BackgroundThe genetic cause of primary immunodeficiency disease (PID) carries prognostic information.ObjectiveWe conducted a whole-genome sequencing study assessing a large proportion of the NIHR BioResource–Rare Diseases cohort.MethodsIn the predominantly European study population of principally sporadic unrelated PID cases (n = 846), a novel Bayesian method identified nuclear factor κB subunit 1 (NFKB1) as one of the genes most strongly associated with PID, and the association was explained by 16 novel heterozygous truncating, missense, and gene deletion variants. This accounted for 4% of common variable immunodeficiency (CVID) cases (n = 390) in the cohort. Amino acid substitutions predicted to be pathogenic were assessed by means of analysis of structural protein data. Immunophenotyping, immunoblotting, and ex vivo stimulation of lymphocytes determined the functional effects of these variants. Detailed clinical and pedigree information was collected for genotype-phenotype cosegregation analyses.ResultsBoth sporadic and familial cases demonstrated evidence of the noninfective complications of CVID, including massive lymphadenopathy (24%), unexplained splenomegaly (48%), and autoimmune disease (48%), features prior studies correlated with worse clinical prognosis. Although partial penetrance of clinical symptoms was noted in certain pedigrees, all carriers have a deficiency in B-lymphocyte differentiation. Detailed assessment of B-lymphocyte numbers, phenotype, and function identifies the presence of an increased CD21low B-cell population. Combined with identification of the disease-causing variant, this distinguishes between healthy subjects, asymptomatic carriers, and clinically affected cases.ConclusionWe show that heterozygous loss-of-function variants in NFKB1 are the most common known monogenic cause of CVID, which results in a temporally progressive defect in the formation of immunoglobulin-producing B cells.

BackgroundVisceral 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.MethodsWe 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.FindingsChAd63-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.ConclusionThe results of this study support the further development of ChAd63-KH as a novel third generation vaccine for VL and PKDL.Trial registrationThis clinical trial (LEISH1) was registered at EudraCT (2012-005596-14) and ISRCTN (07766359).

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G6PC3 deficiency typically causes severe congenital neutropenia, associated with susceptibility to infections, cardiac and urogenital abnormalities. However, here we describe two boys of Pakistani origin who were found to have G6PC3 deficiency due to c.130 C>T mutation, but who have clinical phenotypes that are typical for a systemic autoinflammatory syndrome. The index case presented with combination of unexplained fevers, severe mucosal ulcers, abdominal symptoms, and inflammatory arthritis. He eventually fully responded to anti-TNF therapy. In this study, we show that compared with healthy controls, neutrophils and monocytes from patients have reduced glycolytic reserve. Considering that healthy myeloid cells have been shown to switch their metabolic pathways to glycolysis in response to inflammatory cues, we studied what impact this might have on production of the inflammatory cytokines. We have demonstrated that patients’ monocytes, in response to lipopolysaccharide, show significantly increased production of IL-1β and IL-18, which is NLRP3 inflammasome dependent. Furthermore, additional whole blood assays have also shown an enhanced production of IL-6 and TNF from the patients’ cells. These cases provide further proof that autoinflammatory complications are also seen within the spectrum of primary immune deficiencies, and resulting from a wider dysregulation of the immune responses.

At the population level, rheumatoid arthritis (RA) is generally viewed as autoimmune in nature with a small subgroup of cases having a palindromic form or systemic autoinflammatory disorder (SAID) phenotype. Herein, we describe resistant cases of classical autoantibody associated RA that had clinical, genetic and therapeutic responses indicative of coexistent autoinflammatory disease. Five patients with clinically overlapping features between RA and SAID including polysynovitis and autoantibody/shared epitope positivity, and who had abrupt severe self-limiting attacks including fevers and serositis, are described. Mutations or single nucleotide polymorphisms in recognised autoinflammatory pathways were evident. Generally, these cases responded poorly to conventional Disease-modifying anti-rheumatic drugs (DMARD) treatment with some excellent responses to colchicine or interleukin 1 pathway blockade. A subgroup of RA cases have a mixed autoimmune-autoinflammatory phenotype and genotype with therapeutic implications.

Capsule Summary 34 35 TTC7A deficiency typically causes severe gastrointestinal manifestations such as 36 multiple intestinal atresia or early onset inflammatory bowel disease. In some cases 37 this is associated with severe combined immunodeficiency. Partial loss-of-function 38 mutations appear to be associated with a milder phenotype resulting in common 39 variable immunodeficiency-like condition with enteropathy. 40 41 42 Key words: 43 44 TTC7A 45 CVID 46 Enteropathy 47 Manuscript Click here to download Manuscript Letter to Editor Correction_unmarked.docx Click here to view linked References 36 c4eqfA_ Alignment not modelled 99.9 17 PDB header:protein binding/transport protein Chain: A: PDB Molecule:pex5-related protein; PDBTitle: trip8b-1a#206-567 interacting with the carboxy-terminal seven residues2 of hcn2 37 c4jspA_ Alignment not modelled 99.9 16 PDB header:transferase Chain: A: PDB Molecule:serine/threonine-protein kinase mtor; PDBTitle: structure of mtordeltan-mlst8-atpgammas-mg complex 38 c3pe3D_ Alignment not modelled 99.9 18 PDB header:transferase Chain: D: PDB Molecule:udp-n-acetylglucosamine-peptide n-PDBTitle: structure of human o-glcnac transferase and its complex with a peptide2 substrate 39 c2uy1B_ Alignment not modelled 99.9 13 PDB header:rna-binding protein Chain: B: PDB Molecule:cleavage stimulation factor 77; PDBTitle: crystal structure of cstf-77 40 c3mkrA_ Alignment not modelled 99.9 12 PDB header:transport protein Chain: A: PDB Molecule:coatomer subunit epsilon; PDBTitle: crystal structure of yeast alpha/epsilon-cop subcomplex of the copi2 vesicular coat 41 d1dcea1 Alignment not modelled 99.9 10 Fold:alpha-alpha superhelix Superfamily:Protein prenylyltransferase Family:Protein prenylyltransferase 42 c3draA_ Alignment not modelled 99.9 10 PDB header:transferase Chain: A: PDB Molecule:protein PDBTitle: candida albicans protein geranylgeranyltransferase-i2 complexed with ggpp 43 d2h6fa1 Alignment not modelled 99.9 12 Fold:alpha-alpha superhelix Superfamily:Protein prenylyltransferase Family:Protein prenylyltransferase 44 c3v6tA_ Alignment not modelled 99.9 13 PDB header:dna binding protein/dna Chain: A: PDB Molecule:dhax3; PDBTitle: crystal structure of the dna-bound dhax3, a tal effector, at 1.852 angstrom 45 c4gpkI_ Alignment not modelled 99.9 13 PDB header:transcription, peptide binding protein Chain: I: PDB Molecule:nprr; PDBTitle: crystal structure of nprr in complex with its cognate peptide nprx 46 c4ynvA_ Alignment not modelled 99.9 15 PDB header:chaperone Chain: A: PDB Molecule:acl4; PDBTitle: assembly chaperone of rpl4 (acl4) (residues 28-338) 47 d1d8da_ Alignment not modelled 99.9 13 Fold:alpha-alpha superhelix Superfamily:Protein prenylyltransferase Family:Protein prenylyltransferase 48 c3uq3A_ Alignment not modelled 99.9 15 PDB header:chaperone Chain: A: PDB Molecule:heat shock protein sti1; PDBTitle: tpr2ab-domain:phsp90-complex of yeast sti1 49 c3jb9R_ Alignment not modelled 99.9 11 PDB header:rna binding protein/rna Chain: R: PDB Molecule:pre-mrna-splicing factor cwf4; PDBTitl...

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