The family of disease with the gene we share HLA-B27 info about the pathology

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Spondylarthropathies

The relationship between HLA-B27 and many diseases has not yet been fully elucidated. Though it is associated with a wide range of pathology, it does not appear to be the sole mediator in development of disease. For example, while 90% of people with ankylosing spondylitis (AS) are HLA-B27 positive, only a fraction of people with HLA-B27 ever develop AS. This raises two important questions: why don't all HLA-B27 positive people develop AS, and why do some people who are HLA-B27 negative develop it? There are additional genes being discovered that also predispose to AS and associated diseases.[5] Additionally there are potential environmental factors (triggers) that may also play a role in susceptible individuals.,[6][7]

HLA B27 Gene frequencies[4]
USA Alaska Yupik 11.5
Native American 8.6
Arizona Pima ind. 7.9
Belgium 7.1
Mexico Tarahumara 6.8
Finland 6.1
Ireland South 4.2
India Tamil Nadu Nadar 4.1
India North Hindus 3.8
Croatia 3.7
Portugal North 3.3
Mexico Guadalajara Mestizos 2.9
Czech Republic 2.8
Azores Terceira Island 2.7
Azores Santa Maria & Sao Miguel 2.6
South Korea pop 3 2.5
Cape Verde Northwestern Islands 2.4
France South East 2.3
Morocco Nador Metalsa Class I 2.1
Portugal South 2.0
Spain Eastern Andalusia Gipsy 2.0
Italy North Pavia 1.9
Azores Central Islands 1.8
Bulgaria 1.8
Israel Jews 1.8
Georgia Tibilisi Kurds 1.7
Brazil Belo Horizonte 1.6
Cape Verde Southeastern Islands 1.6
India New Delhi 1.5
Mexico Sonora Seri 1.5


Note: These are gene frequencies which are roughly half of the phenotype frequencies.

[edit] Pathological Mechanism of HLA-B27

Due to its strong association with spondyloarthopathies, HLA-B27 is the most studied HLA-B allele. It is not entirely clear how HLA-B27 influences disease, however there are some prevailing theories as to the mechanism. The theories can be split into antigen-dependent and independent theories.[8]

Antigen-dependent theories

These theories consider a specific combination of antigen peptide sequence and the binding groove (B pocket) of HLA-B27 (which will have different properties to the other HLA-B alleles). The arthritogenic peptide hypothesis suggests that HLA-B27 has a unique ability to present peptide specific to joints, to autoreactive cytotoxic T cells. The molecular mimicry hypothesis is similar, however it suggests that cross reactivity between some bacterial antigens and self peptide can break tolerance and lead to autoimmunity.[8]

Antigen-independent theories

These theories refer to the unusual biochemical properties that HLA-B27 has. The misfolding hypothesis suggests that slow folding during HLA-B27's tertiatary structure folding and assosiation with β2 microglobulin causes the protein to be misfolded, therefore initiating the unfolded protein response (UPR) - a pro-inflammatory endoplasmic reticulum (ER) stress response. Also, the HLA-B27 heavy chain homodimer formation hypothesis suggests that B27 heavy chains tend to dimerise and accumulate in the ER, once again, initiating the UPR.[8] Alternatively, cell surface B27 heavy chains and dimers can bind to regulatory immune receptors such as members of the killer cell immunoglobulin-like receptor family promoting the survival and differentiation of pro inflammatory leukocytes in disease.

[edit] Associated pathology

In addition to its association with ankylosing spondylitis, HLA-B27 is implicated in other types of seronegative spondyloarthropathy[9] as well, such as reactive arthritis (Reiter's Syndrome), certain eye disorders such as acute anterior uveitis and iritis, psoriatic arthritis and ulcerative colitis associated spondyloarthritis. The shared association with HLA-B27 leads to increased clustering of these diseases.[10]

[edit] See also

[edit] External links

[edit] References