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Infants with biallelic IL7R loss-of-function variants have severe combined immune deficiency (SCID) characterized by the absence of autologous T lymphocytes, but normal counts of circulating B and NK cells (T - B + NK + SCID). We report 6 adults (aged 22 to 59 years) from 4 kindreds and 3 ancestries (Colombian, Israeli Arab, Japanese) carrying homozygous IL7 loss-of-function variants resulting in combined immunodeficiency (CID). Deep immunophenotyping revealed relatively normal counts and/or proportions of myeloid, B, NK, and innate lymphoid cells. By contrast, the patients had profound T cell lymphopenia, with low proportions of innate-like adaptive mucosal-associated invariant T and invariant NK T cells. They also had low blood counts of T cell receptor (TCR) excision circles, recent thymic emigrant T cells and naive [CD4.sup.+] T cells, and low overall TCR repertoire diversity, collectively indicating impaired thymic output. The proportions of effector memory [CD4.sup.+] and [CD8.sup.+] T cells were high, indicating IL-7-independent homeostatic T cell proliferation in the periphery. Intriguingly, the proportions of other T cell subsets, including [TCR[gamma][delta].sup.+] T cells and some [TCR[alpha][beta].sup.+] T cell subsets (including Th1, Tfh, and Treg) were little affected. Peripheral [CD4.sup.+] T cells displayed poor proliferation, but normal cytokine production upon stimulation with mitogens in vitro. Thus, inherited IL-7 deficiency impairs T cell development less severely and in a more subset-specific manner than IL-7R deficiency. These findings suggest that another IL-7R-binding cytokine, possibly thymic stromal lymphopoietin, governs an IL-7-independent pathway of human T cell development., Introduction Genetic abnormalities of T lymphocyte-intrinsic development or function can underlie severe combined immunodeficiency (SCID), a life-threatening condition that is fatal unless treated by hematopoietic stem cell transplantation or gene [...]

We report two unrelated adults with homozygous (P1) or compound heterozygous (P2) private loss-of-function variants of V-Rel Reticuloendotheliosis Viral Oncogene Homolog B (RELB). The resulting deficiency of functional RelB impairs the induction of NFKB2 mRNA and NF-κB2 (p100/p52) protein by lymphotoxin in the fibroblasts of the patients. These defects are rescued by transduction with wild-type RELB complementary DNA (cDNA). By contrast, the response of RelB-deficient fibroblasts to Tumor Necrosis Factor (TNF) or IL-1β via the canonical NF-κB pathway remains intact. P1 and P2 have low proportions of naïve CD4+ and CD8+ T cells and of memory B cells. Moreover, their naïve B cells cannot differentiate into immunoglobulin G (IgG)- or immunoglobulin A (IgA)-secreting cells in response to CD40L/IL-21, and the development of IL-17A/F-producing T cells is strongly impaired in vitro. Finally, the patients produce neutralizing autoantibodies against type I interferons (IFNs), even after hematopoietic stem cell transplantation, attesting to a persistent dysfunction of thymic epithelial cells in T cell selection and central tolerance to some autoantigens. Thus, inherited human RelB deficiency disrupts the alternative NF-κB pathway, underlying a T- and B cell immunodeficiency, which, together with neutralizing autoantibodies against type I IFNs, confers a predisposition to viral, bacterial, and fungal infections. [ABSTRACT FROM AUTHOR]

Patients heterozygous for germline CBL loss-of-function (LOF) variants can develop myeloid malignancy, autoinflammation, or both, if some or all of their leukocytes become homozygous for these variants through somatic loss of heterozygosity (LOH) via uniparental isodisomy. We observed an upregulation of the inflammatory gene expression signature in whole blood from these patients, mimicking monogenic inborn errors underlying autoinflammation. Remarkably, these patients had constitutively activated monocytes that secreted 10 to 100 times more inflammatory cytokines than those of healthy individuals and CBL LOF heterozygotes without LOH. CBL-LOH hematopoietic stem and progenitor cells (HSPCs) outgrew the other cells, accounting for the persistence of peripheral monocytes homozygous for the CBL LOF variant. ERK pathway activation was required for the excessive production of cytokines by both resting and stimulated CBL-LOF monocytes, as shown in monocytic cell lines. Finally, we found that about 1 in 10,000 individuals in the UK Biobank were heterozygous for CBL LOF variants and that these carriers were at high risk of hematological and inflammatory conditions. [ABSTRACT FROM AUTHOR]

Background: Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by susceptibility to early-onset lifethreatening bacterial and fungal infections as well as dysregulated chronic inflammation. CGD results from mutations in one of the components of the phagocyte NADPH oxidase, a multimeric complex that consists of two membrane-bound components (gp91phox and p22phox) and 3 cytoplasmic subunits (p40phox, p47phox y p67phox) that function to induce reactive O2 species (ROS) in phagocytic cells to induce microbial killing. To date, only a single patient with granulomatous colitis and compound heterozygous mutations in NCF4 encoding p40phox has been reported as a genetic subgroup of CGD. Method: We performed whole exome-sequencing in a patient with earlyonset systemic histoplasmosis. Functional testing to Investigate phagocyte NADPH oxidase included dihydrorhodamine oxidation assay as well as amplex red and luminol. Protein expression was assessed by FACS and immunoblotting. Results: We found a missense homozygous variation in NCF4 within the phox homology (PX) domain, predicted to be damaging by polyphen and SIFT2 with a CADD score of 35. RT-PCR and immunoblotting demonstrated decreased p40phox protein expression protein both in neutrophils and EBV-transformed B cells from the patient, but not from controls. In addition, intracellular (IC) ROS production was significantly impaired after physiological stimulation with fMLP, Histoplasma capsulatum and Candida albicans on neutrophils and EBV-B, but not with phorbol 12-myristate 13-acetate (PMA). Conclusions: We report a novel homozygous mutation in NCF4 selectively impairing IC ROS production in a Colombian child. Remarkably, systemic histoplasmosis has not been previously reported in association with classical CGD, therefore our results expand the spectrum of genetic and infectious diseases underlying CGD in humans. [ABSTRACT FROM AUTHOR]

Background: The genetic etiology of several primary immunodeficiency diseases (PID) remains elusive. Next generation technologies represent a cost-effective and rapid first-line genetic approach for the evaluation of diseases underlying mendelian traits involved in PID which are characterized by a difficult and late diagnosis. Methods: In the PID group in Medellin (Colombia), up-today we have performed whole exome sequencing in 93 patients and relatives with severe phenotypes expecting for a gene causing disease underlying a PID. Results: From 93 WES analysis, gene causing disease have been identified in (n = 15/93) as follows: recurrent infections (n = 4/5, CYBB), BCGitis (n = 1/1, AR IL-12RB1), disseminated infection by Mycobacterium sp. (n = 1/7, AR IL-12RB1), BCGosis, salmonellosis, Mycobacterium tuberculosis and Klebsiella (n = 1, (PR)-IFNGR1), disseminated infection such as candidiasis (n = 5/5, AD-STAT1-GOF), histoplasmosis (n = 1/6, AR NCF4), invasive Corynespora cassiicola infection (n = 1/1, AR CARD9), recurrent infections and glomerulonephritis (n = 1/1, AR C3). Also, we have found several good candidate genes in a cohort of selective IgA deficiency (n = 2/23, PIK3CD, NFKB2), juvenile paracoccidioidomycosis (n = 3/3, IL17RA, IL18R1, PIK3CA) and finally, a cohort with impaired response against pneumococcal vaccines (n = 1/4, NFKBIA). We are performing further analysis in these candidate genes and exome reanalysis in the rest of patients. Conclusions: We analyzed 93 WES in patients and relatives with several PID phenotypes, we found gene causing defect (n = 15/93) from different cohort of PID patients. WES is emerging as a valuable tool to reach in a timely manner, a PID diagnosis with considerable potential to draw genotypephenotype correlation. [ABSTRACT FROM AUTHOR]

Background: In the world scientific literature, analytical research on tuberculosis has not been meta-analyzed. The objective of this study was to identify risk factors for tuberculosis infection with drug resistance and meta-analyze the causal relationship of prior antibiotic use., Methods: Systematic review with meta-analysis of case-control studies, in five databases. An ex ante, exhaustive and reproducible protocol of search and selection was applied; with criteria of inclusion, exclusion and evaluation of methodological quality. Were performed a qualitative and quantitative synthesis of the articles that evaluated the previous consumption of antibiotics. The PRISMA guide applied and a meta-analysis of random effects was performed for the odds ratios, with analysis of Galbraith, Funelt Plot, Forest plot and sensitivity analysis., Results: We included 36 articles for the qualitative synthesis and 16 in the meta-analysis. We found a wide heterogeneity in the risk factors that include sociodemographic characteristics such as age, sex, schooling, occupation and prison; Clinics as contact with infected, absence of BCG vaccine, hospitalization, chronic comorbidities, malnutrition, HIV coinfection; And microbiological variables such as infection by Beijing genotype and therapeutic adherence. In the studies that evaluated previous consumption of antibiotic, 1880 cases and 5291 controls were studied, most with moderate or low methodological quality, with a combined measure that shows that the odds of developing resistance in patients with previous antibiotic use are 12 (95% = 6.0-23.7) times found for the non-exposed, in the meta-regression the odds were 16.6 (95% CI = 4.1-67.8) for the moderate quality studies and 5.0 (95% CI = 2.9, 8.7) for those with high methodological quality., Conclusions: This meta-analysis revealed a strong causal association between the prior use of anti-tuberculosis antibiotics and drug-resistant Micobacterium tuberculosis infection.