SummaryBullous pemphigoid is a blistering skin disease characterized by autoantibodies against the NC16a domain of bullous pemphigoid 180. This study was performed to characterize and map the fine specificity of T cell responses to NC16a.
In both sickle cell disease and malaria, red blood cells (RBCs) are phagocytosed in the spleen, but receptor-ligand pairs mediating uptake have not been identified. Here, we report that patches of high mannose N-glycans (Man5-9GlcNAc2), expressed on diseased or oxidized RBC surfaces, bind the mannose receptor (CD206) on phagocytes to mediate clearance. We find that extravascular hemolysis in sickle cell disease correlates with high mannose glycan levels on RBCs. Furthermore, Plasmodium falciparum-infected RBCs expose surface mannose N-glycans, which occur at significantly higher levels on infected RBCs from sickle cell trait subjects compared to those lacking hemoglobin S. The glycans are associated with high molecular weight complexes and protease-resistant, lower molecular weight fragments containing spectrin. Recognition of surface N-linked high mannose glycans as a response to cellular stress is a molecular mechanism common to both the pathogenesis of sickle cell disease and resistance to severe malaria in sickle cell trait.
© F e r r a t a S t o r t i F o u n d a t i o nparate population when translated to patients. 1,2,27,28 We have previously mapped peptides containing dominant helper epitopes from the RhD protein, which carries the RhD blood group. 1 In particular, peptides RhD 52-66 , RhD [97][98][99][100][101][102][103][104][105][106][107][108][109][110][111] or RhD [177][178][179][180][181][182][183][184][185][186][187][188][189][190][191] , are each able to stimulate Th-cells in vitro from more than 50% of RhD-negative donors who have been alloimmunized with RhD-positive RBC, with responses to at least one sequence in every donor tested.1 To evaluate whether these peptides have the in vivo tolerogenic properties required for development as immunotherapy to prevent HDN, we generated a humanized murine model of responsiveness to the RhD protein, since the antigen is not immunogenic in wild-type mice.2 As predicted, transgenic expression of HLA-DR15, a major restricting allele for RhD epitope-specific Th-cells, 1 conferred on mice the ability to respond to purified RhD protein.2 When each of the four peptides we had mapped was given by an intranasal route to the transgenic mice, prior to immunization with RhD protein, both Th and antibody responses were prevented.2 However, the unmet clinical need, and initial indication for RhD peptide therapy, is the treatment of women who have existing anti-D antibodies, and so the question now arises as to whether administration of these peptides can also suppress responses to the RhD protein once these have been established in vivo. It is also desirable to establish whether subcutaneous delivery, which raises fewer issues for the approval of eventual human clinical trials, is as effective as the intranasal route.The purpose was to develop a product for suppression of RhD immunity, based on the sequences of the four immunodominant peptides we have identified, 1 and to test its efficacy in vivo in a pre-clinical model of established responses to the RhD protein. The first step was to select soluble forms of each of the four peptides that retain human T-cell recognition, since solubility is a key tolerogenic property. We then wished to test these in combination to verify whether they could inhibit established antibody and Th responses to the RhD protein in our HLA-transgenic immunization model, and to induce Treg cells, comparing mucosal and subcutaneous routes of administration. The results identify a tolerogenic peptide product and simple dosing regimen, suitable for translation to human trials as the first specific treatment for women at risk of HDN due to existing anti-D antibodies. Methods DonorsRhD-negative patients with anti-D antibodies, following incompatible pregnancy, were recruited by the Scottish National Blood Transfusion Service, and samples for preparation of serum or peripheral blood mononuclear cells (PMBC) taken by venipuncture respectively into plain or lithium heparin Vacutainers (Becton Dickinson, Oxford, UK) (patient information is summarized in Table 1). The G...
Purpose: Understanding the mechanisms of immune tolerance to tumor-associated antigens (TAA) is an important step in the design of cancer immunotherapy. The aim was to determine how T helper (Th) cell tolerance is mediated for a prototypic TAA, carcinoembryonic antigen (CEA). Experimental Design: Peripheral blood mononuclear cells from 50 healthy volunteers were stimulated with CEA, and the type and fine specificity of any Th cell responses were identified.
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