NK cell alloreactivity is governed largely through failure to detect self-HLA class I ligands by the clonally distributed inhibitory killer Ig-like receptors (KIR) expressed on the NK cell surface. In this study, we investigated the extent to which HLA class I-KIR interactions influence human NK cell proliferation in the allogeneic setting. NK cells were cultured with feeder cells either matched or mismatched for inhibitory KIR ligands, the latter lacking one or more ligands present in the NK cell donor. In postculture cytotoxicity assays, the ability of polyclonal NK cells to kill KIR ligand-mismatched targets was enhanced by exposure to appropriately mismatched feeder cells in prior culture. This corresponded with an increased frequency of postculture donor NK cells expressing a given inhibitory KIR if the allogeneic feeder cells used in the culture lacked its ligand. Similar skewing of KIR distribution was seen in clonally expanded NK cells. Finally, a flow cytometry-based proliferation assay was used to show KIR-specific NK cell division in response to missing self. The findings demonstrate that KIR distribution among a population of alloresponding peripheral blood NK cells is shaped by the HLA class I environment.
The gastric H/K ATPase beta-subunit, an abundant glycoprotein of the secretory membranes of gastric parietal cells, is the major autoantigen recognized by human parietal cell autoantibodies in gastric autoimmunity. Our previous studies demonstrated that the human autoantibodies recognize the H/K ATPase beta-subunit from a number of species and that glycosylation of the beta-subunit with complex N-glycans is required for autoantibody binding. The N-glycans of the beta-subunit contain polylactosamine chains. The lactosamine chains of the rabbit beta-subunit are terminated with alpha-linked galactosyl residues (alpha-galactosyl epitope) (Tyagarajan et al., Biochemistry, 1996, 35, 3238-3246). Here we have investigated the expression of alpha-galactosyl epitopes on the H/K ATPase beta-subunit from a number of species. Using the alpha-galactosyl binding lectin, BS1-IB4, and naturally occurring anti-alpha-galactosyl antibodies, we have demonstrated that the rat H/K ATPase beta-subunit also contains terminal alpha-galactosyl residues, but not the beta-subunit from pig, dog, and mouse, indicating species-specific differences in the terminal saccharide sequences of the beta-subunit. We also investigated the potential contribution of the alpha-galactosyl epitopes to the binding by human sera. The reactivity of human pernicious anemia serum with gastric parietal cells could not be inhibited with saccharide inhibitors and, in addition, no binding was observed with normal human sera. We conclude that the H/K ATPase beta-subunit oligosaccharides from rabbit and rat are terminated with alpha-galactosyl epitopes, and although the presence of this epitope does not contribute to binding by human parietal cell autoantibodies at the concentrations routinely used, it is recommended that neither rat or rabbit stomachs be used for screening human sera.
In the human leucocyte antigen (HLA)-matched haematopoietic stem cell transplantation (HSCT) setting, minor histocompatibility antigen (mHA) disparities between recipient and donor can lead to graft-vs-host disease (GVHD) or graft rejection. Graft-vs-leukaemia (GVL) effect is a beneficial T-cell-mediated immune response that can also occur following HLA-matched HSCT. mHAs with tissue expression restricted to cells of the haematopoietic system are particularly relevant as immunotherapeutic targets for destroying malignant cells without inducing GVHD. Therefore, it is important to identify further haematopoietic-restricted polymorphic mHAs, which may have the potential to be used clinically for adoptive immunotherapy. Polymorphic mismatching of minor antigens, such as the B-cell-specific protein, the kappa immunoglobulin light chain (kappa) may play a role in the incidence of GVL and therefore the survival of transplant recipients following transplantation for B-cell malignancies. Polymorphisms in the constant region of the immunoglobulin kappa polypeptide chain have been defined involving single amino acid changes at positions 153 and 191. In this study, 51 HLA-matched B-cell malignancy transplant pairs were kappa typed by polymerase chain reaction and restriction enzyme digestion to investigate the association between kappa allotype disparity and outcome after transplantation. Kappa allotype disparity between transplant pairs may be associated with an increased survival compared with pairs not mismatched for kappa, as kappa mismatched recipients had a higher percentage of complete remissions and a decreased level of relapse in comparison with the nonmismatched recipients. HLA peptide prediction software was used to determine which HLA types were the best binders for kappa peptides. It was observed that patients with tissue types predicted to bind the kappa Km(1,2) peptides had better survival outcomes and no relapse compared with those with tissue types not predicted to bind the kappa Km(1,2) peptides. This study may contribute to the assessment of the clinical role of kappa with regard to the outcome of allogeneic transplantation for B-cell malignancies.
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