Human leukocyte antigen Class II associations in serum antimitochondrial antibodies (AMA)-positive and AMA-negative primary biliary cirrhosis
Introduction
Primary biliary cirrhosis (PBC) is an inflammatory disease of the interlobular bile ducts of the liver, causing chronic, nonsuppurative cholangitis, followed by liver fibrosis and cirrhosis. The cause of PBC is not known. However, evidence indicates an immune-mediated etiology. Patients with PBC have increased levels of serum IgM [1] and most test positive for mitochondrial antibodies in serum [2]. Increased catabolism of complement has been observed in PBC [3]. Lymphocytes in the peripheral circulation appear to have been sensitized to components of the PDC-E2 component of the mitochondrial substrate [4]. Examination of intrahepatic lymphocytes taken from patients with PBC suggest that there is a polyclonal response as judged by the T cell receptor Vβ repertoire [5].
A genetic component of susceptibility to PBC is suggested by family studies [6], [7], [8], [9]. Clinical evidence supporting both an immunological and a genetic contribution to the disease has been the basis for immunogenetic studies in PBC. One widely studied disease associated genetic region is the major histocompatibility complex (MHC) which encodes molecules involved in immunological functions including the HLA Class I and II antigens. The cell surface HLA molecules present processed peptide to CD8 cytolytic T cells and to CD4 helper T cells, respectively.
Previous studies have investigated the association between polymorphic HLA haplotypes and PBC. The credence for such studies lies in the hypothesis that Class II HLA genes, i.e. HLA DP, DQ or DR, encode protein molecules capable of presenting processed self antigen to CD4+ T cells, thereby propagating the autoimmune mediated tissue damage as seen in PBC. Recent evidence suggests that a particular allelic pattern may distinguish progressive from non progressive disease [9]. It is also possible that PBC associated HLA Class II extended haplotypes might indicate the location of a ‘disease gene’ linked to the HLA Class II genes, as was the case for the HLA Class I-linked hemochromatosis gene [10].
In the Western world, the association of HLA-DR8 with PBC has been reported in studies of German and North American populations with the class II HLA antigen identified by serological methods [11], [12] and subsequently confirmed by DNA-based testing in a United States population [13] and in two United Kingdom population studies [14], [15]. Additional analysis of the class II region of the MHC, have shown an association of PBC with the HLA DQ and DP alleles, DQβ1*0402 and DPB1*0301 [14], [16]. DQ alleles were also examined in PBC patients from Denmark and an association with DQA1*0501 and DQB1*0201 observed [17].
Serum antimitochondrial antibodies (AMA) are a highly specific hallmark for PBC, but recently a number of studies have reported patients who are clinically, biochemically and histologically indistinguishable from AMA-positive PBC, but do not test positive for AMA even when using the most sensitive technique [18], [19], [20], [21], [22]. Hence, it is unclear whether AMA-positive and AMA-negative PBC are in fact distinct disease entities. Analysis comparing frequencies of alleles at Class II loci in AMA-positive and -negative PBC should determine if genetic markers are similar or different.
Section snippets
Patients studied
Patients included in this study were seen in the Liver Clinic or had a liver transplant at The University Health Network, with the exception of seven AMA-negative patients from the Mayo Clinic, Rochester, MN. The study was approved by The University Health Network Research Ethics Board.
The study population was comprised of 154 AMA-positive patients with PBC, 26 AMA-negative patients with PBC and 216 disease-free controls. All subjects were unrelated Caucasians drawn from Ontario, Canada, apart
Results
A total of 154 AMA-positive patients with PBC were analyzed in this study Of the total 154, 142 (92.2%) were female. Seventy-four (48%) were older than 50 years of age at the time of initial observation of abnormal liver biochemistry (median age 50.5, range 23–83). Of a total of 154 AMA-positive patients with PBC analyzed in this study, 93 (60.3%) had AMA testing by IF on more than one occasion and were found to consistently give a positive serum test. At initial testing none were on treatment
Discussion
The HLA genes are polymorphic, providing informative genetic markers for the study of disease association. The gene products are involved in the specific binding to and presentation of processed peptides derived from both exogenous and endogenous proteins. The association of an HLA allele with a disease has been interpreted as the HLA molecules having a direct functional role in the pathogenesis of the disease, particularly in autoimmune conditions such as PBC. However, the HLA association may
Acknowledgements
Thanks to Ann Begovich and Bill Klitz for discussion and helpful criticism.
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