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Results for “haplotype blocks”

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PubMed2026

Haplotype Blocks Are Associated With Rapid Local Adaptation to Environmental Shifts in Wild Barley.

Genomic mechanisms of local adaptation must be highly responsive in geographic regions where climate is changing rapidly. The Levant region is a critical biodiversity hotspot and the distribution edge for many species, including the wild ancestor of domesticated barley. This region is under an accelerated desertification process, thus enforcing a rapid genomic response to the projected environmental changes. To elucidate the genomic basis of rapid local adaptation, we studied wild barley populations using an ecological-genetic sampling design that decouples environmental variation from demographic background. We collected and sequenced 300 wild barley individuals and evaluated the phenotypes of 3600 progeny plants over 3 years. Our genomic analyses revealed that local adaptation is associated with clusters of candidate genes forming haplotype blocks. These clusters are enriched with environment and stress responsive genes, including flowering time regulators, drought and heat responsive genes. We identified six candidate adaptive haplotype blocks which span 1-8 Mbp and are distributed across chromosomes 1H, 2H, 4H and 5H, each segregating as two major haplotypes. Additionally, we integrated over 2600 occurrence records into ecological and evolutionary modelling to assess the genomic vulnerability of populations to projected future climates. Our study identifies candidate genomic regions and environmental drivers of local adaptation in wild barley and highlights the advantage of haplotype blocks architecture in orchestrating an efficient response to rapid environmental change. We highlight the ecological factors most strongly associated with the observed evolutionary responses and provide insights and guidelines for biodiversity conservation and implementation of crop wild relatives in breeding.

Hordeum↗

PubMed2025

Large Haplotypes Linked to Climate and Life History Variation in Divergent Lineages of Atlantic Salmon (Salmo salar).

Advances in sequencing are revealing that linked genomic architectures, enabling the evolution of co-adapted alleles at multiple loci, often shape complex phenotypes. Several recent studies have identified such architectures (e.g., chromosomal rearrangements and supergenes) contributing to adaptation or divergence across diverse species, from plants to mammals. Specifically, within Atlantic salmon (Salmo salar ), genomic studies are revealing large haplotypes and structural variants that may underpin local adaptation in the species. Using data from > 4000 individuals from 134 locations spanning the North Atlantic Ocean, we identify a large (~3 Mbp) genomic region on Ssa18 showing patterns of differentiation and linkage disequilibrium (LD) indicative of a large haplotype block containing three divergent haplotypes (herein A, B and C haplotypes). In Europe, haplotypes A and B were common, whereas A and C were more common within North America, suggesting a shared 'ancestral' A haplotype, with different continent-specific alternative haplotypes. Data support independent origins of divergent haplotypes in each continent, as well as signals of trans-oceanic introgression of haplotypes. Haplotype frequency is strongly associated with latitude, climate and life history (smolt age); however, the strength and direction of these relationships vary across continents. Overall, our analyses were consistent with other studies that identify chromosomal rearrangements; however, long-read sequence data did not find evidence of a structural variant, and instead an ancestral fusion may explain the formation and maintenance of the observed haplotypes. Our study contributes to ongoing efforts to understand the evolutionary role of linked genomic architecture in Atlantic salmon and its significance in salmonid diversification.

Climate Change↗

PubMed2026

Integrative haplotype and SNP-based GWAS supports the identification of stable genomic loci controlling yield-related traits in soybean.

Soybean yield is vulnerable to environmental variation, therefore, it is important to detect and implement stable genomic regions associated with yield-related traits in soybean breeding programs. In this study, SNP and haplotype-based GWAS were conducted to reveal important candidate genomic regions and putative candidate genes associated with soybean yield-related traits. This study demonstrates that the integration of haplotype and SNP-based GWAS could improve the detection of genomic regions associated with complex traits, enhance statistical power, and facilitate the identification of biologically relevant candidate genes. Ten stable haplotype blocks and six stable SNPs were detected based on the integration of haplotype and SNP-based GWAS, respectively. Furthermore, multiple candidate genes associated with the yield-related traits were identified. For instance, six genes were identified as transporters, including Glyma.15G092800, encoding serine-type endopeptidase activity, Glyma.15G203300 encoding a major facilitator superfamily (MFS) sugar transporter, Glyma.04G163000, transmembrane transporter, and Glyma.04G164100, leucine-rich repeat receptor-like protein kinase (LRR-RLK), as the most promising candidate genes. Additionally, three genes involved in signaling and pathways of various phytohormones can be promising candidates for increasing seed yield through improving plant architecture in soybean plants. The identified superior haplotypes with favourable alleles will be useful for marker-assisted selection in future breeding programs in soybean.

DArT markers↗

PubMed1979

Specific binding of T lymphocytes to macrophages. V. The role of Ia antigens on Mphi in the binding.

The effect of anti-Ia alloantiserum on the capacity of selected peritoneal exudate lymphocytes (selected PEL) to bind to antigen-pulsed F1 (responder x nonresponder) macrophages was investigated. With the use of selected PEL for antigens under Ir gene control, it was shown that anti-Ia serum to the responder haplotype blocked adherence of selected PEL to antigen-pulsed macrophages whereas anti-Ia serum to the nonresponder haplotype did not. The target cell of the anti-Ia alloantiserum appeared to be the macrophage because anti-13 Ia in contrast to anti-2 Ia did not inhibit binding of F1 (2 x 13) DNP-GL selected PEL to DNP-GL pulsed strain-2 Mphi (responder strain). Taken together with previous experiments that indicate that an antibody to the native protein antigen employed is unable to block specific binding, the present results suggest that T cells may recognize fragments of exogenous antigen in association with Ia molecules.

Animals↗

PubMed2025

Optimising parent selection in plant breeding: comparing metaheuristic algorithms for genotype building.

Stacking desirable haplotypes across the genome to develop superior genotypes has been implemented in several crop species. A major challenge in Optimal Haplotype Selection is identifying a set of parents that collectively contain all desirable haplotypes, a complex combinatorial problem with countless possibilities. In this study, we evaluated the performance of metaheuristic search algorithms (MSAs)-genetic algorithm (GA), differential evolution (DE), particle swarm optimisation (PSO), and simulated annealing (SA) for optimising parent selection under two genotype building (GB) objectives: Optimal Haplotype Selection (OHS) and Optimal Population Value (OPV). Using a diverse wheat population of 583 lines genotyped for 29,972 SNPs, forming 7645 haplotype blocks and phenotyped for stripe rust scores, we assessed each algorithm's performance across fitness optimisation, convergence speed, and computational efficiency. GA consistently achieved high fitness and rapid convergence, while DE showed robustness but required longer runtime and careful tuning. PSO performed well under the OHS criterion but was less effective for OPV. SA, although computationally lighter, was less consistent in finding optimal solutions. Simulation over 100 breeding cycles showed that OHS outperformed both OPV and GEBV-based selection in long-term genetic gain and diversity retention. OHS maintained heterozygosity and additive variance, which are key for sustainable improvement, while GEBV selection led to early allele fixation. Our findings underscore the potential of GB strategies that prioritise the collective performance of parent sets rather than individual ranking to enhance selection outcomes in genomic-assisted breeding programmes.

Plant Breeding↗

PubMed2025

Placental CCR5 polymorphisms in relation to fetal growth.

The placenta mediates fetal growth, and its development and function are influenced by immune interactions at the maternal-fetal interface. The cysteine-cysteine chemotactic cytokine receptor type 5 (CCR5) gene codes for a pro-inflammatory protein receptor expressed in the placenta on syncytiotrophoblasts and Hofbauer cells. Associations of the placental-fetal genotype at CCR5 and birth outcomes have not been examined. Furthermore, influence of CCR5 polymorphisms on nearby DNA methylation in the placenta and in the context of infection is understudied. We assessed two functional polymorphisms in CCR5, a 32 base pair deletion (Δ32) in the open reading frame and an A/G promoter point mutation (rs1799987) in EPIC (n = 233) a cohort consisting of complicated and uncomplicated pregnancies ascertained in Vancouver BC and found that the variant alleles were associated with birth weight (p = 0.007 and p = 0.01 respectively). We validated the association of rs1799987 with birthweight (p = 0.003) in the published NICHD dataset of normative term births (n = 286). These variant associations were, however, not present in CARMA-Preg (n = 200) a cohort enriched for HIV-exposure. Interestingly, we found rs1799987 was associated with altered DNA methylation (DNAme) at multiple CpGs spanning over 275 kb, overlapping both the CCR2 and CCR5 genes. DNAme in this region was, however, not associated with birthweight. Further investigations are needed to validate the association of CCR5 variants with fetal growth. Such studies must consider the population structure and demographics, as well as the large haplotype blocks spanning this region, which make it difficult to assign a causal relationship to specific variants.

Humans↗

PubMed2025

Evolutionary Genomics Unravels the Responses and Adaptation to Climate Change in a Key Alpine Forest Tree Species.

Despite widespread biodiversity loss, our understanding of how species and populations will respond to accelerated climate change remains limited. In this study, we integrate population genomics, experimental evolution, and environmental modeling to elucidate the evolutionary responses to climate change in Populus lasiocarpa, a key alpine forest tree species primarily distributed in the mountainous regions of a global biodiversity hotspot. Over historical timescales, our findings demonstrate that demographic dynamics, divergent selection, and long-term balancing selection have shaped and maintained genetic variation within and between populations. In examining genomic signatures of contemporary climate adaptation, we found that haplotype blocks, potentially caused by inversion polymorphisms that suppress recombination, are linked to enriched combinations of locally adaptive environmental variations. We further assessed the relative contributions of environmentally induced plastic responses, constitutive expression divergence between genetic clusters, and their interactions in driving gene expression variation and divergence. Notably, we observed a strong correlation between sequence divergence and constitutive differential expression among genetic clusters. Finally, by incorporating genetic adaptation, migration, and genetic load into our predictions of population-level climate change risks, we identified western populations-primarily distributed in the Hengduan Mountains, a region known for its environmental heterogeneity and significant biodiversity-as the most vulnerable to climate change. These populations should be prioritized for conservation and management. Overall, our study advances the understanding of the relative roles of long-term natural selection, local environmental adaptation, and immediate plastic expression changes in shaping the responses of natural populations of keystone species to climate change.

Climate Change↗

PubMed2026

Identification of Novel Sources and Genetic Mapping for Bacterial Leaf Streak Resistance in a Geographically Diverse Panel of Wheat.

Bacterial leaf streak (BLS), caused by Xanthomonas translucens pv. undulosa (Xtu), has recently emerged as a significant threat to wheat production in the Northern Great Plains region of the United States. Deploying resistant cultivars is an economical and practical method of controlling BLS. To identify novel sources of BLS resistance, we screened a set of 355 bread wheat landraces and cultivars representing global diversity for their response to BLS. A wide distribution of seedling responses against BLS was observed, with most genotypes displaying a moderately to highly susceptible response. Notably, we identified 5 resistant and 33 moderately resistant responses. A high-resolution genome-wide association study using 302,524 high-quality single-nucleotide polymorphisms (SNPs) identified 10 significant marker-trait associations (MTAs) on chromosomes 1A, 1D, 3B, 4A, and 5A corresponding to unique genomic regions associated with BLS resistance. Compared with previous studies, four of these genomic regions are likely novel. Of these, MTA 'scaffold15531_2782724' associated with q5A.1 was highly significant (-log10P = 9.39) and exhibited the highest SNP effect (0.35). An association on chromosome 3B validated a previously identified 3B quantitative trait locus (QTL) mapped at approximately 6 Mbp in the hard red spring wheat cultivar 'Boost', and the high-resolution mapping from our study further refined the interval for this QTL. Furthermore, the narrow haplotype blocks reported in this study could be valuable for fine mapping of important regions. The novel resistant sources, along with identified genomic loci and corresponding SNP markers from this study, would be helpful for wheat-breeding programs to enhance BLS resistance.[Formula: see text] Copyright © 2026 The Author(s). This is an open access article distributed under the CC BY 4.0 International license.

BLS↗

PubMed2025

Molecular characterization, clinical phenotype, and neurological outcome of twelve Palestinian children with beta-ketothiolase deficiency: report of two novel variants in the ACAT1 gene.

BACKGROUND: Beta-ketothiolase deficiency (mitochondrial acetoacetyl-CoA thiolase, T2) deficiency (OMIM #203750, *607809) is an autosomal recessive disorder of isoleucine catabolism and ketone body utilization. It is caused by mutations in the ACAT1 gene and characterized by intermittent ketoacidosis episodes triggered by ketogenic stresses, with no clinical symptoms between the episodes. Neurological complications, particularly extrapyramidal signs may occur as sequelae of the ketoacidosis episodes but may also occur without or before any apparent metabolic crisis. T2 deficiency is characterized by the accumulation of isoleucine metabolites, 2methylacetoacetate, 2-methyl-3-hydroxybutyrate, and tiglylglycine, detected in urine organic acids and blood acylcarnitines with or without hypoglycemia. METHODS: This study presents data from twelve patients with T2 deficiency, diagnosed between 7 months and 22 months of age at two tertiary care centers in Palestine. The clinical, biochemical, molecular genetic data, and neurological outcomes are reviewed. RESULTS: We report on twelve patients (6 females and 6 males) from eight families in four different regions of the West Bank and Gaza Strip. All patients were offspring of consanguineous marriages. Ketoacidotic episodes were the predominant manifestations in all patients, and each episode was triggered by either acute gastroenteritis or upper respiratory infections. One patient initially presented with hypotonia and psychomotor delay, later developing a ketoacidotic episode a few months afterward. The characteristic laboratory finding in all patients was the increased urinary excretion of 2-methyl-3-hydroxybutyrate and tiglylglycine. Ten of the twelve patients had favorable outcomes, while two unfortunately passed away at the time of the study. Molecular genetic analysis of the ACAT1 gene was conducted on nine patients from six families, revealing four different variants, two of which were novel. Additionally, a founder mutation was identified in six patients from three families. CONCLUSIONS: The study underscores the critical role of genetic research in unraveling the complexities of beta-ketothiolase deficiency and related disorders. By identifying haplotype blocks, founder mutations, and novel pathogenic variants, researchers can significantly improve diagnostic precision, enhance genetic counseling, and lay the groundwork for developing targeted therapies. We identified two novel variants and a founder mutation, thereby broadening the genetic spectrum of this rare disease.

Humans↗

PubMed2026

Evolution and domestication-trait associations of ultra-long centromere haplotypes in pepper plants.

Centromeric and pericentromeric regions of most eukaryotic genomes are highly repetitive and strongly recombination-suppressed, confounding efforts to resolve genetic variation, population structure and phenotypic associations. Pepper (Capsicum annuum) centromeres are nearly devoid of satellite repeats, facilitating assembly and population-level comparison of centromeric regions. Here we integrate 9 near-complete genome assemblies, CENH3 ChIP-seq profiles from 26 diverse accessions, and resequencing and phenotypic data from ~400 cultivated and wild accessions to investigate population-level diversity and phenotypic relevance of pepper peri/centromeric regions. Functional centromere positions are largely fixed on 8 of 12 chromosomes, whereas the remaining 4 carry distinct centromeric epialleles shaped mainly by centromere repositioning and pericentromeric inversions. Pepper centromeres are embedded within ultra-long centromere-spanning haplotype (cenhap) blocks, ranging from 29.8 to 112.9 Mb and collectively covering 23.96% of the genome; each block contains only 1-4 major haplotypes. Some cenhaps may act as supergene-like units and are strongly associated with fruit traits, probably because recombination-suppressed intervals harbour multiple fruit-related genes, including OFP and F-box genes. F2 segregation assays further reveal transmission distortion of chromosomes carrying alternative cenhaps. Together, these findings highlight peri/centromeric regions as underrecognized reservoirs of agronomically important variation.

Centromere↗

PubMed1990

Functional and immunogenetic characterization of FcR-blocking antibody.

The characteristics and functional importance of FcR-blocking antibodies and their production were investigated after immunization with whole blood, "buffy coat" and purified platelets. We studied the presence of FcR-blocking antibody in haemodialyzed, transfused patients waiting for kidney transplantation, and we found strong correlation between the blocking effect and better graft survival. We suggest that this blocking antibody does not attack FcR as primary target. Investigation of blocking activity of ten different immune sera on 50 healthy panel cells showed that target antigen has some polymorphic varieties. On basis of family studies it seems that the target antigen is not linked to HLA haplotype. The blocking effect of sera could be removed by absorption of CD8+ cells, B lymphocytes, platelets and granulocytes, but not with erythrocytes, monocytes, CD8- cells and NK cells.

Absorption↗

PubMed1991

Development of diabetogenic T cells from NOD/Lt marrow is blocked when an allo-H-2 haplotype is expressed on cells of hemopoietic origin, but not on thymic epithelium.

Diabetes is a T cell-mediated process in NOD/Lt mice, with a major genetically recessive component of susceptibility linked to homozygous expression of the unique H-2g7 MHC haplotype. Heterozygous expression of the H-2nb1 haplotype derived from the NON/Lt strain confers diabetes resistance both in (NOD x NON)F1 hybrids and in NOD mice congenic for the H-2nb1 haplotype. However, diabetes resistance is abrogated in F1 hybrids by NOD/Lt bone marrow reconstitution. To establish whether the generation of beta cell autoreactive T cells from NOD/Lt bone marrow-derived precursors required at least heterozygous expression of the H-2g7 haplotype on thymic epithelium, adolescent thymectomized (NOD x NON)F1 mice were implanted with neonatal NON/Lt thymus grafts before lethal radiation and reconstitution with NOD/Lt bone marrow. Peripheral T cells maturing through this ectopic thymic implant exclusively expressed the NOD H-2g7 haplotype and were tolerant to H-2nb1 skin grafts. Nevertheless, diabetes developed in 32% of the NON/Lt thymus-grafted chimeras vs 38% of the sham-thymectomized NOD bone marrow chimeras. Thus, homozygous expression of the diabetes-resistant H-2nb1 haplotype on thymic epithelium failed to block development of a diabetogenic T cell repertoire. To examine if expression of H-2nb1 on hemopoietically derived APC could alter the diabetogenic potential of NOD/Lt marrow, diabetes-resistant NOD.NON-H-2nb1 congenic mice were mated with NOD/Lt mice to produce NOD-H-2g7/H-2nb1 heterozygous recipients. These were lethally irradiated and reconstituted with either NOD/Lt marrow alone, NOD.H-2nb1 homozygous congenic marrow alone, or a 1:1 mixture of the two marrow populations. By 25 wk of age, all of the MHC heterozygous recipients of NOD.NON-H-2nb1 marrow remained diabetes-free whereas 75% of the MHC heterozygous recipients of NOD/Lt marrow developed diabetes. A striking decrease in diabetes was observed when T cell precursors derived from NOD/Lt marrow interacted with H-2nb1 gene products on hemopoietically derived APC, inasmuch as only 7% of the MHC heterozygous recipients reconstituted with a 1:1 mixture of NOD/Lt and NOD.NON-H-2nb1 marrow developed diabetes. Peripheral leukocytes in all reconstitution classes expressed the MHC phenotype(s) of the marrow donor(s). Skin grafting confirmed that all reconstitution classes of MHC heterozygous recipients were tolerant to the H-2nb1 haplotype.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1989

Preferential restriction of minor alloantigen-specific suppressor T cells to I-E rather than I-A molecules.

Suppressor T (Ts) cells specific for minor alloantigens can be generated by intravenous administration of high doses (10(8) cells) of alloantigenic spleen cells. Such Ts cells have previously been shown to inhibit the in vivo induction of CTL responses and are now shown to suppress in vitro proliferative responses to specific minor antigens. This report demonstrates that the activity of such antigen-specific Ts cells in four different strain combinations involving two haplotypes is blocked by anti-I-E antibody. The proliferative helper T cells (Th) in the same strain combinations are restricted to I-A molecules. Whether our results reflect a more general bias of suppressor T cells to be restricted to I-E molecules is discussed.

Animals↗

PubMed2026

Integration of GWAS and WGCNA reveals novel candidate genes for cottonseed oil content in Gossypium hirsutum L.

Genetic improvement of cottonseed oil content represents a crucial strategy for enhancing the comprehensive utilization of cotton. Here, genome-wide association study (GWAS) and weighted gene co-expression network analysis (WGCNA) were integrated to elucidate the genetic control underlying oil content. Phenotypic evaluation of 159 cotton accessions revealed extensive genetic variation, with kernel oil content ranging from 17.81% to 39.50%. Population structure analysis based on 20,213 single nucleotide polymorphisms (SNPs) classified the accessions into two major subpopulations. A total of 18 SNPs exhibited significant associations with oil content, two of which were stably detected across multiple environments using the FarmCPU model. Further haplotype analysis within linkage disequilibrium (LD) blocks confirmed a favorable haplotype on chromosome A05 that was strongly correlated with elevated oil content. Integration of publicly available transcriptome data from 11 ovule developmental stages with WGCNA identified modules significantly linked to oil content. Of the 74 candidate genes within LD intervals, 17 were assigned to WGCNA modules. Functional annotation and enrichment analyses highlighted four putative candidate genes (GH_A05G1503, GH_A05G1506, GH_A05G1531, and GH_A10G2150) involved in oil biosynthesis. These findings deepen our understanding of the genetic mechanisms governing cottonseed oil biosynthesis and lay a foundation for breeding high-oil cotton varieties.

Gossypium↗

PubMed1976

T lymphocyte-enriched murine peritoneal exudate cells. III. Inhibition of antigen-induced T lymphocyte Proliferation with anti-Ia antisera.

The recent development of a reliable murine T lymphocyte proliferation assay has facilitated the study of T lymphocyte function in vitro. In this paper, the effect of anti-histocompatibility antisera on the proliferative response was investigated. The continuous presence of anti-Ia antisera in the cultures was found to inhibit the responses to the antigens poly (Glu58 Lys38 Tyr4) [GLT], poly (Tyr, Glu) ploy D,L Ala-poly Lys [(T,G)-A--L], poly (Phe, Glu)-poly D,L Ala-poly Lys [(phi, G)-A--L], lactate dehydrogenase H4, staphylococcal nuclease, and the IgA myeloma protein, TEPC 15. The T lymphocyte proliferative responses to all of these antigens have previously been shown to be under the genetic control of major histocompatibility-linked immune response genes. The anti-Ia antisera were also capable of inhibiting proliferative responses to antigens such as PPD, to which all strains respond. In contrast, antisera directed solely against H-2K or H-2D antigens did not give significant inhibition. Anti-Ia antisera capable of reacting with antigens coded for by genetically defined subregions of the I locus were capable of completely inhibiting the proliferative response. In the two cases studied, GLT and (T,G)-A--L, an Ir gene controlling the T lymphocyte proliferative response to the antigen had been previously mapped to the same subregion as that which coded for the Ia antigens recognized by the blocking antisera. Finally, in F1 hybrids between responder and nonresponder strains, the anti-Ia antisera showed haplotype-specific inhibition. That is, anti-Ia antisera directed against the responder haplotype could completely block the antigen response controlled by Ir genes of that haplotype; anti-Ia antisera directed against Ia antigens of the nonresponder haplotype gave only partial or no inhibition. Since this selective inhibition was reciprocal depending on which antigen was used, it suggested that the mechanism of anti-Ia antisera inhibition was not cell killing or a nonspecific turning off of the cell but rather a blockade of antigen stimulation at the cell surface. Furthermore, the selective inhibition demonstrates a phenotypic linkage between Ir gene products and Ia antigens at the cell surface. These results, coupled with the known genetic linkage of Ir genes and the genes coding for Ia antigens, suggest that Ia antigens are determinants on Ir gene products.

Animals↗

PubMed1987

HLA-D region epitopes associated with juvenile arthritis. Recognition by alloreactive T cell clones and alloantisera.

The HLA-D region antigens DR5 (w11,w12), DRw6 (w13,w14), DRw8, DRw52, and DQw1 have previously been shown to be increased in frequency in subsets of patients with juvenile arthritis. Since the HLA-D region is complex (composed of at least 3 subregions encoding multiple molecules, each in turn presenting multiple alloantigenic epitopes), we sought to clarify whether one strongly associated factor might explain the previous findings. To search for the pertinent HLA-D region stimulatory epitopes, alloreactive T cells were primed against DR5 and DRw6 haplotypes and cloned by limiting dilution. Three T cell clones and 1 alloantiserum met the criteria for significant association with juvenile arthritis on patient testing, including DR5, DRw6, and DRw8 haplotypes. Monoclonal antibody blocking revealed that all 4 recognized epitopes on DR subregion products. For 2 of the clones, the relative risks for JA (10.5 and 9.4) were higher than the risks with any other previously described typing reagents.

Antibodies, Monoclonal↗

PubMed1991

Immunological tolerance induced by liver grafting in the rat: splenic macrophages and T cells mediate distinct phases of immunosuppressive activity.

In the rat combination DA into PVG, liver grafts are not rejected but induce donor-specific transplantation tolerance. We have examined the immunosuppressive properties of spleen cells from PVG recipients of DA liver grafts at various times post-grafting. The results indicate the development of two phases of cell-mediated suppressor activity, which appear to be mediated by separate spleen cell populations. Mitomycin-C-treated spleen cells taken from animals between 5 and 28 days post-grafting were able to suppress rat mixed lymphocyte reactions (MLRs). These 'early' suppressor cells were glass adherent and absent from populations purified by passage through nylon wool or G10 Sephadex columns. Suppression of MLR by purified glass adherent cells was not specific for either stimulator or responder haplotypes and was blocked by indomethacin. Nylon wool purified T cells were not suppressive at this time. Spleen cell suppressor activity declined to background levels after 35 days post-grafting. However, spleen cells from long-term surviving liver graft recipients (20 weeks or more) were again able to suppress MLR; the 'late' suppressor cells were nylon wool non-adherent and suppression was specific for the donor (DA) MHC type. We conclude that liver grafting in this combination generates early and late phases of suppression among spleen cells, that the early phase is produced by macrophages and mediated by prostaglandins and that the late phase is dependent on allospecific suppressor T cells.

Animals↗

PubMed1989

Congenital heart block immunogenetics. Evidence of an additional role of HLA class III antigens and independence of Ro autoantibodies.

Congenital complete heart block (CCHB) occurs in the offspring of mothers who have the HLA-A1;B8; DR3 haplotype and Ro (SS-A) autoantibodies. It has been shown that the presence of HLA-DR3 in mothers may facilitate Ro synthesis, but may not, by itself, be sufficient to induce CCHB in the offspring. However, maternal DR3 and Ro antibody seem to be independent factors associated with CCHB. Other HLA antigens, including class III (complement) genes, may also be necessary to induce CCHB in newborns since A1;B8; DR3 haplotypes, together with BfS and/or C4AQ0B1, are increased in Ro+ mothers of infants with CCHB compared with both controls and with Ro+ mothers whose offspring do not have CCHB. On the other hand, DR3 genes in a different HLA haplotype (i.e., B18; BfF1;DR3) are nonpathogenetic; this latter finding may be due to a DR3 gene's intrinsic difference or to the influence of neighboring genes. Also, a trend toward DR3 bias transmission is observed in DR3+ mothers who are also Ro+; fetal DR3 might protect the fetus against in utero death when Ro antibodies are present.

Antibodies, Antinuclear↗