The IMGT/HLA and IPD databases

The IMGT/HLA database (www.ebi.ac.uk/imgt/hla) has provided a centralized repository for the sequences of the alleles named by the WHO Nomenclature Committee for Factors of the HLA System since 1998. Since its initial release, the database has rapidly grown in size and is recognized as the primary source of information for the study of sequences of the human major histocompatibility complex. The Immuno Polymorphism Database (IPD; www.ebi.ac.uk/ipd) is a set of specialist databases related to the study of polymorphic genes in the immune system. The IPD currently consists of four databases: IPD-KIR contains the allelic sequences of killer-cell immunoglobulin-like receptors; IPD-MHC is a database of sequences of the major histocompatibility complex of different species; IPD-HPA contains alloantigens expressed only on platelets (human platelet antigens or HPA); and IPD-ESTDAB provides access to the European Searchable Tumour Cell-Line Database, a cell bank of immunologically characterized melanoma cell lines.     

Rheumatoid arthritis: how well do the theories fit the evidence?

In this brief review, inspired partly by a symposium at the autumn meeting of the British Society for Immunology, 1992, varying hypotheses concerning the etiopathogenesis of rheumatoid arthritis (RA) are explored and tested against current evidence. Immunogenetic considerations, whilst of interest, have not aided our understanding of the development of this disease. The association with restricted HLA-DR beta chain hypervariable sequences does not hold true with all cases of RA (but may be related to disease severity) and studies of T cell receptor (TCR) beta chain usage fail to show consistent oligoclonality of infiltrating T cells in the synovial compartment. Etiologies based on triggering by bacteria are also considered: homologies between the 'shared epitope' sequences of HLA-DR1 and DR4 beta chains, Escherichia coli dnaJ and Proteus haemolysin do not indicate any feasible mechanisms for the development of RA, and cannot explain the many cases in which such DR sequences do not occur, though new data from man and animals enhance interest in the role of bowel flora. Finally, the striking parallels between slow bacterial infections and RA, in terms of immunogenetics, pathology, IgG glycosylation abnormalities and autoimmune manifestations, are put forward as circumstantial evidence that such bacterial infections may underly, or trigger, this serious disease.     

Vesiculobullous mucocutaneous disease: pemphigus vulgaris

Pemphigus vulgaris is a potentially fatal autoimmune mucocutaneous disease in which oral lesions may be the initial and predominant manifestation. The disease is characterized by acantholysis in the immediately suprabasal layers of the stratified squamous epithelium, giving rise to blisters which readily rupture leaving erosions which show little tendency to heal. Immunogenetic studies indicate a marked genetic susceptibility to the disease, with the immune response-associated HLA-DR4 and DRw6 alleles being especially important. The trigger for autoantibody formation is unknown. The antigen in pemphigus vulgaris is probably a 130-140 kD cell adhesion molecule located in the cell membrane of basal and immediately suprabasal keratinocytes. Antibody binding to this antigen is likely to interfere with normal intercellular adhesion, leading to desmosomal detachment. Propagation of acantholysis and cell damage are attributable to complement activation, with deposition of the membrane attack complex on the keratinocyte cell membrane, and proteolysis due to increased plasminogen activator production. Steroid therapy is the treatment of choice, but significant mortality is still associated with the disease.     

NGS-based typings for 7 HLA loci in three populations from Rio de Janeiro,RJ, Brazil

We investigated HLA class I (HLA-A, -B, and -C) and class II (HLA-DRB1, -DQB1, -DPA1, and -DPB1) alleles by NGS-based typing among 759 Brazilian individuals from three populations in the Rio de Janeiro city based on their self-declared skin color (Caucasian, N = 521, AFND-ID: 3730; Parda, N = 170, AFND-ID: 3728; Black, N = 68, AFND-ID: 3727) to calculate allelic and haplotypic frequencies, plus linkage disequilibrium. Only HLA-DRB1 locus deviated from Hardy-Weinberg equilibrium (in Caucasian and Black populations). The three populations shared the most frequent allele on HLA-A, -C, -DRB1, -DPA1, and -DPB1. Genotype and frequency data are available in the Allele Frequencies Net Database.     

The Human VH Repertoire: A Restricted Set of VH Genes May be the Target of Immune Regulation

During the development of the immune system, a restricted set of V_H gene segments provides the bulk of the immunoglobulin heavy chain repertoire. Most of these V_H genes have been found later in life encoding autospecificities either in normals or in patients with autoimmune diseases. Additionally, there is considerable evidence that the fetal/neonatal B-cell repertoire is autoreactive and idiotypically connected. In the course of sequencing the heavy chain of a panel of human autoantibodies mainly derived from patients with autoimmune diseases, we found that one of the V_H families, and more specifically one single V_H gene contributes to a large extent to the adult autoimmune repertoire in restricted as well as unrestricted responses. This V_H gene segment is not particularly overexpressed in the fetus. Since the only common element to these autoreactive responses is the region encoded by the V_H gene itself, these observations may provide an important insight into B-cell regulation.     

Interleukin-1B (IL-1B) and interleukin-1 receptor antagonist (IL-1RN) gene polymorphisms are not associated with tubal pathology and Chlamydia trachomatis-related tubal factor subfertility

BACKGROUND: Chlamydia trachomatis infections have been associated with tubal pathology. However, not all C.trachomatis-infected women actually develop tubal pathology. Recently, host genetic factors such as the interleukin-1 gene cluster have been linked to inflammatory and infectious diseases. METHODS: Dutch Caucasian women were investigated for (i) the role of interleukin-1B (IL-1B) and interleukin-1 receptor antagonist (IL-1RN) gene polymorphisms in tubal pathology (group 1); and (ii) the presence of these gene polymorphisms in C.trachomatis IgG-positive women with and without tubal pathology (group 2). Group 1 consisted of women with (n = 40) or without (n = 95) tubal pathology, respectively, and group 2 of C.trachomatis IgG-positive women of whom 28 had tubal pathology at laparoscopy and 47 did not. IL-1B-511 and IL-1B+3954 gene polymorphisms were assessed by PCR-restriction fragment length polymorphism (RFLP), and the variable number of tandem repeats (VNTR) of the IL-1RN gene were assessed by a PCR-based assay. RESULTS: Neither IL-1B-511, IL-1B+3954 nor IL-1RN genotypes, allele or carrier frequencies showed significant association with tubal pathology or C.trachomatis post-infection-based tubal pathology. CONCLUSIONS: The data obtained suggest that specific IL-1 gene polymorphisms are not associated with the tubal pathology risk or to the development of C.trachomatis-based post-infectious severe sequelae.     

Overlap syndromes of cholestatic liver diseases and auto-immune hepatitis

Approximately 18% of patients with auto-immune liver disease present with features characteristic of a second auto-immune liver disease. These cases have been termed “overlap syndromes.” The pathogenesis of overlap syndromes is poorly understood, and few data are available regarding the clinical characteristics and outcome of this disease. Therefore, a consensus on the definition of overlap syndromes has not been reached. A common genetic background between auto-immune hepatitis (AIH) and its overlap with primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC) might confer susceptibility to a more inflammatory phenotype, probably requiring combined immunosuppressive treatment. This article focuses on the prevalence, diagnosis, and treatment of the overlap syndrome of AIH and PBC or PSC.     

HLA-F coding and regulatory segments variability determined by massively parallel sequencing procedures in a Brazilian population sample

Human Leucocyte Antigen F (HLA-F) is a non-classical HLA class I gene distinguished from its classical counterparts by low allelic polymorphism and distinctive expression patterns. Its exact function remains unknown. It is believed that HLA-F has tolerogenic and immune modulatory properties. Currently, there is little information regarding the HLA-F allelic variation among human populations and the available studies have evaluated only a fraction of the HLA-F gene segment and/or have searched for known alleles only. Here we present a strategy to evaluate the complete HLA-F variability including its 5′ upstream, coding and 3′ downstream segments by using massively parallel sequencing procedures. HLA-F variability was surveyed on 196 individuals from the Brazilian Southeast. The results indicate that the HLA-F gene is indeed conserved at the protein level, where thirty coding haplotypes or coding alleles were detected, encoding only four different HLA-F full-length protein molecules. Moreover, a same protein molecule is encoded by 82.45% of all coding alleles detected in this Brazilian population sample. However, the HLA-F nucleotide and haplotype variability is much higher than our current knowledge both in Brazilians and considering the 1000 Genomes Project data. This protein conservation is probably a consequence of the key role of HLA-F in the immune system physiology.     

Should HLA Mismatch Acceptability for Sensitized Transplant Candidates Be Determined at the High‐Resolution Rather Than the Antigen Level?

Defining HLA mismatch acceptability of organ transplant donors for sensitized recipients has traditionally been based on serologically defined HLA antigens. Now, however, it is well accepted that HLA antibodies specifically recognize a wide range of epitopes present on HLA antigens and that molecularly defined high resolution alleles corresponding to the same low resolution antigen can possess different epitope repertoires. Hence, determination of HLA compatibility at the allele level represents a more accurate approach to identify suitable donors for sensitized patients. This approach would offer opportunities for increased transplant rates and improved long term graft survivals.     

The Synergistic Effect of Class II HLA Epitope‐Mismatch and Nonadherence on Acute Rejection and Graft Survival

Predicting long‐term outcomes in renal transplant recipients is essential to optimize medical therapy and determine the frequency of posttransplant histologic and serologic monitoring. Nonadherence and human leukocyte antigen (HLA) mismatch are risk factors that have been associated with poor long‐term outcomes and may help individualize care. In the present study, class II HLA mismatches were determined at the HLA epitope level in 195 renal transplant recipients in whom medication adherence was prospectively measured using electronic monitors in medication vial caps. Recipients were grouped by medication adherence and high (≥10 HLA‐DR, ≥17 HLA‐DQ) or low epitope‐mismatch load. We found that the combination of higher epitope mismatch and poor adherence acted synergistically to determine the risk of rejection or graft loss. Nonadherent recipients with HLA‐DR epitope mismatch ≥10 had increased graft loss (35% vs. 8%, p < 0.01) compared to adherent recipients with low epitope mismatch. At the HLA‐DQ locus nonadherent recipients with HLA‐DQ epitope mismatch ≥17 had increased graft loss (33% vs. 10%, p < 0.01) compared to adherent recipients with low epitope mismatch. Subclinical nonadherence early posttransplant combined with HLA class II epitope mismatch may help identify recipients that could benefit from increased clinical, histologic, and serologic monitoring.