bluuebunny/crossref_metadata_2025 huggingface dataset:
Six new DPB1 alleles identified in a study of 1,302 unrelated bone marrow donor‐recipient pairs
Authors: Noreen H. , Steiner L. , Davidson M. , Johnson S. , Segall M. , Begovich A. B.
Published: December 2008

Six new DPB1 alleles were identified by PCR‐SSOP methodologies in the course of a retrospective study of the role of HLA matching in the outcome of unrelated donor bone marrow transplantation. Sequencing confirmed that five of these alleles (DPB1*5901, *6801, *7101, *7201, and *7301) represent novel combinations of previously described sequence motifs in the variable regions of DPB1; the sixth (DPB1*7001) appears to result from a novel point mutation. These data support previous observations which suggest that multiple mechanisms, including segmental exchange and mutation, appear to be responsible for generating sequence diversity at the DPB1 locus. The extremely low discrepancy rate of 0.1% between the two laboratories which typed the samples, and the ability to predict the new sequences from probe hybridization patterns, indicate that SSOP is an accurate and efficient method for studying polymorphism at DPB1.
HLA class I genotyping by cDNA sequence of a Vietnamese family expressing a weak B46 antigen
Authors: Tzeng C.‐M. , Percival L. , Barber L. D. , Cooper S. , Adams E. J. , Stewart D. , Parham P.
Published: December 2008

Serological heterogeneity in HLA‐B46 antigens has been described. Previous studies have identified B*4601 as the allele encoding the “strong” B46 antigen found in Chinese populations. Serological characterization of a Vietnamese family revealed a “weak” B46 antigen. Complementary DNA for the HLA‐A, B and C alleles of three family members were cloned and the coding regions sequenced. The allele encoding the weak B46 antigen has the same coding sequence as B*4601, demonstrating that the antigenic differences are not due to polymorphism in the amino acid sequence of the HLA‐B heavy chain. The recently described HLA‐B*1525 and HLA‐Cw*0403 alleles were also found to segregate in this Vietnamese family.
Identification of a novel HLA‐B allele (B*4202) in a Saudi Arabian family with Behçet's disease
Authors: Ando H. , Mizuki N. , Ohno S. , Tabbara K. F. , Taguchi S. , Yamazaki M. , Mizuki N. , Miyata Y. , Wakisaka K. , Inoko H.
Published: December 2008

A new HLA‐B antigen, tentatively called HLA‐B42AND, was identified as a B42 serologic variant in a Saudi Arabian family. DNA sequencing analysis of the second and third exon of this new B allele revealed that B42AND was identical to B*4201 except for a single T to C substitution at position 97 of exon 2. This substitution results in histidine (CAC) at codon 9 in B42AND instead of tyrosine (TAC) in B*4201. The antigen frequency of B42AND in a Saudi Arabian population was around 10%. This novel B42AND has officially been named HLA‐B*4202.
A novel DRB1 allele (DRB1*0815) defined in an Australian Aborigine
Authors: Trejaut J. , Greville W. , Duncan N. , Dunckley H.
Published: December 2008

The nucleotide sequence reported in this paper has been submitted to GenBank and assigned the accession number U63802. The name DRB1*0815 was officially assigned by the WHO Nomenclature Committee in July 1996. This follows the agreed policy that, subject to the conditions stated in the most recent nomenclature report (10), names will be assigned to new sequences as they are identified. Lists of such new names will be published in the following WHO nomenclature report. The sequence known previously as DRB1*08Taree will now be known as DRB1*0815.
Polymorphisms of tumor necrosis factor receptor 2 are not associated with insulin‐dependent diabetes mellitus or Graves' disease
Authors: Rau H. , Donner H. , Usadel K. H. , Badenhoop K.
Published: December 2008

Insulin‐dependent diabetes mellitus (IDDM) and Graves' disease (GD) are autoimmune endocrinopathies and associated with distinct HLA‐DR and ‐DQ alleles as well as several tumor necrosis factor a (TNF‐α) and β (TNF‐β) alleles. TNF‐α and TNF‐β interact with TNF receptor (TNF‐R), of which two subtypes have been described: TNF‐R1 and TNF‐R2. We investigated TNF‐R2 alleles in 90 patients with IDDM, 101 with GD and 70 healthy controls. Genomic DNA was amplified with specific flanking primers for the untranslated 3 region of TNF‐R2. SSCP analysis revealed two alleles by different fragment patterns: TNF‐R2*1 and TNF‐R2*2. Patients with IDDM or Graves' disease and controls did not differ significantly: TNF‐R2*1/*1:IDDM(8%)/GD(2%)/KO(4%); TNF‐R2*2/*2:IDDM(34%)/GD(48%)/KO(42%), heterozygosity TNF‐R2*1/*2:IDDM(58%)/GD(50%)/KO(54%) (IDDM vs KO: P=0.46, χ2=1.57; GD vs KO: P=0.59, χ2=1.05). In conclusion, the studied polymorphism of TNF‐R2 was associated with neither IDDM nor GD in a German population.
Nucleotide sequence analysis of an HLA‐B47 variant (HLA‐B*4702)
Authors: Fischer G. F. , Broer E. , Faé I. , Leitner D. , Mayr W. R.
Published: December 2008

The name B*4702 has been officially assigned by the WHO Nomenclature Committee in November 1996. This follows the agreed policy that, subject to the conditions staled in the most recent nomenclature report (1), names will be assigned to new sequences as they are identified. Lists of such names will be published in the following WHO nomenclature report. The nucleotide sequence data reported in this article will appear in E.M.B.L. under the accession number Y09118.
The killer cell inhibitory receptor genomic region on human chromosome 19q13.4
Authors: Dupont B. , Selvakumar A. , Steffens U.
Published: December 2008

Multiple genes encoding type I transmembrane molecules and belonging to the immunoglobulin superfamily have recently been localized to human chromosome 19q13.4, These include a family of genes encoding killer cell inhibitory receptors (KIR) expressed on natural killer (NK) cells and subsets of T‐lymphocytes, immunoglobulin‐like transcripts (ILT‐1, ‐2 and 3) expressed on myeloid cells and subsets of lymphoid cells, the gp49 family of receptors expressed on mast cells and NK cells and the gene encoding human myeloid immunoglobulin A Fc receptor (CD89). The receptors have one to four extracellular immunoglobulin domains, and the ligands are known for some of these molecules. This includes the FcaR and KIRs of the p58/p50 and p70/p70ΔA, but the ligands for many others are unknown. Except for CD89, each subfamily of receptors exist, in two forms, of which one has a long cytoplasmic domain containing one to four immunoreceptor tyrosine‐based inhibitory motifs (ITIM) and another form with a short cytoplasmic tail without ITIMs. ITIM‐containing receptors can recruit cytoplasmic tyrosine phosphatases and provide inhibitory signals for cell activation, whereas receptors with a “short” tail induce activating signals. The 19q13.4 chromosomal region is therefore now emerging as the immunoglobulin superfamily linkage group of genes differentially expressed on hematopoietic cell lineages and encoding pairs of receptors with opposing effects on signal transduction pathways and effector functions in hematopoietic cells.
Population studies of the human VK A18 gene polymorphism in Caucasians, blacks and Eskimos
Authors: Juul L. , Hougs L. , Andersen V. , Garred P. , Ryder L. , Svejgaard A. , Høgh B. , Lamm L. , Graugaard B. , Barington T.
Published: December 2008

Immunoglobulin gene polymorphisms are interesting because they reflect differences in the available antibody repertoire which may affect the susceptibility to specific infections. Until recently, the human Vk gene, A18, was known as a nonfunctional gene only. In this study, we cloned and sequenced four apparently functional alleles and determined the gene frequencies in three well‐defined populations: Danish Caucasians, eastern Greenland Eskimos and Mozambican blacks. The A 18b allele that was recently described in Native American Navajos by Atkinson et al. was found in all three populations with gene frequencies of 8%, 45% and 23% in Caucasians, Eskimos and blacks, respectively. Conversely, the frequencies of the nonfunctional A 18a allele were 92%, 55% and 57%. Further, three new A18 alleles, c, d, and e were found exclusively in blacks, among whom they had an total frequency of 19%. These data indicate that both the A 18a and A 18b alleles originated before the diversification of Africans and non‐Africans 90,000 years ago, whereas the A 18c, A18d and A18e alleles may have a more recent origin. The functionality of the A 18b allele was documented by the demonstration of properly rearranged and somatically hypermutated A18b messenger RNA present in the blood lymphocytes of individuals carrying this allele. The expression clearly exceeded that of a known functional V gene, A2, indicating that functional A18 alleles contribute significantly to the available antibody repertoire. In this context, it is surprising that the functional A 18b allele apparently has been negatively selected in the Caucasian population, among whom 85% completely lack a functional gene.
Genetic markers in the Tuvan population of Todja, Siberia
Authors: Pospelov L. E. , Matrakshin A. G. , Erdynieva L. S. , Malenko A. F. , Afanasiev K. I. , Rubtsova G. A. , Egorov I. K. , Yeremeyev V. V. , Apt A. S.
Published: December 2008

Todja is a secluded region of northern Tuva situated in the Sayany Mountains, Siberia. The aboriginal population of Todja is Tuvan. A total of 128 healthy Tuvans living in Todja were typed for HLA‐A, ‐B and ‐C antigens and several plasma and erythrocyte protein polymorphisms (Hp, Tf, Gc, ESD, ACP, PGM1, PGD and ADA). The observed frequencies of all 8 blood protein and HLA genotypes were in agreement with Hardy‐Weinberg expectations. The most frequent HLA antigens in Todjans are A2 (0.36). A3 (0,24), A9 (0.50), B15 (0.34) and B40 (0.50). HLA haplotypes A2B5, A2B40, A9B15 and A9B40 are most common in this population. The observed frequencies of protein polymorphisms and HLA antigens and haplotypes in Todjans are similar to those of other Mongoloid populations. A comparison of HLA frequencies currently observed in Todjans with those obtained 20 years ago at the same locality showed minor changes attributable to the effect of migration.
The novel HLA‐Cw*1802 allele is associated with B*5703 in the Bubi population from Equatorial Guinea
Authors: Vilches C. , Bunce M. , de Pablo R. , Moreno M. E. , Puente S. , Sanz L. , Kreisler M.
Published: December 2008

The HLA‐Cw*1801 specificity, a Cw7/Cw4 hybrid allele, has recently been described in association with B*8101 (formerly B“DT”). In this study, the new Cw*1802 variant, differing from Cw*1801 at exon 5. is found associated with B*5703 in Bubi individuals from Equatorial Guinea. Confirmatory complete coding regions of B*5703 and B*3910 are also reported.
Contribution of human leukocyte antigens to the antibody response to hepatitis B vaccination
Authors: McDermott A. B. , Zuckerman J. N. , Sabin C. A. , Marsh S. G. E. , Madrigal J. A.
Published: December 2008

We present here the analysis of 86 individuals who were true antibody nonresponders to a vaccine containing hepatitis B surface antigen. The HLA type of these individuals and of 248 controls were determined by serology for HLA class I and by molecular typing for the HLA class II loci DRB1 and DQB1. Subsequent analysis of the results revealed that HLA‐DRBI*0701 and HLA‐DQB*02 were significantly associated with antibody non‐response to the “S” ‐containing vaccine compared with the HLA control population. Further, we found that the antibody non‐response was also significantly associated with the above antigens when found in linkage disequilibrium on the HLA haplotype DRB*0701; DQB1*0202. The hepatitis B surface antigen vaccine antibody nonresponder group, compriing 86 individuals, were revaccinated with a noval vaccine Hep B‐3, containing both preS1‐ and preS2‐ derived proteins in a addition to hapatitis B surface antigen, to circumvent their previous nonresponsiveness. The hepatitis B surface antigen antibody results from this group of patients show that 30 of the 86 individuals remained antibody results from this group of patients show that 30 of the 86 individuals remained antibody non‐responders and that 24 individuals (80%) expressed the HLA‐DQB1* and that 21 individuals (70%) expressed HLA‐DRB1*0701. Our results indicate that antibody nonresponse to the Hep B‐3 vaccine is significantly associated with an extended HLA haplotype B44; DRB1*0701; DQB1*0202. A possible indication of these results is that antibody nonresponse to Hep B‐3 vaccine is linked with the HLA allele DQB1*0202. These findings may have an important impact on future vaccine design.
The HLA‐DQ(α1*0102, β1*0602) heterodimer may confer susceptibility to multiple sclerosis in the absence of the HLA‐DR(α1*01, β1*1501) heterodimer
Authors: Spurkland A. , Celius E. G. , Knutsen I. , Belske A. , Thorsby E. , Vartdal F.
Published: December 2008

The frequencies of DR2, DQ6‐related DRB1, DQA1, DQB1 haplotypes were compared in 181 multiple sclerosis patients and 294 controls in Norway. All individuals carried either DR2 or DQ6, i.e., the DQ(α1*0102, β1*0602) heterodimer. The DR(α1*01,β1*1501) and the DQ(α1*O102,β1*O602) heterodimers were carried by 171 of the patients (94%) and 289 (98%) of the controls. Seven of the patients and one of the controls carried the DQ(α1*0102, β1*0603) heterodimer together with the DR(α1*01, β1* 1501) heterodimer. Two patients carried the DQ(α1*0102, β1*O602) heterodimer in the absence of the DR(α1*O1, β1*1501) heterodimer. The DR(α1*01, β1*1501) heterodimer was not observed in the absence of the DQ(α1*0102, β1*O602) heterodimer or the DQ(α1*O102, β1*0603) heterodimer, neither in the patients nor in therols. Our findings indicate that the genes encoding the DQ(α1*0102,β1*0602) heterodimer may confer susceptibility to developing multiple sclerosis in the absence of the DRB 1* 1501 allele.
Polymerase chain reaction haplotyping using 3′ mismatches in the forward and reverse primers: application to the biallelic polymorphisms of tumor necrosis factor and lymphotoxin α
Authors: Fanning G. C. , Bunce M. , Black C. M. , Welsh K. I.
Published: December 2008

A polymerase chain reaction with sequence‐specific primers (PCR‐SSP) system that operates under identical conditions to HLA phototyping was devised for characterizing polymorphisms in tumor necrosis factor (TNF) and lymphotoxin α (LT‐α). Mismatches at the 3′ end were incorporated into the forward and reverse primers of each PCR so as to unequivocally establish the cis / trans status between the biallelic sites. Three previously described biallelic polymorphisms in TNF and three in LT‐α were characterized in a 24‐reaction PCR‐SSP system. The method was used to genotype 20 cell lines and 201 HLA class I and II typed controls from the United Kingdom at the TNF and LT‐α loci. Population frequencies of TNF haplotypes were determined as was linkage disequilibrium with HLA‐A, B, Cw, DRB1 and DQB1 loci. In each gene there were 8 theoretical polymorphic combinations; 4 were observed in TNF and 4 in LT‐α. A total of 11 TNF‐LT‐α haplotypes were determined from apparent homozygous controls and statistical analysis.
A new HLA‐B44 variant (B44BO [B*4408]) identified by serology
Authors: Darke C. , Street J. , Fussell H. , Thomas M. , Guttridge M. , Goldberg T. E. , Arnett K. L. , Parham P.
Published: December 2008

Using HLA serology, we detected a new variant of HLA‐B44 — B44BO — in two families. This antigen reacts with B44 antisera and is negative with over one‐third of B12 (B44, B45) sera but reacts with 50% of antisera with a B62 component, especially if they contain anti‐B57. The variant, B*4408, differs from the common B*4402 by 4 nucleotide substitutions in exon 2: 193, 206 and 209, which produce changes in the α1domain at positions 41, 45 and 46 (TKE in B*4402 and AMA in B44BO); and nucleotide 213, a silent substitution. At each of these positions, B*4408 is identical to B*46, B*57 and many B*15 alleles. As anticipated from its predicted iso‐electric point (5.71), one‐dimensional isoelectric focusing studies showed that B44BO focuses at the same position as B*4402. The sequence and serological reactivity of this rare antigen allowed the identification of two likely epitopes shared by two different groups of HLA‐B antigens.
Lack of HLA‐DR2—associated DRB1 gene in a family
Authors: Singal D. P. , Ye M. , Joseph S.
Published: December 2008

HLA‐DR51 haplotypes co‐express one DRB1 (B1*15 or B1*16) gene and one DRB5 gene. These haplotypes also carry two pseudogenes (DRB6 and DRB9). During routine HLA typing for transplantation, we observed an unexpected DR51 haplotype in two subjects (mother and daughter) in a family. Serological typing showed that these subjects are positive for DR51 and DQ6 but negative for DR15 and DR16. Investigations of genomic DNA by molecular techniques showed that these individuals carry DRB5*0101, DRB6*02 and DQB1*0602 genes, whereas the DRB1 gene associated with either DR15 (B1*1501 to B1*1504) or DR16 (B1*1601 to B1*1606) was not detected in the mother and daughter. It is possible that the new haplotype, DQB1*0602, DRB6*02, DRB5*0101, arose by deletion of DR2‐associated DRB1 gene.
HLA homozygosity and the risk of graft‐versus‐host disease
Authors: Martin P. J. , Petersdorf E. W. , Anasetti C. , Hansen J. A.
Published: December 2008

We explored the relationship between HLA homozygosity and risk of graftversus‐host disease (GVHD) after allogeneic marrow transplantation from an HLA‐genotypically identical sibling. If the variety of minor histocompatibility antigens is decreased by the restricted diversity of major histocompatibility complex (MHC) molecules capable of presenting allogeneic peptides in HLA‐homozygous individuals, then the risk of GVHD should be decreased in comparison to HLA‐heterozygous marrow transplant recipients. Contrary to expectations, we found that HLA‐homozygous individuals and HLA‐heterozygous individuals have comparable risks of GVHD. We propose that the unexpectedly high incidence of GVHD in HLA‐homozygous individuals can be explained by determinant density effects that enable certain peptide‐MHC complexes to function as minor antigens on HLA‐homozygous antigen‐presenting cells but not on HLA‐heterozygous antigen‐presenting cells. Thus the variety of minor antigens expressed by the two types of cells might be similar, despite the differences in the diversity of HLA molecules.
Molecular analysis of HLA polymorphism in Khoton‐Mongolians
Authors: Munkhbat B. , Sato T. , Hagihara M. , Sato K. , Kimura A. , Munkhtuvshin N. , Tsuji K.
Published: December 2008

We have investigated polymorphism of the HLA class I and class II genes in Mongolians for the first time using PCR‐based techniques. A minor population of Khoton‐Mongolians was studied and compared to the major Khalkh‐Mongolian population. Eighty‐five Khoton‐and 41 Khalkh‐Mongolian samples were analyzed for polymorphism in HLA‐A, ‐B, ‐DRB1, ‐DRB3, ‐DRB5, ‐DQA1, ‐DQB1, ‐DPA1, and ‐DPB1 loci using PCR‐SSOP and PCR‐RFLP methods. Allele and haplotype frequencies were calculated. The results were then compared to those obtained from other human populations. In Khoton‐Mongolians, the frequency of HLA‐B38, DRB1*0301, DQA1*0502, DQB1*0201 and DPB1*0401 were significantly higher than those in other Mongoloid populations including Khalkh‐Mon‐golians, Buryat, Chinese, Northern Han, Southern Han, Koreans and Japanese. In contrast, the frequency of HLA‐A2, DQA1*0102, DPB1*0201 and DPB1*0501 were significantly lower in Khoton‐Mongolians. Haplotype frequency analysis revealed that Khoton‐Mongolians shared the same haplotypes specific to Mongoloids as well as to Caucasoids. On the other hand, several haplotypes were found to be specific for the Khoton. The phylogenetic tree analysis constructed by the NJ method based on allele frequencies of HLA‐A, ‐B, ‐DRB1, ‐DQA1, and ‐DQB1 genes revealed that the Khoton belong to the Northeast Asian cluster and are most closely related to the Khalkh, Inner Mongolian, Uygur and Buryat populations. These data suggest a unique genetic background for Khoton‐Mongolians. Furthermore, they are closely related genetically to both Mongoloids and Caucasoids.
A simultaneous negative and positive selection method that can detect chimerism at a frequency of 1 per 10,000 by flow cytometry
Authors: Pei R. , Chen T. , Orpilla J. , Lee J.‐H.
Published: December 2008

A three‐color flow cytometric method with a simultaneous negative and positive selection (SNAPS) approach has been developed to detect blood chimerism using a FITC‐conjugated recipient‐specific HLA monoclonal antibody, a biotinylated donor‐specific HLA monoclonal antibody and Cy5‐PE‐conjugated streptavidin and a PE‐conjugated CD3 monoclonal antibody. Detection of simulated blood chimerism at a frequency of 0.01% was achieved by SNAPS. In contrast, by one‐color flow cytometry methods, chimerism can be detected at only about 3–4% with the same donor‐specific HLA monoclonal antibody. The percentages of donor CD3 cells detected by SNAPS are proportional to the percentages of donor CD3 cells counted. SNAPS method provides a fast, sensitive and reliable way to analyze trace amounts of donor cells in a recipient's blood.
Full‐length cDNA nucleotide sequence of a serologically undetectable YLLA‐DQA1 allele: HLA‐DQA1*“LA”
Authors: Lardy N. M. , Otting N. , van der Horst A. R. , Bontrop R. E. , de Waal L. P.
Published: December 2008

This study describes the characterization of a serological HLA‐DQ “blank” specificity that segregates with the HLA‐A2, ‐B7, ‐DR14, ‐DR52 haplotype. Although conventional serological typing techniques could not detect an HLA‐DQ product on the haplotype positive for the HLA‐DQ “blank” specificity, sequence‐specific oligonucleotide (SSO) dot‐blot analysis demonstrated the presence of the HLA‐DQA1*01 and HLA‐DQB1*05 alleles. Full‐length cDNA nucleotide sequence analysis revealed that the HLA‐DQB1 allele that segregated with the HLA‐DQ “blank” specificity was identical to HLA‐DQB1*05031. As for the HLA‐DQA1 allele, one nucleotide substitution distinguished the HLA‐DQA1 “blank” allele from HLA‐DQA1*0104. In exon 2 at nucleotide position 304 a C was substituted for a T (Arg→Cys). Pending official recognition by the WHO Nomenclature Committee, this HLA‐DQA1 “blank” allele is termed HLA‐DQA1*“LA”. Furthermore, it is postulated that the introduction of cysteine at amino acid position 102 abrogates the classical HLA‐DQ1 specificity.
Error rate for HLA‐B antigen assignment by serology: implications for proficiency testing and utilization of DNA‐based typing methods
Authors: Bozón M. V. , Delgado J. C. , Selvakumar A. , Clavijo O. P. , Salazar M. , Ohashi M. , Alosco S. M. , Russell J. , Yu N. , Dupont B. , Yunis E. J.
Published: December 2008

Until recently, the majority of HLA class I typing has been performed by serology. Expensive commercial typing trays are frequently used for testing non‐Caucasian subjects and new strategies using DNA‐based methods have been adopted for improving clinical histocompatibility testing results and adapted as supplements in proficiency testing. A double‐blind comparison of the typing of HLA‐B specificities in 40 samples was carried out between serology and two polymerase chain reaction (PCR) methods, PCR amplification with sequence‐specific primers (PCR‐SSP) and PCR amplification and subsequent hybridization with sequence‐specific oligonucleotide probes (PCR‐SSOP). The results demonstrated 22.5% misassignments of HLA‐B antigens by serology. There was complete concordance between the results obtained with the two PCR based typing methods. A second panel of 20 donor samples with incomplete or ambiguous serologic results was analyzed by PCR‐SSP and SSOP. Both PCR methods identified correctly the HLA‐B antigens. Our results suggest that more accurate typing results can be achieved by complementing serologic testing with DNA‐based typing techniques. The level of resolution for HLA‐B antigen assignment can be obtained by this combination of serology and limited DNA‐based typing is equivalent to the HLA‐B specificities defined by the WHO‐HLA Committee. This level of resolution cannot routinely be achieved in clinical histocompatibility testing or in proficiency testing using serologic reagents only.
CD101 is expressed by skin dendritic cells Role in T‐lymphocyte activation Role in T‐lymphocyte activation
Authors: Bagot M. , Martinel I. , Charue D. , Weill F. , Boulland M. L. , Wechsler J. , Freeman G. J. , Bensussan A. , Boumsell L.
Published: December 2008

CD 101 was first described in our laboratory using two different monoclonal antibodies, BA27 and BB27, recognizing a 140‐kDa disulfide‐bonded homodimeric polypeptide on a small subset of circulating T lymphocytes and on most activated T cells in vitro. Further, it has been reported that most intestinal mucosal T lymphocytes expressed CD101. The gene coding for the CD101 antigen has been cloned and found to be identical to the gene coding for the recently described V7 antigen, corresponding to a type I trans‐membrane protein with seven immunoglobulin‐like loops in its extracellular domain. To define surface proteins that are involved in skin dendritic cell (DC) localization or function, we looked for the expression of CD101 on skin DC migrating from human skin explants. The majority of these DC had a phenotype of Langerhans cell (LC)‐like mature DC, i.e., HLA‐DR+CDla+CDlc+CDlla+CDllc+CD40+CD50+CD54+CD58+CD80+CD83+CD86+. We found that CD101 was expressed by a major subset of these HLA‐DR+CDla+CDlc+ LC‐like skin DC. Next, we studied the effect of anti‐CD 101 monoclonal antibodies on primary allogeneic and on soluble antigen‐specific mixed skin DC‐lymphocyte reactions. We showed that two different monoclonal antibodies, BB27 and V7.1, inhibited the T‐lymphocyte proliferative responses and that the inhibitory effect was overcome by high doses of exogenous IL‐2. As both DC and T lymphocytes expressed CD101 molecules, we determined that the inhibitory effect was achieved both at the responder T‐cell level and at the DC level. Thus, CD101 which is expressed on a subset of circulating T lymphocytes, has also been found on a subpopulation of LC‐like DC. This molecule plays a major role in the activation of T cells by skin DC.
Adherent neoplastic cells grown at confluence downregulate HLA class I expression and enhance their susceptibility to lysis mediated by natural killer cells
Authors: Ferlazzo G. , Semino C. , Quartarone G. , Pietra G. , Melioli G.
Published: December 2008

The number of HLA class I molecules and the susceptibility to lysis mediated by natural killer (NK) cells were evaluated on cell targets obtained from confluent and sparsely plated cultures of both normal and tumor cell lines. Sparsely plated proliferating cells expressed high amounts of HLA class I molecules and were more resistant to NK cell‐mediated lysis than confluent cells, which expressed low amounts of HLA class I antigens. This characteristic could be involved in the control of cancer progression and could also explain the wide variability of assays of lymphocyte‐mediated cytotoxic activity.
Highly polymorphic promoter regions of HLA DQA1 and DQB1 genes do not help to further define disease susceptibility in insulin‐dependent diabetes mellitus
Authors: Donner H. , Rau H. , Braun J. , Herwig J. , Usadel K. H. , Badenhoop K.
Published: December 2008

HLA DQA1, HLA DQB1 genes confer susceptibility to insulin‐dependent (type 1) diabetes mellitus (IDDM). Since variants of their upstream regulatory regions are linked to the exons, we investigated their promoter polymorphisms (QAP and QBP) by a combination of PCR‐based typing protocols in 136 IDDM patients, 167 controls and 6 families with an IDDM proband to identify possible additional susceptibility markers. Of major interest for IDDM susceptibility are the promoter “splits” of HLA DQA1*0301 (QAP3.1 and QAP3.2) and HLA DQB1*0302 (QBP3.2 and QBP3.3). QAP 3.1 (96% in patients vs 98% in controls) and QBP3.2 (100% vs 99%) were found to be the most frequent promoter variants for HLA DQA1*0301 and DQB1*0302, respectively, whereas QAP3.2 and QBP3.3 were very rare. Furthermore the promoter “splits” were equally distributed on the respective exon alleles in all groups and cosegregated in families as expected. In conclusion, HLA DQ‐mediated susceptibility and protection in IDDM is not restricted to the exon but extends to the promoter region without further defining the genetic risk.
HLA and alveolar echinococcosis
Authors: Eiermann T.H. , Bettens F. , Tiberghien P. , Schmitz K. , Beurton I. , Bresson‐Hadni S. , Ammann R.W. , Goldmann S.F. , Vuitton D.‐A. , Gottstein B. , Kern P.
Published: December 2008

Abstract: Evidence in animal intermediate hosts that susceptibility to larval infection with Echinococcus multilocularis is restricted to individual host factors prompted us to investigate the susceptibility markers in humans. Because antigens of the extracellular parasite E multilocularis are possibly presented by MHC molecules in a restricted way, we speculated that MHC polymorphism may influence resistance of the host towards infection and course of disease. We studied HLA‐A, ‐B, ‐DRB1, ‐DQB1 and ‐DPB1 polymorphism in 151 patients with alveolar echinococcosis. Patients with an observation period of more than 2 years were grouped according to the clinical follow‐up into cured (no recurrence following surgery) patients and patients with regressive or progressive forms of disease during benzimidazole chemotherapy. By comparing phenotypic frequency between patients with alveolar echinococcosis and healthy controls, HLA‐DRB1*11 was associated with a reduced risk for disease development (odds ratio=0.55, 95% confidence interval=0.34–0.88; P=0.01). HLA‐DQB1*O2 was more frequent in patients with progressive disease when compared with patients with regressive disease (54.3% vs 28.3%, P=0.02). The result suggests that HLA‐DRB1*11 might confer protection against alveolar echinococcosis and that HLA‐DQB1*02 may indicate a risk for progressive disease development. The findings may facilitate the search for immunodominant T‐cell epitopes of E. multilocularis.
HLA‐DP‐associated susceptibility to the optico‐spinal form of multiple sclerosis in the Japanese
Authors: Ito H. , Yamasaki K. , Kawano Y. , Horiuchi I. , Yun C. , Nishimura Y. , Kira J.
Published: December 2008

Abstract: We studied polymorphism of the HLA‐DP gene in 46 patients with optico‐spinal form (Asian type) multiple sclerosis (MS) showing recurrent opticomyelitis and 46 patients with Western type MS with disseminated central nervous system involvement. We previously reported a significant association between an HLA‐DRB1*1501‐DRB5*0101 haplotype and susceptibility to Western type but not Asian type MS. In the present study, we found that the frequencies of DPAl*0202 and DPB1*0501 alleles were significantly increased in patients with Asian type MS, as compared with findings in 92 healthy control subjects (91.3% vs 65.2%, Pcorr<0.05 and 89.1% vs 63.0%, Pcorr < 0.05 respectively), but not in Western type MS. Our data provide further evidence that Asian and Western type MS are distinct regarding the immunogenetic background.
Polymorphism of Mhc‐DRB alleles in Cercopithecus aethiops (green monkey): generation and functionality
Authors: Rosal‐Sánchez M. , Paz‐Artal E. , Moreno‐Pelayo M.A. , Martinez‐Quiles N. , Martinez‐Laso J. , Martin‐Villa J.M. , Arnaiz‐Villena A.
Published: December 2008

Abstract: DRB genes have been studied for the first time in green monkeys (Cercopithecus aethiops). Eleven new DRB alleles (exon 2, exon 3) have been obtained and sequenced from cDNA. A limited number of lineages have been identified: DRB1*03 (4 alleles), DRB1*07(3 alleles), DRB5 (1 allele), DRB*w6 (1 allele), and DRB*w7(2 alleles). The existence of Ceae‐DRB1 duplications is supported by the finding of 3 DRB1 alleles in 3 different individuals. Ceae‐DRB1 *0701 may be non‐functional because it bears serine at position 82, which hinders molecule surface expression in mice; the allele is only found in Ceae‐DRB duplicated haplotypes. Base changes in cDNA Ceae‐DRB alleles are consistent with the generation of polymorphism by point mutations or short segment exchanges between alleles. The eleven green monkey DRB alleles meet the requirements for functionality as antigen‐presenting molecules (perhaps, excluding DRBl*0701), since: 1) they have been isolated from cDNA and do not present deletions, insertions or stop codons: 2) structural motifs necessary for a correct folding of the molecule, for the formation of DR/DR dimers and for CD4 interactions are conserved, and 3) the number of non‐synonymous substitutions is higher than the number of synonymous substitutions in the peptide binding region (PBR), while the contrary holds true for the non‐PBR region.
Virtual DNA analysis — a new tool for combination and standardised evaluation of SSO, SSP and sequencing‐based typing results
Authors: Helmberg W. , Lanzer G. , Zahn R. , Weinmayr B. , Wagner T. , Albert E.
Published: December 2008

Abstract: In order to obtain reliable information on HLA types, DNA typing with sequence‐specific oligonucleotide/primer (SSO/SSP) typing sets or sequencing‐based typing (SBT) is increasingly performed. The quality of the evaluation depends on the presence of a complete listing of all typed alleles as well as on the ability of detecting all corresponding alleles/allele pairs. We have developed the concept of virtual DNA analysis (VDA), which is able to combine all types of SSO/SSP/SBT results and evaluate this typing in combination according to the latest published allele sequence lists. The concept is based on the target DNA recognised by the respective typing techniques. All SSO/SSP or SBT results are transformed to a virtual sample DNA, which subsequently is analysed. Evaluation of generic or allele‐speci‐fic DNA typing or the combination of both is supported. Due to this flexible approach, all kinds of SSO/SSP sets, as far as the respective SSO/SSP sequences are available, can be entered and evaluated immediately. The combination of collected data of different typing sets and procedures leads to the highest possible typing resolution. If more than one possible allele combination persists, the program reduces the result to the most specific common denominator in a stepwise manner. VDA offers the possibility of re‐evaluation of former SSO/SSP/SBT results, alone or in combination. No solutions are omitted. This might be a first step towards standardisation of evaluating DNA‐based HLA typing results or transfer of the respective typing data for later evaluation.
Role of HLA‐B and C alleles in development of psoriasis in patients from North India
Authors: Rani R. , Narayan R. , Femandez‐Vina M.A. , Stastny P.
Published: December 2008

Abstract: The association of HLA antigens with susceptibility for development of psoriasis vulgaris has been studied mostly using serologic methods. A number of different HLA class I antigens have been reported to be associated with predisposition to develop this disease. While Cw6 is the allele most commonly thought to confer risk for psoriasis, a number of HLA‐B locus alleles have also been thought to be involved and, recently, in at least three studies, a specific amino acid in the HLA‐C heavy chain has been implicated. With the recent development of molecular methods for typing for HLA class I alleles, it has become possible to re‐examine this association by performing high resolution typing. In the present study we have investigated 38 psoriasis patients and 84 ethnically and geographically matched controls from North India. They were typed for HLA‐B and HLA‐C. The results showed the Cw*0602 was the main allele that was increased in this group of patients. The previously reported association with alanine‐73 was not found to be significant. Cw*0602 was found in 71% of the patients. B*5701 and B*3701 were also increased but appeared to be secondary to linkage disequilibrium with Cw*0602.
HLA class I phenotype and genotype alterations in cervical carcinomas and derivative cell lines
Authors: Koopman L.A. , Mulder A. , Corver W.E. , Anholts J.D.H. , Giphart M.J. , Claas F.H.J. , Fleuren G.J.
Published: December 2008

Abstract: Downregulation of HLA class I expression is a common event in tumor biology. Various underlying mechanisms have been defined in different tumors, but the knowledge of HLA loss mechanisms in cervical carcinoma is limited. To identify causalities for loss of surface expression, we performed a detailed investigation of HLA class I phenotypes and genotypes in 5 primary cervical tumors and on derivative cell lines. Protein expression on primary tissues and cell lines was evaluated by immunohisto‐chemistry and flow cytometry respectively, using a broad panel of allele‐specific monoclonal antibodies. Loss of expression was seen in 3 cases, comprising B15‐locus loss, B15‐allelic loss, and loss of an A74/B15 haplotype and an A24 allele of the other haplotype. Cytokine treatment induced re‐expression of the B15‐locus loss, suggesting a regulatory defect underlying lack of constitutive expression in this tumor. In contrast, molecular analyses at the DNA and/or RNA level showed that the other, non‐inducible, losses were associated with chromosomal HLA gene defects. Loss of heterozygos‐ity analysis was performed to confirm larger genomic deletions. This study shows that HLA gene defects by mutation or loss of heterozygosity as well as regulatory defects are involved in cervical carcinogenesis. The resulting changes in HLA expression may directly affect the efficacy of the immune response to these human papillomavirus‐related neoplasms. Heterogeneity in the underlying loss mechanisms may offer individual tumors various opportunities to escape immune surveillance, and may severely compromise T‐cell based therapy.
Indications of immunological tolerance in kidney transplantation
Authors: Christensen L.L. , Grunnet N. , Rüdiger N. , Møller B. , Birkeland S.A.
Published: December 2008

Abstract: As a complication to immunosuppressive treatment in allotrans‐plantation, malignant diseases such as post‐transplant lymphoproliferative disorder (PTLD) may occur. The patient in the present case is a 21‐year‐old man transplanted at the age of 11 with a kidney from his mother and at the age of 15 with a kidney from his father. During the immunosuppressive treatment the patient developed PTLD resulting in the withdrawal of the immunosuppressive drugs. At the time of writing, the immunosuppressive drugs have been withdrawn for more than 3 years. We report the findings of a state of donor‐specific tolerance occurring after transplantation. Post‐transplant cells from the patient show a non‐reactive response in mixed lymphocyte cultures (MLCs) to cells from both the mother and the father. We demonstrate a reduction in the mRNA expression of the Thl cytokines LL‐2 and LFN‐γ in the very same MLCs. The expression of Thl cytokine mRNA was measured semi‐quanritatively using competitive reverse bran‐scription‐polymerase chain reaction (RT‐PCR). The reduction in the Thl cytokine mRNA expression is not seen in the MLCs with patient cells against cells from a paternal HLA‐A, B and DR‐matched individual, suggesting the influence of other allorecognition factors than HLA‐A, B and DR. Detection in vitro of a lowered expression of Thl cytokine mRNA supports the notion of these mRNAs as indicators of post‐transplant tolerance. Further studies will reveal whether the cytokine mRNA measurements on short time stimulated lymphocytes can be used more generally as a monitoring parameter of tolerance in kidney transplantation.
Associations between HLA class II alleles in a North Indian population
Authors: Rani R. , Fernandez‐Viña M.A. , Stastny P.
Published: December 2008

Abstract: The HLA DR and DQ class II genes are in strong linkage disequilibrium and recombinaton is quite rare. However, many different DR‐DQ haplotypes appear to have developed during evolution, giving rise to a variety of combinations with different distributions in populations. In the present report, 138 subjects from North India were studied for the alleles of HLA‐DRB1, DRB3, DRB5, DQB1 and DQA1 loci using PCR‐oligotyping. The probable haplotypes were constructed based on two‐locus associations observed in this population. A frequent haplotype in this population, DRB1*1501‐DRB5*0101‐DQA1*0103‐DQB1 *0601, has been reported very rarely in other ethnic groups. Other DR2 haplotypes, like DRB1*1502‐DRB5*0102‐DQA1*0103‐DQB1*0601, earlier reported in Caucasians, Chinese and Latin Americans, and DRB1*1502‐DRB5*0102‐DQA1*0103‐DQB1*0503, earlier reported in Gypsies, were also observed. A relatively rare haplotype in Caucasians which was earlier reported in Gypsies from the Czech Republic, DRB1*1404‐DRB3*0202‐DQA1*0101‐DQB1*0503, was observed frequently in Indians, suggesting the probable migration of Gypsies from India. The results suggest that the North Indian population contains a mixture of Caucasoid, Black and Chinese genes. Similarities with Gypsies and South‐East Asian populations suggest the role of ancient migrations from India.
HLA‐DQB1*0303 and *0301 alleles influence susceptibility to and prognosis in cutaneous malignant melanoma in the British Caucasian population
Authors: Bateman A.C. , Turner S.J. , Theaker J.M. , Howell W.M.
Published: December 2008

Abstract: The presence of lymphocytic infiltrates within primary cutaneous malignant melanoma (CMM), documented spontaneous tumour regression and genetic linkage with chromosome six in familial cases all suggest that immunogenetic factors may modulate disease progression. An association has been suggested between HLA DQB1*0301 and CMM in US patients but no such investigation has been performed in the UK population. Polymerase chain reaction‐based HLA class 0 DRB1, DQA1 and DQB1 typing of 99 UK‐based CMM patients was performed using DNA extracted from archival formalin‐fixed and paraffin wax‐embedded surgical biopsies, enabling retrospective access to clinical follow‐up data. An increase in frequency of the HLA DQBl*0303 genotype among CMM patients was identified compared to control subjects (19.2% vs 5.8%; Pc=0.003; RR=3.9) while HLA DQBl*0301 was associated with more advanced and therefore poorer prognosis primary tumours (e.g. HLA DQBl*0301 allele frequency: 20.1% vertical growth phase vs 4.0% horizontal growth phase; Pc=0.03; RR=6.1). These findings suggest that the HLA DQB1 locus, and in particular the HLA DQB1*0303 and *0301 alleles, may play an important role in determining the risk of development and the prognosis of CMM within the UK population.
HLA DPA1/DPB1 genotype and haplotype frequencies, and linkage disequilibria in Nigeria, Liberia, and Gabon
Authors: May J. , Mockenhaupt F.P. , Loliger C.‐C. , Ademowo G.O. , Falusi A.G. , Jenisch S. , Dippmann K. , Schnittger L. , Kremsner P.G. , Bienzle U. , Meyer C.G.
Published: December 2008

Abstract: The frequencies of DPA1 and DPB1 alleles and their occurrence in haplotypic linkage were assessed and compared in Nigerian, Liberian, and Gabonese individuals. Differences were seen in the distribution patterns; these differences were more pronounced between the Gabonese and the other two populations than between Liberians and Nigerians. Several haplotypic DPA1‐DPB1 combinations could be verified by homozygosity. Linkage disequilibria of DPA1‐DPB1 combinations, indicating further probable haplo‐types, were estimated. Although different allele and haplotype frequencies were recognized in the three subgroups, the linkage disequilibria were mostly either positive or negative in all populations.
The effect of immunotoxins directed against CD80 and CD86 on primary T‐cell alloresponses
Authors: Often H.G. , Vooijs W.C. , van der Gouw L. , de Boer M. , de Gast G.C.
Published: December 2008

Abstract:Activation of primary resting T cells requires costimulation which can be delivered by the B7 molecules (CD80 and CD86) expressed on activated antigen‐presenting cells (APC). In the present study, we examinedin vitroeffects of immunotoxins (ITs) composed of gelonin conjugated to mAbs against CD80 or CD86 (αCD80‐IT and αCD86‐IT). The specificity of both ITs was demonstrated using CD80 and CD86 transfected cell lines. In primary mixed lymphocyte cultures (MLCs), it was found that the average inhibitory capacity of αCD86‐IT (72%) and αCD80‐IT (30%) was significantly higher than αCD86 (54%) and αCD80 (11%). In reculture MLC experiments it was found that peripheral blood mononuclear cells pretreated with αCD86/αCD80 regained full stimulatory capacity whereas αCD86‐IT/ αCD80‐IT pretreatment induced >95% loss of stimulatory capacity. Our results therefore demonstrate that these αB7‐ITs functionally block B7‐CD28 costimulatory signaling and eliminate activated APC.
HLA‐Cw alleles associated with HLA extended haplotypes and C2 deficiency
Authors: Clavijo O.P. , Delgado J.C. , Awdeh Z.L. , Fici O. , Turbay D. , Alper C.A. , Truedsson L. , Yunis E.J.
Published: December 2008

Abstract: There are four MHC‐linked complement genes, BF, C2, C4A and C4B, that are inherited as single DNA units, known as complotypes. Extended haplotypes were initially defined by studying the distribution of complotypes in relation to HLA‐B and HLA‐DR loci in Caucasian families. In order to analyze the distribution of HLA‐Cw alleles in relation to extended haplotypes, we studied a large panel of MHC homozygous and heterozygous cell lines representing previously described Caucasian‐derived extended haplotypes and 14 patients with complete C2 deficiency. HLA alleles were assigned using sequence‐specific oligonucleotide probe hybridization (SSOP). Family analysis served to assign haplotypes for heterozygous samples. We found distinctive HLA‐Cw alleles for each independent extended haplotype. Their association in each instance was statistically significant All patients with C2 deficiency carrying the haplotype [HLA‐B18, S042, DR2] were associated with HLA‐Cw*1203. These conserved allelic combinations may become an important tool for the study of human evolution and may contribute to the expeditious selection of prospective donors in clinical transplantation.
Differential regulation of HLA‐DQ expression by keratinocytes and Langerhans cells in normal and premalignant cervical epithelium
Authors: Mota F.F. , Rayment N.B. , Kanan J.H. , Singer A. , Chain B.M.
Published: December 2008

Abstract: Keratinocytes in normal ectocervix did not express major histo‐compatibility complex class II molecules. In low‐grade intraepithelial lesions expression was confined to HLA‐DR, while in high‐grade disease there was expression of HLA‐DR and occasional expression of HLA‐DQ. HLA‐DR was expressed constitutively on the majority of Langerhans cells. In contrast, few Langerhans cells expressed HLA‐DQ in normal cervix, but there was a steady upregulation of the proportion expressing HLA‐DQ which paralleled the severity of disease. There was no direct correlation between human papil‐lomavirus 16 and the expression of major histocompatibility complex class II by keratinocytes and Langerhans cells. Significant upregulation of HLA‐DQ by Langerhans cells is observed in high‐grade intraepithelial cervical lesions, suggesting antigen‐presenting cell activation in papillomavirus‐re‐lated premalignant disease.
Definition of the gene encoding the minor histocompatibility antigen HA‐1 and typing for HA‐1 from genomic DNA
Authors: Tseng L‐H. , Lin M.‐T. , Martin P.J. , Pei J. , Smith A.G. , Hansen J.A.
Published: December 2008

Abstract: Recipient mismatching for the minor histocompatibility antigen HA‐1 has been associated with acute graft‐versus‐host disease after allogeneic marrow transplantation. Two polymorphic nucleotides near an exonintron junction of the gene encoding this minor histocompatibility antigen have been identified. In this study, we determined the genomic DNA sequence of the intron downstream from this polymorphic exon. Based on this sequence, primers were designed to amplify the genomic HA‐1 gene sequence, and analysis of restriction fragment length polymorphisms was used to assign the HA‐1 genotypes of 160 unrelated probands and a paired sibling for each proband. Among probands, the HA‐1H allele frequency was 0.441, and the HA‐1R allele frequency was 0.559. The distribution of HA‐1 genotypes showed close fit with Hardy‐Weinberg equilibrium. Likewise, the number of sibling pairs with disparity for HA‐1 alleles showed close fit with predictions based on Hardy‐Weinberg equilibrium. These results provide a simple and well validated method for future studies correlating HA‐1 disparity with clinical outcome after allogeneic marrow transplantation.