Immunodeficiency in DiGeorge Syndrome and Options for Treating Cases with Complete Athymia.

The commonest association of thymic stromal deficiency resulting in T-cell immunodeficiency is the DiGeorge syndrome (DGS). This results from abnormal development of the third and fourth pharyngeal arches and is most commonly associated with a microdeletion at chromosome 22q11 though other genetic and non-genetic causes have been described. The immunological competence of affected individuals is highly variable, ranging from normal to a severe combined immunodeficiency when there is complete athymia. In the most severe group, correction of the immunodeficiency can be achieved using thymus allografts which can support thymopoiesis even in the absence of donor-recipient matching at the major histocompatibility loci. This review focuses on the causes of DGS, the immunological features of the disorder, and the approaches to correction of the immunodeficiency including the use of thymus transplantation

Current and Future Therapeutic Approaches for Thymic Stromal Cell Defects

Inborn errors of thymic stromal cell development and function lead to impaired T-cell development resulting in a susceptibility to opportunistic infections and autoimmunity. In their most severe form, congenital athymia, these disorders are life-threatening if left untreated. Athymia is rare and is typically associated with complete DiGeorge syndrome, which has multiple genetic and environmental etiologies. It is also found in rare cases of T-cell lymphopenia due to Nude SCID and Otofaciocervical Syndrome type 2, or in the context of genetically undefined defects. This group of disorders cannot be corrected by hematopoietic stem cell transplantation, but upon timely recognition as thymic defects, can successfully be treated by thymus transplantation using cultured postnatal thymic tissue with the generation of naïve T-cells showing a diverse repertoire. Mortality after this treatment usually occurs before immune reconstitution and is mainly associated with infections most often acquired pre-transplantation. In this review, we will discuss the current approaches to the diagnosis and management of thymic stromal cell defects, in particular those resulting in athymia. We will discuss the impact of the expanding implementation of newborn screening for T-cell lymphopenia, in combination with next generation sequencing, as well as the role of novel diagnostic tools distinguishing between hematopoietic and thymic stromal cell defects in facilitating the early consideration for thymus transplantation of an increasing number of patients and disorders. Immune reconstitution after the current treatment is usually incomplete with relatively common inflammatory and autoimmune complications, emphasizing the importance for improving strategies for thymus replacement therapy by optimizing the current use of postnatal thymus tissue and developing new approaches using engineered thymus tissue

T-cell reconstitution after thymus xenotransplantation induces hair depigmentation and loss

Here we present a mouse model for T-cell targeting of hair follicles, linking the pathogenesis of alopecia to that of depigmentation disorders. Clinically, thymus transplantation has been successfully used to treat T-cell immunodeficiency in congenital athymia, but is associated with autoimmunity. We established a mouse model of thymus transplantation by subcutaneously implanting human thymus tissue into athymic C57BL/6 nude mice. These xenografts supported mouse T-cell development. Surprisingly, we did not detect multiorgan autoimmune disease. However, in all transplanted mice, we noted a striking depigmentation and loss of hair follicles. Transfer of T cells from transplanted nudes to syngeneic black-coated RAG(-/-) recipients caused progressive, persistent coat-hair whitening, which preceded patchy hair loss in depigmented areas. Further transfer experiments revealed that these phenomena could be induced by CD4+ T cells alone. Immunofluorescent analysis suggested that Trp2+ melanocyte-lineage cells were decreased in depigmented hair follicles, and pathogenic T cells upregulated activation markers when exposed to C57BL/6 melanocytes in vitro, suggesting that these T cells are not tolerant to self-melanocyte antigens. Our data raise interesting questions about the mechanisms underlying tissue-specific tolerance to skin antigens

Non-palimpsested crowded Skolithos ichnofabrics in a Carboniferous tidal rhythmite: Disentangling ecological signatures from the spatio-temporal bias of outcrop

Funder: International Association of Sedimentologists; Id: http://dx.doi.org/10.13039/501100007463A heterolithic tidalite succession yielding spring–neap bundles is newly reported from a mid- Carboniferous (Serpukhovian) section of the Alston Formation of Northumberland, England. The rhythmite records deposition over an interval that can be confidently calibrated to at least 84 lunar days, and attests to a non-negligible tidal range in parts of the Northwest European Seaway in the late Mississippian. The tidalite is notable for the presence of a striking crowded Skolithos ichnofabric on both bedding planes and in vertical section. Bedding plane expressions of the ichnofabric reveal true substrates of sand piles excavated during burrow construction, in addition to an apparently remarkable equal spacing between individual burrows that is shown to be genuine through pair correlation function analysis. These characteristics show that the burrowed horizons were registered by contemporaneous ichnocoenoses, with no palimpsesting of burrows. The irregular vertical distribution of burrow horizons, despite a near-continuous semi-diurnal record of sedimentation, is suggested to be an artefact of spatial patchiness of burrowing communities in the depositional environment; imperfectly registered in a vertical profile with high-temporal, lowspatial resolution. The succession proves that burrow palimpsesting is not an inevitable ichnological conclusion of sedimentary stasis, and attests to intermittent palaeoecological fidelity of the stratigraphic record at the small spatio-temporal scales recorded a

T cell phenotype in paediatric heart transplant recipients

Paediatric heart transplantation recipients suffer an increased incidence of infectious, autoimmune and allergic problems. The relative roles of thymus excision and immunosuppressive treatments in contributing to these sequelae are not clear. We compared the immunological phenotypes of 25 heart transplant recipients (Tx), 10 children who underwent thymus excision during non-transplantation cardiac surgery (TE) and 25 age range–matched controls, in two age bands: 1-9 and 10-16 years. Significant differences from controls were seen mainly in the younger age band with Tx showing lower CD3 and CD4 cell counts whilst TE showed lower CD8 cell counts. Naïve T cell and recent thymic emigrant proportions and counts were significantly lower than controls in both groups in the lower age band. T cell recombination excision circle (TREC) levels were lower than controls in both groups in both age bands. There were no differences in regulatory T cells, but in those undergoing thymus excision in infancy, their proportions were higher in TE than Tx, a possible direct effect of immunosuppression. T cell receptor V beta spectratyping showed fewer peaks in both groups than in controls (predominantly in the older age band). Thymus excision in infancy was associated with lower CD8 cell counts and higher proportions of Tregs in TE compared to Tx. These data are consistent with thymus excision, particularly in infancy, being the most important influence on immunological phenotype after heart transplantation

Correction of both immunodeficiency and hypoparathyroidism by thymus transplantation in complete DiGeorge Syndrome

Combined immune deficiency due to athymia in patients with complete DiGeorge syndrome can be corrected by allogeneic thymus transplantation. Hypoparathyroidism is a frequent concomitant clinical problem in these patients, which persists after thymus transplantation. Cotransplantation of allogeneic thymus and parental parathyroid tissue has been attempted but does not achieve durable correction of the patients' hypoparathyroidism due to parathyroid graft rejection. Surprisingly, we observed correction of hypoparathyroidism in one patient after thymus transplantation. Immunohistochemical analysis and fluorescence in situ hybridization confirmed the presence of allogeneic parathyroid tissue in the patient's thymus transplant biopsy. Despite a lack of HLA‐matching between thymus donor and recipient, the reconstituted immune system displays tolerance toward the thymus donor. Therefore we expect this patient's hypoparathyroidism to be permanently cured. It is recognised that ectopic parathyroid tissue is not infrequently found in the thymus. If such thymuses could be identified, we propose that their use would offer a compelling approach to achieving lasting correction of both immunodeficiency and hypoparathyroidism

Allosteric mechanism of action of the therapeutic anti-IgE antibody omalizumab

Immunoglobulin E and its interactions with receptors FcϵRI and CD23 play a central role in allergic disease. Omalizumab, a clinically approved therapeutic antibody, inhibits the interaction between IgE and FcϵRI, preventing mast cell and basophil activation, and blocks IgE binding to CD23 on B cells and antigen-presenting cells. We solved the crystal structure of the complex between an omalizumab-derived Fab and IgE-Fc, with one Fab bound to each Cϵ3 domain. Free IgE-Fc adopts an acutely bent structure, but in the complex it is only partially bent, with large-scale conformational changes in the Cϵ3 domains that inhibit the interaction with FcϵRI. CD23 binding is inhibited sterically due to overlapping binding sites on each Cϵ3 domain. Studies of omalizumab Fab binding in solution demonstrate the allosteric basis for FcϵRI inhibition and, together with the structure, reveal how omalizumab may accelerate dissociation of receptor-bound IgE from FcϵRI, exploiting the intrinsic flexibility and allosteric potential of IgE

A Spatial Analysis of Rift Valley Fever Virus Seropositivity in Domestic Ruminants in Tanzania

Rift Valley fever (RVF) is an acute arthropod-borne viral zoonotic disease primarily occurring in Africa. Since RVF-like disease was reported in Tanzania in 1930, outbreaks of the disease have been reported mainly from the eastern ecosystem of the Great Rift Valley. This cross-sectional study was carried out to describe the variation in RVF virus (RVFV) seropositivity in domestic ruminants between selected villages in the eastern and western Rift Valley ecosystems in Tanzania, and identify potential risk factors. Three study villages were purposively selected from each of the two Rift Valley ecosystems. Serum samples from randomly selected domestic ruminants (n = 1,435) were tested for the presence of specific immunoglobulin G (IgG) and M (IgM), using RVF enzyme-linked immunosorbent assay methods. Mixed effects logistic regression modelling was used to investigate the association between potential risk factors and RVFV seropositivity. The overall RVFV seroprevalence (n = 1,435) in domestic ruminants was 25.8% and species specific seroprevalence was 29.7%, 27.7% and 22.0% in sheep (n = 148), cattle (n = 756) and goats (n = 531), respectively. The odds of seropositivity were significantly higher in animals sampled from the villages in the eastern than those in the western Rift Valley ecosystem (OR = 1.88, CI: 1.41, 2.51; p<0.001), in animals sampled from villages with soils of good than those with soils of poor water holding capacity (OR = 1.97; 95% CI: 1.58, 3.02; p< 0.001), and in animals which had been introduced than in animals born within the herd (OR = 5.08, CI: 2.74, 9.44; p< 0.001). Compared with animals aged 1-2 years, those aged 3 and 4-5 years had 3.40 (CI: 2.49, 4.64; p< 0.001) and 3.31 (CI: 2.27, 4.82, p< 0.001) times the odds of seropositivity. The findings confirm exposure to RVFV in all the study villages, but with a higher prevalence in the study villages from the eastern Rift Valley ecosystem

Atypical audiovisual speech integration in infants at risk for autism

The language difficulties often seen in individuals with autism might stem from an inability to integrate audiovisual information, a skill important for language development. We investigated whether 9-month-old siblings of older children with autism, who are at an increased risk of developing autism, are able to integrate audiovisual speech cues. We used an eye-tracker to record where infants looked when shown a screen displaying two faces of the same model, where one face is articulating/ba/and the other/ga/, with one face congruent with the syllable sound being presented simultaneously, the other face incongruent. This method was successful in showing that infants at low risk can integrate audiovisual speech: they looked for the same amount of time at the mouths in both the fusible visual/ga/− audio/ba/and the congruent visual/ba/− audio/ba/displays, indicating that the auditory and visual streams fuse into a McGurk-type of syllabic percept in the incongruent condition. It also showed that low-risk infants could perceive a mismatch between auditory and visual cues: they looked longer at the mouth in the mismatched, non-fusible visual/ba/− audio/ga/display compared with the congruent visual/ga/− audio/ga/display, demonstrating that they perceive an uncommon, and therefore interesting, speech-like percept when looking at the incongruent mouth (repeated ANOVA: displays x fusion/mismatch conditions interaction: F(1,16) = 17.153, p = 0.001). The looking behaviour of high-risk infants did not differ according to the type of display, suggesting difficulties in matching auditory and visual information (repeated ANOVA, displays x conditions interaction: F(1,25) = 0.09, p = 0.767), in contrast to low-risk infants (repeated ANOVA: displays x conditions x low/high-risk groups interaction: F(1,41) = 4.466, p = 0.041). In some cases this reduced ability might lead to the poor communication skills characteristic of autism