HLA: Immunology Basics, Transplantation, Autoimmunity Flashcards
Define MHC.
Major histocompatibility complex.
This is the cluster of genes that encode molecules involved in antigen presentation. Nearly every mammal has one in its genome.
Define HLA.
Human Leukocyte antigen.
It is used to refer to genes & to the molecules that they encode. The HLA region is the human MHC.
The loci are class I and class 2.
What are the class I loci? (3)
HLA-A, HLA-B & HLA-C
What are the class 2 loci? (3)
HLA-DP, HLA-DQ & HLA DR
Talk about alpha and beta chains in class II.
DQA, DPA, DRA encode alpha chains, & DPB, DQB, & DRB encode beta chains.
What do the HLA molecules do?
They present peptide antigen to T-lymphocytes.
Endogenous antigen is presented on what class?
What T lymphocytes do they present antigens to?
Class I HLA molecules
CD8 T cells
C locus seems to be more concerned with NK cells.
Think.. I ‘ate (8) killing in the END (endogenous/CD8/class I).
Exogenous antigen is presented on what class?
What T lymphocytes do they present antigens to?
Class II HLA molecules
CD4 T cells
Think… EXtra help 4 you 2 (exogenous/CD4/class II).
What upregulates expression of HLA molecules?
Cytokines, especially Interferon gamma.
What is meant by a haplotype?
The team of alleles encoded on a short section of one
chromosome. A single haplotype will have been inherited from one parent, & will usually be passed on intact to offspring, if the segment of chromosome is short enough. The longer the segment of chromosome considered, the more likely it is that crossovers
will occur in the formation of the gametes, & the haplotype. passed on to the child will be a mixture of one parent’s two haplotypes.
You would expect no association between particular alleles at one locus and particular alleles at a neighbouring locus if the alleles were randomly distributed.
However, there is a common haplotype.
What is this phenomenon called?
A1, B8, DR3, DQ2
Linkage disequilibrium
What are two explanations for the linkage disequilibrium phenomenon?
- Founder effect
2. Advantageous combination
Compare no. of different specificities on one cell in innate vs adaptive immunity.
Innate - A variety. 20-30? Toll, lectins.
Adaptive - One specificity
Comparing innate vs adaptive immunity - cells different from one another?
Innate - no, all cells of one kind/same
Adaptive - yes, diversity of specificities
Comparing innate vs adaptive immunity - is antigen receptor directly encoded?
Innate - yes
Adaptive - no, each cell randomly mutates gene
Comparing innate vs adaptive immunity - clonal? Mediate memory?
Innate - no
Adaptive - yes, clonal expansion
Comparing innate vs adaptive immunity - danger of autoimmunity?
Innate - no
Adaptive - yes, clonal deletion required
Comparing innate vs adaptive immunity - cells.
Innate - neutrophils, monocytes, eosinophils, mast cells
Adaptive - B and T lymphocytes
Where do T cells mature?
Thymus
Antigen receptor is antibody for T or B cells?
B cells
Recognition of antigen for B cells?
For T cells?
B cells - ANYWHERE
T cells - ONLY WHEN PRESENTED ON SURFACE OF
ANOTHER CELL, i.e. so antigen needs to presented by another cell
Explain clonal deletion of B lymphocytes.
A pool of lymphocytes in bone marrow are sensitive to clonal deletion at this stage. If they encounter a component of self, the lymphocyte is deleted. If they don’t, they survive and mature and move out of the bone marrow and into the circulation. They are no longer sensitive to clonal deletion. If they encounter an antigen that fits their receptor now, they will become activated and DIVIDE!!
Also, this can occur in lymph node cortex and germinal centre, for T-dependent B cells, if they fail to get help from CD4 T cells.
Explain clonal expansion.
A pool of lymphocytes in the peripheral lymphoid tissues. If they encounter an antigen, then a few days later, those with specificity to that antigen are greater in number than before and easier to activate (memory cells).
Class I molecules encoded at A, B and C loci.
How many locus alleles can any individual have?
Any individual can have 2 A locus alleles, 2 B locus alleles, & 2 C locus alleles, and all of these can be expressed on each cell that expresses class I (most cells in the body).
Class II molecules encoded at DR, DQ, and DP loci.
How many locus alleles can any individual have?
Any individual can have 2 DR locus alleles, 2 DQ locus alleles, & 2 DP locus alleles, and all of these can be expressed on each cell that expresses class II (mostly antigen presenting cells: dendritic cells, macrophages, monocytes, B-lymphocytes, though class II expression can be induced on other cells by cytokines).
In a full allelic name, there are 8 digits after the locus letter, e.g. A*02:01:02:11.
What do these digits mean?
The first pair of digits defines the “cross-reactive group”. All alleles that have the same first two digits have similar shapes on the exposed parts, & “look” the same to antibodies. They represent the alleles as they were originally defined by serology (antibodies).
The second pair of digits represent differences in the amino-acid sequence that cannot be detected by antibodies: these are revealed by molecular biology. The polymorphisms may be within the groove, where they cannot be detected by antibodies, but can effect peptide selection for presentation, and therefore
function.
The third pair of digits represent silent polymorphisms within the exons: where the amino-acid sequence is the same, but the DNA base sequence differs.
The fourth pair of digits represents polymorphisms in the introns.
Why is the nomenclature more complicated for class II alleles encoded at the DR, DQ, and DP loci?
Both chains are polymorphic. For example, the DPA locus encodes the DP alpha chain, and the DPB locus encodes the DP beta chain.
Alleles at each of these loci are named with the locus first, followed by eight digits with the same significance as in the class I loci above.
Eg DPB*01:04:10:05
To survive selection process in the thymus, T lymphocytes must be …? They must not be…?
Positively selected (i.e must be attracted to some of the “HLA + peptide” complexes displayed in the thymus)
Negatively selected (ie they must not be too strongly attracted to any “HLA + peptide” complex in the thymus).
When might T lymphocytes undergo clonal deletion?
- In the thymus, if the receptors on a developing T-lymphocyte show a “passionate interest” in any HLA + peptide being expressed on the thymic epithelial cells or dendritic cells.
- After leaving the thymus, if the T-lymphocyte recognises an HLA + peptide being expressed on a dendritic cell, but does not get the second signal via CD28 engaging with its CD80 & CD86.
