HUMAN LEUKOCYTE ANTIGEN-B27 AND
DISEASE SUSCEPTIBILITY IN VOJVODINA, SERBIA
Vojvodić S1,*, Ademović-Sazdanić D1, Busarčević I2
*Corresponding Author: Assistant Professor Svetlana Vojvodić, M.D., Ph.D., Department for Laboratory
Testing, Tissue Typing Compartment, Institute for Blood Transfusion of Vojvodina, Hajduk Veljkova 9a,
21000 Novi Sad, Serbia; Tel.: +381-21-4877-963; Mobile: +381-64-861-58-12; Fax: +381-21-4877-978;
E-mail: ssvu@EUnet.rs
page: 55
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INTRODUCTION
One of the most interesting areas of research
within the field of histocompatibility concerns the
observation that the major histocompatibility system
is deeply involved in the development of a variety of
diseases. Major histocompatibility complex (MHC)
class I molecules are heterodimeric complexes consisting
of a heavy chain (HC), β2-microglobulin (β2
m or light chain), and a peptide (commonly 8-11
amino acids in length) that are located on the surface
of most nucleated cells. Their biological function is to
present peptides to a variety of ligands, in particular
T cell receptors (TCR), residing on the surface of
cytotoxic T cells (CTL) [1].
The human MHC class I molecule, human leukocyte
antigen-B27 (HLA-B27), is strongly associated
with spondyloarthropathies (SpA), a group of closely
related inflammatory arthritic diseases, the most common
of which is ankylosing spondylitis (AS) [1-3].
Spondyloarthropathies comprise several disorders
that are more heterogenous clinically and where genetic susceptibility is likely to be more complex and
variable [3]. The association degree varies markedly
among different diseases of this group and also between
different populations [2]. Association of AS and
HLA-B27 remains one of the strongest known association
of diseases with HLA-B27. About 95.0% of AS
patients express HLA-B27, although the frequency of
this antigen in Caucasians is below 10.0%. However,
the causative role of HLA-B27 in SpA is still not understood,
although various studies confirmed that the
HLA-B27 molecule itself is the strongest predisposing
factor for disease pathogenesis [1].
A number of theories explaining the pathogenetic
role of HLA-B27 have been proposed [1,4].
The theories proposed to explain the mechanism by
which HLA-B27 induces disease susceptibility are:
1) HLA B27 is in genetic linkage with a diseaseassociated
gene; 2) HLA-B27 binds and presents
“arthritogenic” peptides to T cells; 3) HLA-B27 is involved
in thymic selection of a T-cell repertoire that is
susceptible to SpA; 4) HLA-B27 has an unusual cell
biology compared with other HLA class I molecules;
5) the HLA-B27 free cysteine at position 67 can be
chemically modified, leading to an “altered self;” 6)
there is cross reactivity between antibodies directed
at bacterial protein(s) and HLA-B27; 7) HLA-B27
is a receptor for a bacterial ligand; 8) interaction of
HLA-B27 with bacterial superantigens causes non
specific T-cell stimulation; 9) HLA-B27-derived
peptides are presented by HLA class II molecules
to CD4+ T cells [4-6]. None of the existing theories
have as yet satisfactorily explained the underlying
mechanism and the differential association of HLAB27
subtypes with AS. There are 86 HLA-B27 alleles
based on nucleotide sequence differences, but at
the translated protein level, the number of subtypes
includes 81 different isoforms [7]. The common subtypes
B*27:02, B*27:04 and B*27:05 are strongly
associated with AS. Although some of the HLA-B27
subtypes, such as B*27:09 in Sardinia and B*27:06 in
Thailand, have been clearly shown not to predispose
to the disease [1,3,8]; sequencing of the HLA-B27
subtypes that are commonly associated with disease
have shown no differences between healthy subjects
and patients with AS. It is therefore believed that
other genes and/or environmental factors are also
involved in determining susceptibility to disease,
and furthermore, that the degree of expression of
the HLA-B27 gene may also be relevant [9].
The recent development of the genome-wide association
study approach has revolutionized genetic
studies of AS by finding some non MHC genes, some
of which also confer susceptibility to psoriasis and
chronic inflammatory bowel disease, such as the gene
for the interleukin-23 (IL-23) receptor. The IL-23R
gene has recently been found to contribute approximately
9.0% of the population- attributable genetic
risk for AS in Caucasians. Another gene, ARTS1
(also called ERAAP and ERAP1) that encodes a trans
membrane amino peptide with diverse immunological
functions and is located on chromosome 5, shows
strong association with AS, contributing roughly
23.0% of the population-attributable genetic risk for
AS in Caucasian populations. The IL-1 gene cluster,
IL1A, contributes approximately 5.0% of the population-
attributable genetic risk for AS in Caucasian
populations. Thus, the popula-tion-attributable genetic
risk for HLA-B27 (40.0%), ARTS1 (23.0%), IL-23R
(9.0%) and IL-1A (5.0%) add up, and one can conclude
that approximately three-fourths of the total genetic
risk of developing AS has been uncovered [8]. The aim
of the present study was to determine the involvement
of HLA-B27 in pathogenesis of AS, polyarthralgia,
lumboishialgia, acute anterior uveitis (AAU), psoriatic
arthritis (PA), synovitis coxae and rheumatoid arthritis
(RA) in patients from Vojvodina, Serbia.
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