Bialellic Mutations in Tetratricopeptide Repeat Domain 7A (TTC7A) Cause Common Variable Immunodeficiency-Like Phenotype with Enteropathy

TTC7A deficiency typically causes severe gastrointestinal manifestations such as multiple intestinal atresia or early-onset inflammatory bowel disease. In some cases, this is associated with severe combined immunodeficiency. Partial loss-of-function mutations appear to be associated with a milder phenotype resulting in common variable immunodeficiency-like condition with enteropathy

A third generation vaccine for human visceral leishmaniasis and post kala azar dermal leishmaniasis : First-in-human trial of ChAd63-KH

BACKGROUND: Visceral leishmaniasis (VL or kala azar) is the most serious form of human leishmaniasis, responsible for over 20,000 deaths annually, and post kala azar dermal leishmaniasis (PKDL) is a stigmatizing skin condition that often occurs in patients after successful treatment for VL. Lack of effective or appropriately targeted cell mediated immunity, including CD8+ T cell responses, underlies the progression of VL and progression to PKDL, and can limit the therapeutic efficacy of anti-leishmanial drugs. Hence, in addition to the need for prophylactic vaccines against leishmaniasis, the development of therapeutic vaccines for use alone or in combined immuno-chemotherapy has been identified as an unmet clinical need. Here, we report the first clinical trial of a third-generation leishmaniasis vaccine, developed intentionally to induce Leishmania-specific CD8+ T cells. METHODS: We conducted a first-in-human dose escalation Phase I trial in 20 healthy volunteers to assess the safety, tolerability and immunogenicity of a prime-only adenoviral vaccine for human VL and PKDL. ChAd63-KH is a replication defective simian adenovirus expressing a novel synthetic gene (KH) encoding two Leishmania proteins KMP-11 and HASPB. Uniquely, the latter was engineered to reflect repeat domain polymorphisms and arrangements identified from clinical isolates. We monitored innate immune responses by whole blood RNA-Seq and antigen specific CD8+ T cell responses by IFNγ ELISPOT and intracellular flow cytometry. FINDINGS: ChAd63-KH was safe at intramuscular doses of 1x1010 and 7.5x1010 vp. Whole blood transcriptomic profiling indicated that ChAd63-KH induced innate immune responses characterized by an interferon signature and the presence of activated dendritic cells. Broad and quantitatively robust CD8+ T cell responses were induced by vaccination in 100% (20/20) of vaccinated subjects. CONCLUSION: The results of this study support the further development of ChAd63-KH as a novel third generation vaccine for VL and PKDL. TRIAL REGISTRATION: This clinical trial (LEISH1) was registered at EudraCT (2012-005596-14) and ISRCTN (07766359)

Autosomal dominant STAT6 Gain of function causes severe atopy associated with lymphoma

The transcription factor STAT6 (Signal Transducer and Activator of Transcription 6) is a key regulator of Th2 (T-helper 2) mediated allergic inflammation via the IL-4 (interleukin-4) JAK (Janus kinase)/STAT signalling pathway. We identified a novel heterozygous germline mutation STAT6 c.1255G > C, p.D419H leading to overactivity of IL-4 JAK/STAT signalling pathway, in a kindred affected by early-onset atopic dermatitis, food allergy, eosinophilic asthma, anaphylaxis and follicular lymphoma. STAT6 D419H expression and functional activity were compared with wild type STAT6 in transduced HEK293T cells and to healthy control primary skin fibroblasts and peripheral blood mononuclear cells (PBMC). We observed consistently higher STAT6 levels at baseline and higher STAT6 and phosphorylated STAT6 following IL-4 stimulation in D419H cell lines and primary cells compared to wild type controls. The pSTAT6/STAT6 ratios were unchanged between D419H and control cells suggesting that elevated pSTAT6 levels resulted from higher total basal STAT6 expression. The selective JAK1/JAK2 inhibitor ruxolitinib reduced pSTAT6 levels in D419H HEK293T cells and patient PBMC. Nuclear staining demonstrated increased STAT6 in patient fibroblasts at baseline and both STAT6 and pSTAT6 after IL-4 stimulation. We also observed higher transcriptional upregulation of downstream genes (XBP1 and EPAS1) in patient PBMC. Our study confirms STAT6 gain of function (GOF) as a novel monogenetic cause of early onset atopic disease. The clinical association of lymphoma in our kindred, along with previous data linking somatic STAT6 D419H mutations to follicular lymphoma suggest that patients with STAT6 GOF disease may be at higher risk of lymphomagenesis

Study population.

<p>Study population.</p

Innate immune response to ChAd63-KH vaccination.

<p>Whole blood from high dose subjects was collected before vaccination and at 24h post vaccination and processed for RNA-Seq. <b>A.</b> Volcano plot showing Log2FC in gene expression (y axis) against signal intensity (Log2CPM). <b>B.</b> Principle component analysis showing clustering of pre- (black, by subject number) and post- (red, by subject number) vaccination samples. <b>C.</b> Frequency of naïve and resting memory CD4⁺ T cells, monocytes and activated DCs pre and post vaccination, as determined by CIBERSORT analysis. <b>D</b>. Module level analysis comparing gene representation pre and post vaccination. Colour code represents proportion of genes significantly changed (over-represented, red; under-represented, blue) for each of the 28 modules described by Chaussabel et al [<a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0005527#pntd.0005527.ref047" target="_blank">47</a>].</p

Antibody and CD4⁺/CD8⁺ T cell responses to ChAd63-KH vaccination.

<p><b>A.</b> ELISPOT response to ChAd63-KH vaccination over time for individual low dose (Don 1, 3,4,6,10, open symbols) and high dose (closed symbols) subjects. Data represent sum of response to peptide pools A, B and C at each time indicated. <b>B</b>. Peak response to each peptide pool for low (open circles) and high (black circles) dose subjects. Median responses for high (solid line) and low (dotted line) dose subjects are also shown. <b>C.</b> Antibodies specific for the rKH protein were assayed by ELISA. Data are shown for all subjects at the indicated times post vaccination.</p

CONSORT diagram for LEISH1 first-in-human clinical trial.

<p>CONSORT diagram for LEISH1 first-in-human clinical trial.</p