This document discusses the association between HLA alleles and susceptibility to disease. It notes that HLA allelic diversity helps the immune system recognize pathogens, but some alleles may recognize self-molecules and cause autoimmune diseases. Most disease associations are with Class I or Class II HLA alleles. Specific examples discussed include associations between HLA-B27 and various conditions like ankylosing spondylitis, HLA-DQ genes and celiac disease, and HLA-DRB1 alleles and rheumatoid arthritis. The document hypothesizes that HLA molecules play a key role in thymic selection of T-cells and presentation of peptides to initiate or propagate immune responses, providing a basis for HLA-associated disease susceptibility.
1. Association of HLA alleles
with susceptibility to disease
Christa Maria Joel
2. It has long been claimed that infections provide the driving force for
allelic diversification seen in HLA system
Consequence of this hypothesis: resistance to specific pathogens may
differ between 2 individuals based on HLA genotype.
Extraordinary scope of HLA allelic diversity increases the likelihood that
most new pathogens will be recognised by some HLA molecules, helping
to ensure immune fitness to host.
Some alleles may become capable of recognition of “innocent
bystanders” molecules like drugs, environmental molecules.
2
3. Single HLA alleles display a strong selectivity for binding of a particular
agent that accounts for a genetically determined response.
It is very likely the class I and class II alleles themselves are the true
susceptibility alleles for most of the genetic associations.
In some cases, the susceptibility gene may be one of the HLA linked
genes located near the class I or class II region, but not the HLA gene
itself and in other cases the susceptibility gene may be a non HLA gene
such as TNF- alpha which is nearby.
3
4. Almost all of the diseases associated with specific HLA alleles have an
immunologic component to their pathogenesis.
Another group of diseases is genetically linked to HLA because they are
caused by autosomal dominant or recessive abnormal alleles at loci that
happen to reside in or near the HLA region.
Examples: 21- hydroxylase deficiency, hemochromatosis,
spinocerebellar ataxia.
4
6. Class I association with disease
B27 is among the most negatively charged of HLA class I heavy
chains and the overall preference is for positively charged peptides.
Hla- B 2705: most predominant subtype in whites and most other non
Asian populations.
This subtype highly associated with ankylosing spondylitis, chronic
inflammatory bowel disease, psoriasis vulgaris, reactive arthritis,
acute anterior uveitis.
This subtype found in 50-90% of individuals with these conditions.
6
7. B27 is involved in disease pathogenesis.
Association of B27 with these diseases may derive from the
specificity of a particular peptide or family of peptides bound to B27.
HLA B27 forms heavy chain homodimers, utilizing the cysteine
residue at position 67 of B57 alpha chain.
These homodimers are expressed on surface of lymphocytes and
monocytes from patients, and receptors including KIR3DL1, KIR3DL2
and ILT4 are capable of binding to them, promoting the activation and
survival of cells expressing these receptors.
7
9. Class II disease associations
Majority of associations of HLA and disease are with class II alleles.
Diseases like-
- Celiac disease
- Pemphigus vulgaris
- Juvenile arthritis
- Type 1 diabetes mellitus
- Rheumatoid arthritis
9
10. Celiac disease
HLA-DQ genes: primary basis for
disease association.
HLA-DQ genes present on both
the celiac associated DR3 and
DR7 haplotypes include the
DQB1*0201 gene and a specific
class II alpha beta dimer encoded
by the DQA1*0501 and
DQB1*0201 genes- contribution to
celiac disease susceptibility.
10
11. Pemphigus vulgaris
There are 2 HLA genes associated with disease- DRB1*0402 and
DQB1*0503.
Peptides derived from desmoglien 3, an epidermal autoantigen, bind to
the DRB1*0402 and DQB1*0503 encoded HLA molecules.
This combination is sufficient to stimulate desmoglien specific T cells.
Bullous pemphigoid clinical variant not involving desmoglien
recognition has been found to be associated with HLA-DQB1*0301.
11
12. Juvenile arthritis
Pauciarticular juvenile arthritis: autoimmune disease associated with
genes at the DRB1 locus and also with genes at the DPB1 locus.
Patients with both DPB1*0201 and a DRB1 susceptibility allele have
a higher relative risk than expected from the additive effect of those
genes alone.
In juvenile patients with rheumatoid factor positive polyarticular
disease, heterozygotes carrying both, DRB1*0401 and *0404 have
a relative risk >100 reflecting an apparent synergy in individuals
inheriting both of these suspectibility genes.
12
13. Type 1 diabetes mellitus
Type 1 diabetes mellitus is associated with MHC genes on more than one
haplotype.
Presence of both the DR3 and DR4 haplotypes in one individual confers a
twentyfold increased risk for type 1 diabetes.
Strongest single association with DQB1*0302.
Relative risk associated with inheritance of this gene can be modified
depending on other HLA genes present either on the same or a second
haplotype.
Characteristic structural features of diabetes associated DQ molecule
encoded by DQB1*0302- capability for binding peptides that have negatively
charged amino acids near their C termini.
May indicate a role for specific antigenic peptides or T cell interactions in the
immune response to islet associated proteins.
13
15. Rheumatoid arthritis
HLA genes associated encode a distinctive sequence of amino acids
from codons 67-74 of the DRB molecule.
RA associated class II molecules carry the sequence-
LeuLeuGluGlnArgArgAlaAla while non RA associated genes carry
one or more differences in this region.
These residues form a portion of the molecule that lies in the middle
of the helical portion of the DRB1- encoded class II molecule –
shared epitope.
Highest risk for susceptibilty to RA who carries – DRB1*0401 and
DRB1*0404 gene.
15
16. These alleles are most frequent among patients with more severe,
erosive disease.
This portion of class II molecule may allow-
- Preferential binding of an arthritogenic peptide.
- May favor the expansion of a type of self reactive T lymphocyte.
- Or, it may form part of the pMHC ligand recognized by TCR that
initiates synovial tissue recognition.
16
17. Molecular mechanisms for HLA disease
associations
HLA molecules play key role in the selection and establishment of the
antigen specific T cell and a major role in the subsequent activation of
those T cells during initiation of an immune response.
Fate of developing T cells within the thymus determined by the affinity
of interaction between T cell receptor and HLA molecules.
Primary basis for HLA associated disease susceptibility may lie within
this thymic maturation pathway.
17
18. Positive selection of potentially auto reactive T cells based on the
presence of HLA susceptibility genes may establish the threshold
for disease risk in a particular individual.
At time of onset of an immune response- primary role of HLA
molecule is to bind peptide and present it to antigen specific T cells.
These antigenic peptides are capable of stimulating T cell immune
responses.
This genetic control of immune response is mediated by
polymorphic sites within the HLA antigen binding groove that
interact with bound peptides.
18
19. In autoimmune and immune mediated diseases- specific tissue
antigens that are targets for pathogenic lymphocytes are complexed
with the HLA molecules encoded by specific susceptibility alleles.
Autoimmune diseases with an infectious etiology: immune responses
to peptides derived from initiating pathogen are bound and presented
by particular HLA molecules to activate T lymphocytes which
contribute to pathogenesis.
Immune mediated disease is a multistep process in which one of the
HLA associated functions is to establish potentially reactive T cells
while another HLA associated function is to provide the essential
peptide binding specificity for T cell recognition.
19