TCR cross-reactivity and allorecognition: new insights into the immunogenetics of allorecognition

Alloreactive T cells are core mediators of graft rejection and are a potent barrier to transplantation tolerance. It was previously unclear how T cells educated in the recipient thymus could recognize allogeneic HLA molecules. Recently it was shown that both naïve and memory CD4+ and CD8+ T cells are frequently cross-reactive against allogeneic HLA molecules and that this allorecognition exhibits exquisite peptide and HLA specificity and is dependent on both public and private specificities of the T cell receptor. In this review we highlight new insights gained into the immunogenetics of allorecognition, with particular emphasis on how viral infection and vaccination may specifically activate allo-HLA reactive T cells. We also briefly discuss the potential for virus-specific T cell infusions to produce GvHD. The progress made in understanding the molecular basis of allograft rejection will hopefully be translated into improved allograft function and/or survival, and eventually tolerance induction

Exposure and risk factors to Coxiella burnetii, spotted fever group and typhus group rickettsiae, and Bartonella henselae among volunteer blood donors in Namibia

Background: The role of pathogen-mediated febrile illness in sub-Saharan Africa is receiving more attention, especially in Southern Africa where four countries (including Namibia) are actively working to eliminate malaria. With a high concentration of livestock and high rates of companion animal ownership, the influence of zoonotic bacterial diseases as causes of febrile illness in Namibia remains unknown.Methodology/Principal Findings: The aim of the study was to evaluate exposure to Coxiella burnetii, spotted fever and typhus group rickettsiae, and Bartonella henselae using IFA and ELISA (IgG) in serum collected from 319 volunteer blood donors identified by the Blood Transfusion Service of Namibia (NAMBTS). Serum samples were linked to a basic questionnaire to identify possible risk factors. The majority of the participants (64.8%) had extensive exposure to rural areas or farms. Results indicated a C. burnetii prevalence of 26.1% (screening titre 1:16), and prevalence rates of 11.9% and 14.9% (screening titre 1:100) for spotted fever group and typhus group rickettsiae, respectively. There was a significant spatial association between C. burnetii exposure and place of residence in southern Namibia (P0.012), especially cattle (P>0.006), were also significantly associated with C. burnetii exposure. Males were significantly more likely than females to have been exposed to spotted fever (P<0.013) and typhus (P<0.011) group rickettsiae. Three (2.9%) samples were positive for B. henselae possibly indicating low levels of exposure to a pathogen never reported in Namibia.Conclusions/Significance: These results indicate that Namibians are exposed to pathogenic fever-causing bacteria, most of which have flea or tick vectors/reservoirs. The epidemiology of febrile illnesses in Namibia needs further evaluation in order to develop comprehensive local diagnostic and treatment algorithms.Peer reviewedEntomology and Plant Patholog

Introduction to electromagnetics and microwave engineering

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Die Rehabilitasie van Pasiente met Serebrovaskulere Ongelukke

CITATION: Van W-Van Der Colf, C., Wicht C. L., & Willers E. 1978. Die rehabilitasie van pasiente met serebrovaskulere ongelukke. South African Medical Journal, 53(20):797-801.The original publication is available at http://www.samj.org.zaA rehabilitation programme for patients with cerebrovascular accidents is outlined. The effectiveness of this programme was assessed in 220 patients transferred from Tygerberg Hospital to Goodwood Aftercare Hospital during the past 4 years. They were accepted after the acute phase and when the strokes were completed. The results of rehabilitation were judged by evaluating activities of daily living, namely eating, washing and dressing, and factors such as mobility and use of an affected hand, sphincter control, and ability to communicate. Other factors used to evaluate the rehabilitation programme were complications during treatment and eventual placing of the patients. Of 130 patients (72.6%) who were bedridden on admission, 62 (34.6%) could walk unaided and 46 (25.7%) could walk with aid after discharge. Thus, 108 patients (60.3%) could walk, either with or without aid. Thirty-six patients (20.1%), in whom stroke rendered their upper limbs useless, regained the use of their hands. On admission 90 patients (50.2%) were incontinent of urine, and 82 (45.8%) were faecally incontinent. On discharge the figures were 45 (25.1%) and 29 (16.2%) respectively. Dysphasia was present in 56 patients of whom 24 (37.5%) improved on therapy. Thirty-eight patients were admitted with dysarthria, of whom 26 (68%) either recovered or improved. On admission 35 of the survivors (19.6%) could eat independently, and on discharge 121 patients (67.6%) could eat unaided. Only 17 patients (9.5%) were independent as far as washing and dressing were concerned, but on discharge 77 (43%) could wash and 75 (41.9%) could dress without aid. During the rehabilitation phase 41 of the 220 patients admitted (18.6%) died. Deep venous thrombosis occurred in 28 patients (12.7%) and clinically diagnosed pulmonary embolism in 4 (1.8%). Urinary tract infections presented a problem in patients with indwelling catheters. Reactive depression was a major problem. Subluxation of the hemiplegic shoulder occurred in 32 patients (17.6%). No new decubitus ulcers developed. On discharge 29 of the 114 patients who returned to their previous homes needed some form of help. Thirty-one were placed in old-age homes with nursing care and 9 in private nursing homes. A total of 25 were admitted to institutions for chronically ill or terminal-care patients.Publisher’s versio

Solution mapping of T cell receptor docking footprints on peptide-MHC

T cell receptor (TCR) recognition of peptide-MHC (pMHC) is central to the cellular immune response. A large database of TCR–pMHC structures is needed to reveal general structural principles, such as whether the repertoire of TCR/MHC docking modes is dictated by a “recognition code” between conserved elements of the TCR and MHC genes. Although ≈17 cocrystal structures of unique TCR–pMHC complexes have been determined, cocrystallization of soluble TCR and pMHC remains a major technical obstacle in the field. Here we demonstrate a strategy, based on NMR chemical shift mapping, that permits rapid and reliable analysis of the solution footprint made by a TCR when binding onto the pMHC surface. We mapped the 2C TCR binding interaction with its allogeneic ligand H–2Ld–QL9 and identified a group of NMR-shifted residues that delineated a clear surface of the MHC that we defined as the TCR footprint. We subsequently found that the docking footprint described by NMR shifts was highly accurate compared with a recently determined high-resolution crystal structure of the same complex. The same NMR footprint analysis was done on a high-affinity mutant of the TCR. The current work serves as a foundation to explore the molecular dynamics of pMHC complexes and to rapidly determine the footprints of many Ld-specific TCRs

Structure and membrane remodeling activity of ESCRT-III helical polymers.

The endosomal sorting complexes required for transport (ESCRT) proteins mediate fundamental membrane remodeling events that require stabilizing negative membrane curvature. These include endosomal intralumenal vesicle formation, HIV budding, nuclear envelope closure, and cytokinetic abscission. ESCRT-III subunits perform key roles in these processes by changing conformation and polymerizing into membrane-remodeling filaments. Here, we report the 4 angstrom resolution cryogenic electron microscopy reconstruction of a one-start, double-stranded helical copolymer composed of two different human ESCRT-III subunits, charged multivesicular body protein 1B (CHMP1B) and increased sodium tolerance 1 (IST1). The inner strand comprises "open" CHMP1B subunits that interlock in an elaborate domain-swapped architecture and is encircled by an outer strand of "closed" IST1 subunits. Unlike other ESCRT-III proteins, CHMP1B and IST1 polymers form external coats on positively curved membranes in vitro and in vivo. Our analysis suggests how common ESCRT-III filament architectures could stabilize different degrees and directions of membrane curvature

Variations in the association of papillomavirus E2 proteins with mitotic chromosomes

The E2 protein segregates episomal bovine papillomavirus (BPV) genomes to daughter cells by tethering them to mitotic chromosomes, thus ensuring equal distribution and retention of viral DNA. To date, only the BPV1 E2 protein has been shown to bind to mitotic chromosomes. We assessed the localization of 13 different animal and human E2 proteins from seven papillomavirus genera, and we show that most of them are stably bound to chromosomes throughout mitosis. Furthermore, in contrast to the random association of BPV1 E2 with mitotic chromosomes, several of these proteins appear to bind to more specific regions of mitotic chromosomes. Using human papillomavirus (HPV) type 8 E2, we show that this region is adjacent to centromeres/kinetochores. Therefore, E2 proteins from both HPV and animal papillomavirus bind to mitotic chromosomes, and there are variations in the specificity of this binding. Only the α-papillomavirus E2 proteins do not stably associate with mitotic chromatin throughout mitosis. These proteins closely associate with prophase chromosomes and bind to chromosomes in telophase but not in metaphase. However, extraction of mitotic cells before fixation results in α-E2 proteins binding to the pericentromeric region of metaphase chromosomes, as observed for HPV8 E2. We postulate that this is the authentic target of these E2 proteins but that additional factors or a specialized cellular environment is required to stabilize this association. Thus, E2-mediated tethering of viral genomes to mitotic chromosomes is a common strategy of papillomaviruses, but different viruses have evolved different variations of this theme