[DISCUSSION] MODULE 1 UNIT 5 Flashcards
-MAJOR HISTOCOMPATIBILITY COMPLEX IS ALSO CALLED
Human Leukocyte antigens (HLA)
-MAJOR HISTOCOMPATIBILITY COMPLEX PRPONENT
Dausset
- First defined by discovering an antibody response to circulating wbcs
MAJOR HISTOCOMPATIBILITY COMPLEX
– Determine whether transplanted tissue is histocompatible and thus accepted or recognized as foreign and rejected
MAJOR HISTOCOMPATIBILITY COMPLEX
-all nucleated cells in the body
(Class I)
-professional APC’s (dendritic cells, macrophages, B cells)
(Class II)
-Play a pivotal role in the development of both humoral and cellular immunity
MAJOR HISTOCOMPATIBILITY COMPLEX
MHC Main Function
- Bring antigen to the cell surface for recognition by T cells, because T cell activation will occur only when antigen is combined with only MHC molecules
– Clinical relevance of MHC
transfusion reactions
graft rejection
autoimmune diseases
– Genes controlling expression of these molecules are actually a system of genes known as the
MAJOR HISTOCOMPATIBILITY COMPLEX (MHC)
-Most polymorphic system found in humans
Genes coding for MHC molecules
– Found on the short arm of chromosome 6 (6p)
GENES CODING FOR MHC MOLECULES
CATEGORIES OF GENES CODING FOR MHC MOLECULES
Class I molecules
Class II molecules
Class III molecules
classical class I molecules
HLA-A, HLA-B and HLA-C antigens
classical class II molecules
D region → HLA-DR, HLA-DQ, HLA-DP
classical class Ill molecules
Code for complement proteins and cytokines such as tumor necrosis factor
- Polymorphic
MAJOR HISTOCOMPATIBILITY COMPLEX
- There are so many possible alleles at each location
- E.g., at least 580 alleles of HLA-A
- Polymorphic
- alleles of HLA-B
921
- alleles of HLA-C
312
- Probability that any two individuals will express the
same MHC molecules is
very low
GENES ARE
CODOMINANT
Consists of a structurally distinct a chain associated with a second, shorter polypeptide called b2
-microglobulin
CLASS I MHC MOLECULES
is organized in three folded domains ( a1
, a2
, and a3
) has a
carboxy-terminal membrane anchor
Class I a chain
(?), with one folded domain, is linked to the
membrane only indirectly through its association with the a chain
smaller b2
-microglobulin
Critical for stabilizing the class I molecule and for facilitating its transport to the cell surface
smaller b2
-microglobulin
The peptide-binding site in a class I protein is formed by the
a1 and a2 domains
Can only accommodate peptides that are (?) amino acids long
8 – 10
are similar to the constant regions found in immunoglobulin molecules
a3 and b2 regions
reacts with CD8 on cytotoxic T cells
a3 region
Expressed on all nucleated cells, but differ in the level of expression
CLASS I
Highest on lymphocytes and lowest on liver
hepatocytes, neural cells and muscle cells
CLASS I
are expressed at a lower level
than HLA-A and HLA-B antigens so the latter two
are the most important to match for transplantation
HLA-C antigens
Another group of molecules called the nonclassical class I antigens
HLA-E, HLA-F, HLA-G
are not expressed on cell surfaces and do not
function in antigen recognition but may play other roles in the immune
response
HLA-E, HLA-F
Expressed on trophoblast cells during the first trimester of pregnancy
HLA-G
Found primarily on antigen-presenting cells (B cells, dendritic cells, monocytes, macrophages)
CLASS II
Consist of two (2) noncovalently bound polypeptide chains that are both encoded by genes in the MHC complex
CLASS II
DR is expressed at the highest level
CLASS II
Accounts for ½ of the all the class II molecules on a particular cell
DR
Both the a chain (MW = 33 kD) and the b chain (MW = 27 kD) are anchored to the cell membrane
CLASS II
Each has two domains
CLASS II
Peptide binding site →formed by the a1 and b1 domains
CLASS II
Both ends of the peptide-binding cleft are open
CLASS II
Allow the capture of longer peptides ( 9 – 20 amino acids) than is the case for class I molecules
CLASS II
CD4 contacts sequences in the b2 domain
CLASS II
Nonclassical class II genes
HLA-DM, HLA-DN, HLA-DO
Products of these genes play a regulatory role in antigen processing
HLA-DM, HLA-DN, HLA-DO
ENDOCYTIC PATHWAY Major antigen
sources
Endocytosed extracellular
proteins (host & foreign)
Membrane proteins (host &
foreign)
CYTOSOLIC PATHWAY Major antigen
sources
Cytosolic proteins of host or
intracellular pathogens (viral,
bacterial, parasitic)
Signal peptides (host & foreign)
ENDOCYTIC PATHWAY Processing machinery
Lysosomal enzymes
CYTOSOLIC PATHWAY Processing
machinery
Proteasomes (including low-
molecular-weight protein (LMPs)
ENDOCYTIC PATHWAY Cell types where active
Professional APCs
CYTOSOLIC PATHWAY Cell types where active
All nucleated cells
ENDOCYTIC PATHWAY Site of antigen –
MHC binding
Endocytic vesicles,
prelysosomes
CYTOSOLIC PATHWAY Site of antigen –
MHC binding
Rough endoplasmic reticulum
ENDOCYTIC PATHWAY MHC utilized
Class II
CYTOSOLIC PATHWAYbMHC utilized
Class I
ENDOCYTIC PATHWAY Presents to
CD4 (helper) T cells
CYTOSOLIC PATHWAY Presents to
CD8 (cytotoxic) T cells
CLINICAL SIGNIFICANCE OF MHC
- MHC molecules can induce a response that leads to graft
rejection - Play a role in development of autoimmune diseases
- Determine the type of peptides to which an individual can mount
an immune response - Presence of a particular MHC protein may confer additional
protection (e.g., HLA-B8 and increased resistance to HIV) - Future developments to tailor vaccines to certain groups of
molecules
