Closing the gap: discrimination of the expression profile of HLA questionable alleles by a cytokine‐induced secretion approach using HLA‐A*32:11Q

Föll, Daniel; Hinrichs, Jan B.; Tischer, Sabine; Battermann, Anja; Schambach, Axel; Figueiredo, Constança; Immenschuh, Stephan; Blasczyk, Rainer

doi:10.1111/j.1399-0039.2012.01864.x

Cited by 5 publications

(7 citation statements)

References 41 publications

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“…Discrimination between low and higher expression alleles is vital to minimize HLA mismatching in the host‐versus‐graft direction if the patient has a low expression allele and the donor has the higher expressing allele or in the graft‐versus‐host direction if the donor has a low expression allele and the patient has the higher expressing allele (Foll et al ., ). Thymic and peripheral expression levels from low expression alleles may, however, be sufficient to induce tolerance to their common higher expressing allelic variants, even though the reduced expression may result in products that are less prone to eliciting immunological responses (Shankarkumar et al ., ).…”

Section: Discussionmentioning

confidence: 97%

A group‐specific sequencing approach to investigate the presence of atypical human leucocyte antigen alleles

Foster

Tate

Poulton

2013

Int J Immunogenetics

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Accurate human leucocyte antigen (HLA) typing results are essential in determining the degree of compatibility between donor and recipient in both solid organ (SO) and hematopoietic stem cell (HSC) transplantation. Current HLA typing methodologies can generate ambiguous results which may need resolving. This group-specific sequencing approach allowed investigation into the presence of the low expressor HLA-A*24:02:01:02L allele and the rare HLA-A*02:64 allele in a SO transplant recipient and a HSC transplant recipient, respectively. Locus-specific amplification of HLA-A was performed. Exons 2 and 3 were sequenced in both directions followed by group-specific sequencing to resolve ambiguities. Hemizygous sequence data of intron 2 generated from the HLA-A*24 allele indicated the presence of the HLA-A*24:02:01:01 allele. HLA-A*02:64 was identified by sequencing the allele in isolation over exons 2 and 3 and allowed confirmation of this allele sequence with the IMGT/HLA database (Accession number AY297166). This approach is cost efficient and can be modified to sequence alleles at other HLA loci. It has also been adapted to characterize the novel HLA-DQB1*06:48 allele (Accession number HE647646) as well as the non-HLA gene, UGT2B17, making it a useful tool to augment existing typing methodologies.

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Section: Discussionmentioning

confidence: 97%

A group‐specific sequencing approach to investigate the presence of atypical human leucocyte antigen alleles

Foster

Tate

Poulton

2013

Int J Immunogenetics

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“…Since HLA mismatches may produce severe graft –vs host disease (GvHD) and graft rejection, a misinterpretation of these variants could strongly affect transplant‐related mortality. Hence, several studies proposed assays and methods to discriminate between low expressed or non‐expressed HLA alleles, mainly based on EBV‐transformed cell lines or on recombinant HLA‐molecules' cloning and transfection in established cell lines, not easily reproducible in most laboratories. Gerritsen et al demonstrated that HLA‐A*23:19Q , which has a single polymorphism at position 619 (G > A) compared with HLA‐A*23:01:01 , has no expression by serology and flow cytometry, therefore, it should be reclassified as a null allele .…”

Section: Discussionmentioning

confidence: 99%

“…Later, Hinrichs et al demonstrated by a cytokine‐induced secretion assays that HLA‐A*30:14L was a lowly expressed allele . Using the same approach, Foll et al reported the HLA‐A*32:11Q as a low expressed variant . More recently, Yin et al demonstrated that HLA‐B*38:68Q is a low expressing allele using the CRISPR/Cas9 gene‐editing technology …”

Section: Discussionmentioning

confidence: 99%

“…Zeff et al, indeed, reported that the mutated MHC Class I molecules' transport was confined between the endoplasmatic reticulum and the plasma membrane, resulting in intracellular transport's blockade . Foll et al demonstrated by FACS analysis an intracellular accumulation of HLA‐A*32:11Q molecules, although correctly folded, suggesting that its mutation interfered with protein export . On the other hand, the recent literature reports increasing evidences that the knowledge of the expression level of the HLA molecules may be significant in HLA matching process.…”

Section: Discussionmentioning

confidence: 99%

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Expression profile of HLA‐B38:55Q* allele

Fusco¹,

Cervelli

Mas

et al. 2020

HLA

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The identification of null or questionably expressed HLA allelic variants is a major issue in HLA diagnostics, because the mistyping of the aberrant expression of such alleles can have a major impact on the outcome of both hematopoietic stem cell transplantation (HSCT) and solid organ transplants. It is debated how questionable (Q) alleles, because of their unknown expression profile, should be considered in an allogenic HSCT setting. The HLA-B*38:55Q allele was detected as an HLA-B blank specificity; DNA sequencing identified a single polymorphism at position 373 in exon 3 (TGC > CGC), which results in the replacement of cysteine 101 with an arginine in the HLA-B heavy chain, thus, impairing disulfide bridge formation in the alpha-2 domain, essential for the normal expression of the HLA molecules. In order to determine the RNA and protein expression profile of this allelic variant, we analyzed antigenic expression at different levels, transcriptional and transductional, using a combination of cellular methods, such as serological testing and flow cytometric analysis, polymerase chain reaction (PCR) sequence-specific primer (SSP) cDNA group-specific amplification and immunocytochemical assay, demonstrating the prevalent cytoplasmatic distribution of the HLA-B*38:55Q protein.Our findings suggest that in matching process the HLA-B*38:55Q allele needs to be considered as a low expressed allele, able to elicit an allogenic T-cell response in vivo and impair the transplant outcome. K E Y W O R D S hematopoietic stem cell transplantation, HLA expression variants, HLA-B*38:55Q, null alleles, questionable expression allele

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“…A number of HLA alleles, mainly of class I, have been registered as a low (L) expression or a questionable (Q) expression allele. The low level of expressions of some of these class I alleles have been confirmed through the generation of a soluble form of HLA and detection by enzyme‐linked immunosorbent assay (ELISA) . However, it has remained difficult to discriminate null‐ and low‐expression phenotypes through the conventional expression analyses.…”

Section: Discussionmentioning

confidence: 99%

Questionable expression of unstable DQ heterodimer containing HLA‐DQA1*01:07

Miyadera

Bungener

Kusano³

et al. 2015

Tissue Antigens

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Human leukocyte antigens (HLA)-DQA1*01:07 was identified as an HLA-DQ blank specificity that segregated with the serological HLA-A2, -B7, -DR14, -DR52 haplotype, which carried DQB1*05:03. The blank specificity of DQA1*01:07-DQB1*05:03 may be because of lack of reactivity of available typing sera, or disruption of proper assembly of DQ heterodimer. The cDNA sequence of DQA1*01:07 is nearly identical to DQA1*01:04 except for a variant at position 304, which results in the replacement of an arginine with a cysteine at 79α. To determine whether the DQA1*01:07 product can be expressed on cell-surface, we co-expressed DQA1*01:07 with various DQB1*05 or *06 alleles in fibroblast cells. Cell-surface expression of DQ was detectable when DQA1*01:07 was co-expressed with DQB1*06:04 but undetectable with other DQB1*05 and DQB1*06 alleles, including DQB1*05:03, to which DQA1*01:07 was encoded in cis. These data suggest that DQA1*01:07 may act as a phenotypically null allele in the DQA1*01:07-DQB1*05:03 haplotype, while it can be expressed at a low level in the presences of certain DQB1*06 alleles, such as DQB1*06:04, in trans. Based on the null or low expression of DQA1*01:07 as shown in the previous and present studies, DQA1*01:07 has recently been renamed to DQA1*01:07Q, indicating its questionable expression.

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Closing the gap: discrimination of the expression profile of HLA questionable alleles by a cytokine‐induced secretion approach using HLA‐A*32:11Q

Cited by 5 publications

References 41 publications

A group‐specific sequencing approach to investigate the presence of atypical human leucocyte antigen alleles

A group‐specific sequencing approach to investigate the presence of atypical human leucocyte antigen alleles

Expression profile of HLA‐B38:55Q* allele

Questionable expression of unstable DQ heterodimer containing HLA‐DQA1*01:07

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Closing the gap: discrimination of the expression profile of HLA questionable alleles by a cytokine‐induced secretion approach using HLA‐A*32:11Q

Cited by 5 publications

References 41 publications

A group‐specific sequencing approach to investigate the presence of atypical human leucocyte antigen alleles

A group‐specific sequencing approach to investigate the presence of atypical human leucocyte antigen alleles

Expression profile of HLA‐B*38:55Q allele

Questionable expression of unstable DQ heterodimer containing HLA‐DQA1*01:07

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Expression profile of HLA‐B38:55Q* allele