[Show abstract][Hide abstract] ABSTRACT: Hyperacute rejection of a transplanted liver is rare even when the recipient has circulating donor-specific alloantibodies
(DSA). There is also evidence that a transplanted liver may provide immunological protection for other organs transplanted
from the same donor. We monitored the kinetics of circulating DSA in a highly sensitized recipient of a combined split liver
and kidney transplant and demonstrated a reduction in antibody titres immediately after liver perfusion. The absorption of
DSA was not compromised by the smaller liver mass transplanted. DSA titres remained low at 3 months post-transplant, and the
recipient did not experience antibody-mediated rejection.
[Show abstract][Hide abstract] ABSTRACT: The core pathology of Parkinson's disease (PD) is a loss of the dopaminergic neurons in the nigro-striatal pathway, but this is only part of a more widespread pathological process, the nature of which is unknown. Recent data suggest a possible role for inflammation in this disease process. The Human Leucocyte Antigen (HLA) region is one of the most important genetic susceptibility factors in many immune-mediated diseases but has not been extensively investigated in PD.
The authors typed the HLA class II loci HLA-DRB1 and -DQB1 in 528 patients with Parkinson's disease and 3430 controls from the UK.
The authors observed an association of HLA-DRB1 with susceptibility to Parkinson's disease. In particular, HLA-DRB1*03 was more common in patients compared with controls.
These data suggest a possible role of the HLA region in susceptibility to Parkinson's disease and as such are consistent with other evidence supporting the role of an inflammatory process in the cellular loss in Parkinson's disease, especially of the nigral dopaminergic neurons.
Journal of neurology, neurosurgery, and psychiatry 05/2010; 81(8):890-1. DOI:10.1136/jnnp.2008.162883 · 5.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Human leukocyte antigen (HLA) matching strategies for kidney transplantation assign equal weighting to mismatches at a particular locus and take no account of variation in immunogenicity according to recipient HLA type. We examined the ability of intra- and interlocus analysis of amino-acid polymorphisms at continuous (triplet) and discontinuous positions (eplet) defined by the HLAMatchmaker program to predict alloantigen immunogenicity.
Sera from highly sensitized patients were screened for HLA class-I alloantibodies and mismatched combinations were analyzed using HLAMatchmaker to determine the number of triplet or extended-triplet and eplet mismatches.
Logistic regression analysis revealed a strong correlation between the number of triplet or extended-triplet and eplet mismatches and both the presence and magnitude of alloantibody to mismatched HLA-A and -B specificities. The additional structural information provided by eplet analysis gave increased discrimination of mismatched-HLA specificities for alloantigens with greatest sequence disparity but this did not further improve the ability of triplet analysis to predict alloantigen immunogenicity. High antibody levels were observed for several mismatched-HLA combinations with zero triplet or eplet mismatches indicating that self triplets or eplets expressed in different conformations do not always predict nonimmunogenic epitopes.
Analysis of recipient HLA type and mismatched-HLA alloantigens using the HLAMatchmaker algorithm allows prediction of immunogenic donor HLA types.
[Show abstract][Hide abstract] ABSTRACT: To investigate the association between Mooren's ulcer and human leucocyte antigen (HLA) type DR17(3) in patients from the Tamil Nadu State of South India.
Blood samples from 38 patients with Mooren's ulcer and 45 age- and sex-matched controls were obtained prospectively. HLA-DR and HLA-DQ typing was performed by PCR using sequence-specific primers.
Fifteen (40%) of the patients with Mooren's ulcer tested positive for HLA-DR17(3) compared with seven (16%) of the controls (p = 0.01). Seventeen (45%) of the patients also tested positive for the closely linked HLA-DQ2 compared with 11 (24%) of controls (p = 0.05). When adjusted for multiplicity, the correlation between HLA-DR17(3) and Mooren's ulcer remained significant (p = 0.03).
These data demonstrate an association between HLA-DR17(3) and Mooren's ulcer in South Indian patients, supporting autoimmune theories about the pathogenesis of the disorder.
The British journal of ophthalmology 03/2008; 92(2):179-81. DOI:10.1136/bjo.2007.127050 · 2.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) plays an important role in leukocyte-endothelial cell adhesion and transmigration. Single nucleotide polymorphisms of PECAM-1 encoding amino acid substitutions at positions 98 leucine/valine (L/V), 536 serine/asparagine (S/N), and 643 arginine/glycine (R/G) occur in strong genetic linkage resulting in two common haplotypes (LSR and VNG). These PECAM-1 polymorphisms are associated with graft-versus-host disease after hematopoietic stem cell transplantation and with cardiovascular disease, but whether they influence PECAM-1 function is unknown.
We examined the effect of homozygous and heterozygous expression of the PECAM-1 LSR and VNG genotypes on the adhesive interactions of peripheral blood monocytes and activated endothelial cell monolayers under shear stress in a flow-based cell adhesion assay.
There was no difference in monocyte adhesion between the two homozygous genotypes of PECAM-1 but when monocytes expressed both alleles in heterozygous form, firm adhesion of monocytes to endothelial cells was markedly increased. PECAM-1 polymorphism expressed in homozygous or heterozygous form by endothelial cells did not influence monocyte adhesion.
This is, to our knowledge, the first demonstration that PECAM-1 genotype can alter the level of monocyte binding to endothelial cells and a demonstration that heterozygous expression of a polymorphic protein may lead to altered function.
[Show abstract][Hide abstract] ABSTRACT: By comparison with the neighboring island of Sicily, the frequency of multiple sclerosis (MS) in Malta is remarkably low.
To explore whether the relative rarity of MS in Malta might be the result of lower population frequencies of major histocompatibility complex susceptibility alleles, we genotyped the HLA-DRB1 locus in 77 Maltese-born patients (97% of the prevalent unrelated native cases) and 206 Maltese controls. We made comparisons with previously published data for Sicily and other European countries.
The anticipated association with HLA-DRB1*15, the main susceptibility allele in most other populations, was confirmed (p(c) = 0.009) but, in addition, we also observed an equally strong, and apparently protective, effect of the HLA-DRB1*11 allele (p(c) = 0.016). In comparison with previously published data from Sicily, we found that all HLA-DRB1 risk alleles were more common in Malta, whereas HLA-DRB1*11 was slightly less common.
The difference in prevalence seen between the neighboring islands of Malta and Sicily cannot be explained by differences in background HLA-DRB1 population allele frequencies, which if anything would predict a higher rate of disease in Malta than in Sicily.
[Show abstract][Hide abstract] ABSTRACT: Variation in the major histocompatibility complex (MHC) on chromosome 6p21 is known to influence susceptibility to multiple sclerosis with the strongest effect originating from the HLA-DRB1 gene in the class II region. The possibility that other genes in the MHC independently influence susceptibility to multiple sclerosis has been suggested but remains unconfirmed.
Using a combination of microsatellite, single nucleotide polymorphism, and human leukocyte antigen (HLA) typing, we screened the MHC in trio families looking for evidence of residual association above and beyond that attributable to the established DRB1*1501 risk haplotype. We then refined this analysis by extending the genotyping of classical HLA loci into independent cases and control subjects.
Screening confirmed the presence of residual association and suggested that this was maximal in the region of the HLA-C gene. Extending analysis of the classical loci confirmed that this residual association is partly due to allelic heterogeneity at the HLA-DRB1 locus, but also reflects an independent effect from the HLA-C gene. Specifically, the HLA-C*05 allele, or a variant in tight linkage disequilibrium with it, appears to exert a protective effect (p = 3.3 x 10(-5)).
Variation in the HLA-C gene influences susceptibility to multiple sclerosis independently of any effect attributable to the nearby HLA-DRB1 gene.
Annals of Neurology 03/2007; 61(3):228-36. DOI:10.1002/ana.21063 · 11.91 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In highly sensitized patients (HSP) awaiting renal transplantation, accurate delineation of acceptable human leukocyte antigen (HLA) mismatches (AMM) aids identification of suitable crossmatch negative donors. Comparison of differences in polymorphic triplet amino acid sequences in antibody accessible regions of HLA may predict immunogenicity. We have examined the ability of the HLAMatchmaker computer algorithm to predict AMM determined by antibody screening using the full repertoire of single-antigen HLA-A and -B specificities.
The HLA types of 24 HSP awaiting kidney transplantation were analyzed using HLAMatchmaker to determine the number of triplet amino acid (TAA) mismatches for each of 64 mismatched HLA-A and -B specificities. Patient sera with the highest immunoglobulin (Ig)G HLA-specific antibody reactivity were tested against the 64 individual HLA-A and -B specificities using single-antigen HLA antibody detection beads. Logistic regression analysis was performed to determine the association between AMM and the number of TAA mismatches.
There was a strong positive association between the number of TAA mismatches and the presence of HLA-specific antibody. HLA specificities with zero TAA mismatches were antibody positive in only 4 of 47 (9%) cases. A single TAA mismatches was sufficient to invoke an antibody response in 40 (41%) of 98 cases, increasing to 97 (87%) of 112 cases with 9 or more TAA mismatches. However, there was considerable heterogeneity between individual patients, and only 16 (67%) of the 24 HSP studied fitted the logistic regression model for TAA mismatches and HLA-specific antibody.
Identification of TAA mismatches using HLAMatchmaker is a helpful tool for predicting potential donors with an acceptable HLA mismatch in HSP.
[Show abstract][Hide abstract] ABSTRACT: The diagnosis of graft-versus-host disease (GvHD) after liver transplantation can be difficult because early symptoms are often nonspecific. In this study, the presence of donor lymphocyte macrochimerism in recipient peripheral blood was examined as a diagnostic aid for GvHD after cadaveric donor liver transplantation.
Between 1996 and 2002, 33 liver transplant recipients with a clinical suspicion of GvHD (skin rash, diarrhea, pyrexia, pancytopenia, or anemia, without an obvious alternative cause) were investigated for peripheral blood donor lymphocyte macrochimerism. Donor macrochimerism was determined at the time of first clinical presentation by a low-sensitivity polymerase chain reaction (PCR) to detect donor human leukocyte antigen (HLA) alleles using genomic DNA extracted from recipient peripheral blood. Where donor HLA alleles were detected, the percentage of donor T cells was quantified by two-color flow cytometric analysis using antibodies specific for mismatched donor and recipient HLA alleles. The relationship between the presence or absence of donor lymphocyte macrochimerism and final diagnoses based on clinical and histological criteria was examined.
Seven of the 33 patients were PCR positive for donor HLA alleles. All had macrochimerism, with donor T lymphocyte levels ranging from 4% to 50% of circulating lymphocytes. All seven patients had normal liver function tests, skin rash, and diagnosis of GvHD histologically confirmed by skin or gut biopsies. Twenty-six patients were PCR negative, and, in 23, an alternative diagnosis was eventually established. The remaining three patients made a rapid and spontaneous recovery with no further symptoms suggestive of GvHD.
Donor lymphocyte macrochimerism was present in all patients in whom the diagnosis of GvHD was confirmed. In patients with symptoms consistent with GvHD and a negative PCR for donor HLA, an alternative diagnosis was eventually established or the patients recovered spontaneously. Detection of donor HLA alleles in recipient peripheral blood by PCR is a useful diagnostic tool for GvHD after liver transplantation.
[Show abstract][Hide abstract] ABSTRACT: Chronic rejection is a leading cause of graft loss in thoracic transplant recipients. Studies on the pathogenesis of chronic rejection have suggested a contributory role for certain cytokines and growth factors. The activity of these mediators is subject to genetic variation if a polymorphism alters expression, or function, of the ligand or its receptor. Here we have asked if certain cytokine and growth factor gene polymorphisms correlate with chronic rejection in recipients of thoracic allografts. In a retrospective analysis of 179 recipients of thoracic organ transplants (128 heart; 36 heart-lung; and 15 lung), polymorphisms in 8 genes that influence the inflammatory process, namely IL1B, IL1R1, IL1RN, IL6, IL10, TNFA, TGFB1 and FCGRIIA, were examined. Genotypic data from recipients who had either died or been re-transplanted as a result of chronic rejection (n = 96) were then compared to those of recipients who had a functioning graft for more than 11 years (n=83). In the heart graft recipients, only those polymorphisms that influenced expression of the IL1 receptor antagonist gene had a significant correlation with graft survival, with homozygosity for the IL1RN*1 allele being associated with rejection. The alternative, less frequent IL1RN alleles emerged as genomic predictors of long-term allograft survival. This association was especially strong when IL1 region haplotypes were considered, particularly when analysis was confined to heart transplant recipients who had had multiple acute rejection episodes (OR>20). This case-control study indicates that gene polymorphisms which influence IL1 bioactivity also influence the progression of chronic rejection in heart grafts.
American Journal of Transplantation 01/2002; 2(1):76-83. DOI:10.1034/j.1600-6143.2002.020113.x · 6.19 Impact Factor