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

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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