Monitoring of intragraft and peripheral blood TIRC7 expression as a diagnostic tool for acute cardiac rejection in humans

Shulzhenko, Natalia; Morgun, Andrey; Rampim, Gisele F; Franco, Marcello; Almeida, Dirceu Rodrigues; Diniz, R.V.Z; Carvalho, Antonio C.C; Gerbase‐DeLima, Maria

doi:10.1016/s0198-8859(01)00211-7

Cited by 28 publications

(22 citation statements)

References 9 publications

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“…18,45,46 This is a novel ATP6i gene product consisting of an ϳ75-kd transmembrane protein expressed in the early stages of T-cell activation, which does not share structural or sequence homology with any of the known T-cell accessory molecules.…”

Section: Discussionmentioning

confidence: 99%

“…18 TIRC7 expression increases during acute rejection of cardiac allografts, 45,46 however its molecular and cellular roles are at present still unclear. Despite this, detection of TIRC7 expression could be used as a valid tool for a rapid diagnosis of ATP6i-dependent osteopetrosis, at least in those cases in which the genetic mutation leads to loss of the a3/TIRC7 C-terminus (the majority so far).…”

Section: Discussionmentioning

confidence: 99%

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Genotype-Phenotype Relationship in Human ATP6i-Dependent Autosomal Recessive Osteopetrosis

Taranta¹,

Migliaccio²,

Recchia³

et al. 2003

The American Journal of Pathology

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Autosomal-recessive osteopetrosis is a severe genetic disease caused by osteoclast failure. Approximately 50% of the patients harbor mutations of the ATP6i gene, encoding for the osteoclast-specific a3 subunit of V-ATPase. We found inactivating ATP6i mutations in four patients, and three of these were novel. Patients shared macrocephaly, growth retardation and optic nerve alteration, osteosclerotic and endobone patterns, and high alkaline phosphatase and parathyroid hormone levels. Bone biopsies revealed primary spongiosa lined with active osteoblasts and high numbers of tartrate-resistant acid phosphatase (TRAP)-positive, a3 subunit-negative, morphologically unremarkable osteoclasts, some of which located in shallow Howship lacunae. Scarce hematopoietic cells and abundant fibrous tissue containing TRAP-positive putative osteoclast precursors were noted. In vitro osteoclasts were a3-negative, morphologically normal, with prominent clear zones and actin rings, and TRAP activity more elevated than in control patients. The osteoclast vacuolar-type translocating ATPase (VATPase) is central to the mechanism of bone resorption. It is located in the ruffled border membrane where it releases protons underneath the resorbing lacuna, acidifying this microenvironment and permitting solubilization of the hydroxyapatite crystals.1-3 This event requires continuous release of protons because of the high-buffering capacity of phosphates, and 8 mol of H ϩ are required to solubilize 1 mol of hydroxyapatite.4 Therefore, efficient activity of the V-ATPase is mandatory for bone matrix demineralization.The V-ATPase shares similarity with the F 0 -F 1 ATPsynthase complex present in mitochondria, chloroplasts, and bacteria.5-8 It consists of a V 0 transmembrane proton channel and a V 1 ATP hydrolytic domain. The structure of the V 1 complex is well defined. It is a 570-kd peripheral protein composed of eight subunits (A to H), with three copies of the A and B subunits and single copies of the remaining subunits. The V 0 transmembrane domain contains five subunits (a, d, c, cЈ, and cЉ), with six copies of c and cЈ, and single copies of the others. c, cЈ, and cЉ subunits span the membrane and contribute to the organization of the proton channel. The a subunit is found in three isoforms, a1, a2, and a3, with the a3 being the one that is osteoclast-specific. 5,9 -11 Transcription of this subunit increases in resorption-competent osteoclasts and the protein is transferred to the ruffled border membrane during the process of cell polarization. 12,13The a subunit is a transmembrane glycoprotein possessing a large N-terminal hydrophilic domain and a C-terminal hydrophobic domain, containing multiple putative transmembrane helices. It has several buried charged residues that appear to be in a position to influence proton translocation. It also emerges to possess the binding site for the V-ATPase inhibitor bafilomycin.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Genotype-Phenotype Relationship in Human ATP6i-Dependent Autosomal Recessive Osteopetrosis

Taranta¹,

Migliaccio²,

Recchia³

et al. 2003

The American Journal of Pathology

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Section: Heart Transplantsmentioning

confidence: 99%

“…In a previous study, we had found by RT-PCR analysis that samples collected a short period (Ϸ2 weeks) before a rejection episode display increased expression of some immune activation molecules, and we called these "prerejection" samples. [17][18][19] The third "nonconcordant" sample had been classified as rejection but was retrospectively determined not to be a rejection episode, but, instead, a sign of leprosy, as the patient soon presented with cutaneous and cardiac manifestations of this disease.There is currently no consensus about the best mathematical algorithm for class prediction, and the use of multiple algorithms increases the confidence and the validity of the results. 11 We therefore used 6 different class prediction algorithms, as well as leave-one-out cross-validation (see Materials and Methods), to analyze the data sets from the 23 samples.…”

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confidence: 99%

Molecular Profiling Improves Diagnoses of Rejection and Infection in Transplanted Organs

Morgun

Shulzhenko

Pérez-Díez

et al. 2006

Circulation Research

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Abstract-The monitoring of transplanted hearts is currently based on histological evaluation of endomyocardial biopsies, a method that is fairly insensitive and that does not always accurately discriminate between rejection and infection in the heart. Accurate diagnosis of rejection and infection is absolutely crucial, however, as the respective treatments are completely different. Using microarrays, we analyzed gene expression in 76 cardiac biopsies from 40 heart recipients undergoing rejection, no rejection, or Trypanosoma cruzi infection. We found a set of genes whose expression patterns were typical of acute rejection, and another set of genes that discriminated between rejection and T cruzi infection. These sets revealed acute rejection episodes up to 2 weeks earlier, and trypanosome infection up to 2 months earlier than did histological evaluation. When applied to raw data from other institutions, the 2 sets of predictive genes were also able to accurately pinpoint acute rejection of lung and kidney transplants, as well as bacterial infections in kidneys. In addition to their usefulness as diagnostic tools, the data suggest that there are similarities in the biology of the processes involved in rejection of different grafts and also in the tissue responses to pathogens as diverse as bacteria and protozoa.(Circ Res. 2006;98:e74-e83.)Key Words: cardiac transplantation Ⅲ acute rejection Ⅲ infection Ⅲ microarray Ⅲ gene expression T he health of transplanted hearts is most often assessed by histological analysis of small biopsies that are routinely taken at least once a month for the first year after transplant. Although this is still considered the gold standard for diagnosis of acute rejection, a comparison between histological diagnosis of biopsies and of the whole organ at autopsy 1,2 showed that the overall sensitivity of histological evaluation of endomyocardial biopsy is only Ϸ70% and that a number of important rejections can be missed.In addition to rejection, infection is also a serious complication in the posttransplant period, 3 and histology does not discriminate very well between a rejection response and the type of immune response involved in fighting an infection in the heart. 4 Nevertheless, discrimination is essential because the treatment for the 2 conditions is quite different. A patient undergoing acute rejection needs an increase in the immunosuppressive regimen to dampen the damaging immune response, whereas a patient experiencing infection needs specific treatment for the infectious agent, along with a decrease in immunosuppression so as to allow the immune system to mount a strong response against the pathogen. Each year, in spite of heroic efforts by transplant physicians, a number of transplant patients die who might have been saved by a better diagnostic technique.In this study, we tested whether molecular profiling by microarray analysis of gene expression patterns might offer a more accurate picture. As a model transplant, we studied cardiac allografts, and, as a model infection, we...

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“…RNA isolation, reverse transcription, PCR mixture, primer design, and competitor construction were performed as previously described in detail [11,12]. As an internal control we used the expression of RNA polymerase II subunit K gene (POLR2K).…”

Section: Reverse Transcription-polymerase Chain Reactionmentioning

confidence: 99%

Expression of Fas, FasL, and Soluble Fas mRNA in Endomyocardial Biopsies of Human Cardiac Allografts

et al. 2006

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Monitoring of intragraft and peripheral blood TIRC7 expression as a diagnostic tool for acute cardiac rejection in humans

Cited by 28 publications

References 9 publications

Genotype-Phenotype Relationship in Human ATP6i-Dependent Autosomal Recessive Osteopetrosis

Genotype-Phenotype Relationship in Human ATP6i-Dependent Autosomal Recessive Osteopetrosis

Molecular Profiling Improves Diagnoses of Rejection and Infection in Transplanted Organs

Expression of Fas, FasL, and Soluble Fas mRNA in Endomyocardial Biopsies of Human Cardiac Allografts

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