, even matched ones, can show slight differences between people)
-Rejection is by host
Describe Hyperacute Rejection
-due to pre-existing antibodies to ABO antigens or MHC Class 1 antigens [LAWSUIT :) ]
-Preformed ABO antibodies will bind complement and lead to vascular damage that will affect the graft
-Prevented by careful testing and tissue matching
Describe Acute Rejection
-occurs within first few days to weeks
-Due to activation of T-cells in recipient to donor antigens
-Difficult to prevent and predict
Describe Chronic Rejection
-occurs over longer periods of time, sometimes even years
-Leads to gradual loss of graft tissue structure and function
-Rejection tends to be both cellular and humoral
-May also be due to similar disease process in donor as what the recipient had
What is Graft vs. Host?
-Occurs mostly in severely immunocompromised or immunosuppressed recipients
-T lymphocyes from DONOR recognize recipient antigens and will mount an immune response
-The recipient if unable to reject the transfused lymphocytes, will suffer severe tissue destruction
-Can occur in IMMUNOCOMPETENT recipients of blood from biologically related donor--> it is because the donor is homozygous and recipient isn't
-Recipient will not recognize donor as foreign but homozygous donor will see recipient as foreign
-Blood products are irradiated to prevent
Explain the 3 ways chemical immune suppressants work.
1. Inhibition of mitosis (↓ B and T cell proliferation) EX.) Azathioprine
2.Inhibtion of protein synthesis (inhibit the syntheis of IL-2 and IL-2 receptors on TH cells)
3.Anti-inflammatories (decrease # of circulating lymphs and ↓ phagocytic and cytotoxic abilities of macrophages) EX.) Corticosteroids
How do biological agent immune suppressants work?
Biological agents are directed agaisnt immune cells
EX.) Anti-lymphocyti serum marks lymphocytes for removal
How does radiation work as an immune suppressant?
Radiation depletes patient's lymphocytes prior to transplantation. Often used prior to bone marrow transplantation
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Immunological Testing Methods
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