Geziena M.Th. Schreuder

Nomenclature for factors of the HLA system, 1991

Abstract The WHO Nomenclature Committee for factors of the HLA system met in Hakone after the Eleventh International Histocompatibility Workshop and Conference during November 1991 to consider additions and revisions to the nomenclature of specificities defined by both molecular and serological techniques following the principles established in previous reports (1 – 10).

Nomenclature for Factors of the HLA System, 1996

Recently a number of new genes have been identified within the HLA region including some whose functions are related to HLA class I and I1 genes. The Committee discussed what its strategy should be for the naming of these and further new Julia G. Bodmer, Steven 6. E. Marsh, Ekkehard D. Albert, Walter F. Bodmer, Ronald E. lontrop, Dominique Charron, Bo Dupant, Henry A. Erlich, Renee Fauchet, Bernard Mach, Wolfgang R. Mayr, Peter Parham, Takehlko Sasazuki, Geziena M. Th. Schreuder, Jack 1. Strominger, Arne Svejgaard and Paul la Terasaki

Nomenclature for Factors of the HLA System, 1994

1. Several clones should have been sequenced. 2. Sequencing should have been performed in both directions. 3. An accession number in a databank should have been obtained. 4. Full length sequences are preferable though not essential. 5. Where possible a paper should have been submitted for publication. 6. DNA or other material, in particular cell lines, should be made available in a publicly accessible repository or at least in the originating laboratory. Documentation on this will be maintained by the Nomenclature Committee.

Nomenclature for factors of the HLA system, 2002

This chapter provides the nomenclature for factors of the HLA system, 2002. A number of previously described class I and II gene fragments within the HLA region are named in this system. Official designations are given to these gene fragments. The names LMP2 and LMP7 used previously for the two proteasome genes in the HLA class II region have been renamed by the Human Genome Nomenclature committee (HGNC) as PSMB9 and PSMB8, respectively. This system introduces the additional digit for synonymous variation and all allele names that are currently five digits or above are renamed accordingly. The use of an optional “N’” or “L” suffix to an allele name to indicate either “Null” or “Low” expression was introduced in previous Nomenclature Reports. Three new suffixes are introduced in this system. An “S” to denote an allele specifying a protein that is expressed as a soluble “Secreted” molecule but is not present on the cell surface; a “C” to indicate an allele product that is present in the “Cytoplasm” but not at the cell surface; an “A” to indicate “Aberrant” expression where there is some doubt as to whether a protein is expressed or not. There is evidence of differential splicing of HLA-G that leads to the production of both membrane-bound and soluble forms of the same allele. The IMGT/HLA Sequence Database contains sequences for all HLA alleles officially recognized by the WHO Nomenclature Committee for Factors of the HLA System and, provides users with online tools and facilities for their retrieval and analysis.

Relation between Skin Cancer and HLA Antigens in Renal-Transplant Recipients

BACKGROUND Recipients of renal allografts are at an increased risk for skin cancer. It is also known that recipients who are homozygous for HLA antigens are at an increased risk for certain cancers, as are those who are mismatched with their donors for these antigens. In a case-control study we assessed the relation between skin cancer in renal-transplant recipients and HLA homozygosity and mismatching. METHODS Of 764 patients who received renal transplants between 1966 and 1988, 66 had squamous-cell carcinoma or basal-cell carcinoma of the skin after transplantation. HLA homozygosity was assessed in all 66 recipients, and HLA mismatching in 39; the results were compared with those in 124 recipients without skin cancer. We also investigated the relation between skin cancer and the use of immunosuppressive drugs. In separate case-control analyses we investigated the influence of exposure to the sun and keratotic skin lesions on the risk of skin cancer. RESULTS The risk of squamous-cell carcinoma was increased in recipients mismatched for HLA-B antigens; the relative risks were 2.6 (95 percent confidence interval, 1.1 to 6.5) and 5.0 (95 percent confidence interval, 1.3 to 19.0) with mismatching for one and two antigens, respectively, as compared with no mismatching. Mismatching for HLA-A or HLA-DR antigens had no effect on the risk of squamous-cell carcinoma, and there was no association between mismatches at any of the HLA loci and the occurrence of basal-cell carcinoma. The total doses of azathioprine and prednisone were not associated with the occurrence of skin cancer or with HLA matching. Exposure to sunlight and keratotic skin lesions were strongly associated with skin cancer but not with HLA mismatching. Homozygosity for HLA-DR was more frequent among the patients with squamous-cell carcinoma (relative risk, 2.5; 95 percent confidence interval, 0.95 to 4.6) and among patients with 100 or more keratotic skin lesions (relative risk, 4.8; 95 percent confidence interval, 1.5 to 15.1). CONCLUSIONS HLA-B mismatching is significantly associated with the risk of squamous-cell carcinoma in renal-transplant recipients, as is HLA-DR homozygosity. An indirect effect on the level of immunosuppression does not appear to explain these findings, nor does exposure to sunlight or the number of keratotic skin lesions account for this observation.

Nomenclature for factors of the HLA system, 2002.

This chapter provides the nomenclature for factors of the HLA system, 2002. A number of previously described class I and II gene fragments within the HLA region are named in this system. Official designations are given to these gene fragments. The names LMP2 and LMP7 used previously for the two proteasome genes in the HLA class II region have been renamed by the Human Genome Nomenclature committee (HGNC) as PSMB9 and PSMB8, respectively. This system introduces the additional digit for synonymous variation and all allele names that are currently five digits or above are renamed accordingly. The use of an optional “N’” or “L” suffix to an allele name to indicate either “Null” or “Low” expression was introduced in previous Nomenclature Reports. Three new suffixes are introduced in this system. An “S” to denote an allele specifying a protein that is expressed as a soluble “Secreted” molecule but is not present on the cell surface; a “C” to indicate an allele product that is present in the “Cytoplasm” but not at the cell surface; an “A” to indicate “Aberrant” expression where there is some doubt as to whether a protein is expressed or not. There is evidence of differential splicing of HLA-G that leads to the production of both membrane-bound and soluble forms of the same allele. The IMGT/HLA Sequence Database contains sequences for all HLA alleles officially recognized by the WHO Nomenclature Committee for Factors of the HLA System and, provides users with online tools and facilities for their retrieval and analysis.

Biotinylated DRB sequence-specific oligonucleotides : comparison to serologic HLA-DR typing of organ donors in Eurotransplant

A novel HLA-DR typing method was applied using PCR-amplified fragments and biotin-labeled oligonucleotides (PCR-biotin-SSO). The PCR-biotin-SSO method can be used efficiently to perform HLA-DR typing for a large number of individuals when time is not the limiting factor. The reliability of HLA typing of cadaveric organ donors is of vital importance for organ exchange organizations such as ET. Due to lack of time, these typings are usually performed by the complement-dependent cytotoxicity. The individual donor center typings are immediately reported to ET, where the recipient selection procedure is started. DNA isolated from donor spleen material, sent to the ETRL for retyping purposes, was subjected to PCR-biotin-SSO typing. The results were compared with the serological HLA-DR typings as reported to ET. The analysis of 1052 donor samples for the broad DR1-DR10 antigens revealed a concordance rate of over 90% between the donor center and the ETRL. The majority of the discrepancies involved specificities of the HLA-DR5, DR6, and DR8 cross-reacting group, with DR6 as the predominant discordant specificity. The results indicate (a) that PCR-biotin-SSO is a reliable technique for DNA-based HLA-DR typing and (b) that HLA-DR serology is still a useful technique when time is limited, such as for cadaveric donor typing.

HLA-DQ-associated predisposition to and dominant HLA-DR-associated protection against rheumatoid arthritis

We have recently proposed a new hypothesis to explain the association of Human Leukocyte Antigen (HLA) with rheumatoid arthritis (RA) predisposition. In this model, which challenges the Shared Epitope (SE) hypothesis, HLA-DQ predisposes while HLA-DR protects. In the present study, we have compared these two models in an Early Arthritis Clinic started in 1993 in the Department of Rheumatology at the Leiden University Medical Centre. Out of 524 patients who enrolled this programme in the period 1993-1998 and completed the one year follow-up, 155 have been classified as RA. These patients along with 306 consecutive cadaveric renal organ donors have been typed for HLA-DR and -DQ. The distributions of predisposing DR alleles according to SE, and predisposing DQ and protective DR according to our model were analysed. We found that two doses of predisposing DQ alleles strongly predisposed to RA, even in individuals with a single dose of SE while DRB1 alleles carrying the motif DERAA confered a dominant protection in DQ5-positive individuals. We conclude that the present findings are consistent with our previously described model of HLA and RA association. Using this new model, we have been able to characterise two novel groups of individuals on the basis of their HLA typing: one strongly predisposed to RA and one protected. Knowing the mechanism of HLA-related dominant natural protection may help in designing novel treatment modalities for RA.

HLAmatchmaker: a molecularly based algorithm for histocompatibility determination. III. Effect of matching at the HLA-A,B amino acid triplet level on kidney transplant survival1

Background. HLAMatchmaker is a recently developed computer-based algorithm to determine donor-recipient HLA compatibility at the molecular level. Originally designed for highly alloimmunized patients, this algorithm is based on the concept that immunogenic epitopes are represented by amino acid triplets on exposed parts of protein sequences of HLA-A, -B, and -C chains accessible to alloantibodies. Donor HLA compatibility is determined by intralocus and interlocus comparisons of triplets in polymorphic sequence positions. For most patients, HLAMatchmaker can identify certain mismatched HLA antigens that are zero-triplet mismatches to the patient’s HLA phenotype and should, therefore, be considered fully histocompatible. The present study was designed to determine how class I HLA matching at the triplet level affects kidney transplant outcome. Methods. We analyzed two multicenter databases of zero-HLA-DR–mismatched kidneys transplanted from 1987 to 1999. One database consisted of 31,879 primary allografts registered by U.S. transplant centers in the United Network for Organ Sharing database and the other consisted of 15,872 transplants in the Eurotransplant program. Results. HLA-A,B mismatched kidneys that were compatible at the triplet level exhibited almost identical graft survival rates as the zero-HLA-A,B antigen mismatches defined by conventional criteria. This beneficial effect of triplet matching was seen for both nonsensitized and sensitized patients and also for white and nonwhite patients. Conclusions. These findings suggest that the application of HLAMatchmaker will increase the number of successful transplants, at least in the HLA-DR match combinations.

Sarcoid arthritis: clinical characteristics, diagnostic aspects, and risk factors

Objectives: (a) To describe the clinical characteristics of acute sarcoid arthritis and the diagnostic value of its presenting clinical features; (b) to evaluate whether disease onset is seasonal; and (c) to evaluate whether smoking behaviour or the presence of HLA class II alleles is a risk factor for the disease. Methods: 579 consecutive patients with recent onset arthritis who had been newly referred to a rheumatology outpatient clinic were included in a prospective cohort study. The presenting clinical features, the smoking behaviour, and the results of HLA-DQ and HLA-DR DNA typing of 55 patients with sarcoid arthritis, 524 patients with other arthritides of recent onset, and samples of the normal population were compared. Results: In all cases the disease showed a self limiting arthritis and overall good prognosis. The diagnostic ability of a combination of four clinical features—symmetrical ankle arthritis, symptoms of less than two months, age below 40 years, and erythema nodosum—was exceptionally high. When test positivity is defined as the presence of at least three of four criteria the set rendered a sensitivity of 93%, a specificity of 99%, a positive predictive value of 75%, and a negative predictive value of 99.7%. The disease clustered in the months March–July. The disease was negatively associated with smoking (odds ratio (OR) 0.09; 95% confidence interval (95% CI) 0.02 to 0.37) and positively associated with the presence of the DQ2 (DQB1*0201)-DR3 (DRB1*0301) haplotype (OR 12.33; 95% CI 5.97 to 25.48). Conclusion: The disease entity acute sarcoid arthritis has highly diagnostic clinical features. The seasonal clustering, the protective effect of smoking, and the association with specific HLA class II antigens support the hypothesis that it results from exposure of susceptible hosts to environmental agents through the lungs.