Mutations in PIGS, Encoding a GPI Transamidase, Cause a Neurological Syndrome Ranging from Fetal Akinesia to Epileptic Encephalopathy.

Inherited GPI deficiencies (IGDs) are a subset of congenital disorders of glycosylation that are increasingly recognized as a result of advances in whole-exome sequencing (WES) and whole-genome sequencing (WGS). IGDs cause a series of overlapping phenotypes consisting of seizures, dysmorphic features, multiple congenital malformations, and severe intellectual disability. We present a study of six individuals from three unrelated families in which WES or WGS identified bi-allelic phosphatidylinositol glycan class S (PIGS) biosynthesis mutations.

Mutations in GPAA1, Encoding a GPI Transamidase Complex Protein, Cause Developmental Delay, Epilepsy, Cerebellar Atrophy, and Osteopenia.

Approximately one in every 200 mammalian proteins is anchored to the cell membrane through a glycosylphosphatidylinositol (GPI) anchor. These proteins play important roles notably in neurological development and function. To date, more than 20 genes have been implicated in the biogenesis of GPI-anchored proteins.

A Novel PGM3 Mutation Is Associated With a Severe Phenotype of Bone Marrow Failure, Severe Combined Immunodeficiency, Skeletal Dysplasia, and Congenital Malformations.

Congenital disorders of glycosylation (CDGs) affect multiple systems and present a broad spectrum of clinical features, often including skeletal dysplasia. Exome sequencing has led to the identification of new CDG genes. Immune and skeletal phenotypes associated with mutations in PGM3, encoding a protein that converts N-acetyl-glucosamine-6-phosphate into N-acetyl-glucosamine-1-phosphate, were recently reported.

Compound heterozygous mutations in the gene PIGP are associated with early infantile epileptic encephalopathy.

There are over 150 known human proteins which are tethered to the cell surface via glycosylphosphatidylinositol (GPI) anchors. These proteins play a variety of important roles in development, and particularly in neurogenesis. Not surprisingly, mutations in the GPI anchor biosynthesis and remodeling pathway cause a number of developmental disorders.

Mutations in the phosphatidylinositol glycan C () gene are associated with epilepsy and intellectual disability.

Background: Of our 1400 exome-studied patients, 67% originate from consanguineous families. ∼80% suffer from variable degree of intellectual disability (ID). The search for disease causing genes using homozygosity mapping was progressing slowly until 2010, then markedly accelerated by the introduction of exome analysis.

Human mesenchymal stromal cell-secreted lactate induces M2-macrophage differentiation by metabolic reprogramming.

Human mesenchymal stromal cells (MSC) have been shown to dampen immune response and promote tissue repair, but the underlying mechanisms are still under investigation. Herein, we demonstrate that umbilical cord-derived MSC (UC-MSC) alter the phenotype and function of monocyte-derived dendritic cells (DC) through lactate-mediated metabolic reprogramming. UC-MSC can secrete large quantities of lactate and, when present during monocyte-to-DC differentiation, induce instead the acquisition of M2-macrophage features in terms of morphology, surface markers, migratory properties and antigen presentation capacity.

Variants in TRIM22 That Affect NOD2 Signaling Are Associated With Very-Early-Onset Inflammatory Bowel Disease.

Background & Aims: Severe forms of inflammatory bowel disease (IBD) that develop in very young children can be caused by variants in a single gene. We performed whole-exome sequence (WES) analysis to identify genetic factors that might cause granulomatous colitis and severe perianal disease, with recurrent bacterial and viral infections, in an infant of consanguineous parents.

Methods: We performed targeted WES analysis of DNA collected from the patient and her parents.

A case of C3 glomerulonephritis successfully treated with eculizumab.

Background: C3 glomerulonephritis (C3GN) is a rare form of glomerulopathy that is characterized by predominant C3 deposits. Eculizumab, a humanized monoclonal C5 antibody, has recently emerged as a treatment option for C3GN. We report a C3GN patient successfully treated with eculizumab.

Multiple intestinal atresia with combined immune deficiency related to TTC7A defect is a multiorgan pathology: study of a French-Canadian-based cohort.

Hereditary multiple intestinal atresia (HMIA) is a rare cause of intestinal obstruction in humans associated with a profound combined immune deficiency. Deleterious mutations of the tetratricopeptide repeat domain-7A (TTC7A) gene lead to HMIA, although the mechanism(s) causing the disease in TTC7A deficiency has (have) not yet been clearly identified. To evaluate the consequences of TTC7A deficiency, we studied the morphology of several organs from HMIA patients at different developmental stages, as well as the expression of the TTC7A protein.

ICON: the early diagnosis of congenital immunodeficiencies.

Primary immunodeficiencies are intrinsic defects in the immune system that result in a predisposition to infection and are frequently accompanied by a propensity to autoimmunity and/or immunedysregulation. Primary immunodeficiencies can be divided into innate immunodeficiencies, phagocytic deficiencies, complement deficiencies, disorders of T cells and B cells (combined immunodeficiencies), antibody deficiencies and immunodeficiencies associated with syndromes. Diseases of immune dysregulation and autoinflammatory disorder are many times also included although the immunodeficiency in these disorders are often secondary to the autoimmunity or immune dysregulation and/or secondary immunosuppression used to control these disorders.

Implication of different effector mechanisms by cord blood-derived and peripheral blood-derived cytokine-induced killer cells to kill precursor B acute lymphoblastic leukemia cell lines.

Background Aims: Cytokine-induced killer (CIK) cells ex vivo-expanded from cord blood (CB) or peripheral blood (PB) have been shown to be cytotoxic against autologous and allogeneic tumor cells. We have previously shown that CD56(+) CIK cells (CD3(+)CD56(+) and CD3(-)CD56(+)) are capable of killing precursor B-cell acute lymphoblastic leukemia (B-ALL) cell lines. However, the lytic pathways used by CD56(+) PB and CB-CIK cells to kill B-ALL cell lines have not been studied.

Invasive group A Streptococcus disease in French-Canadian children is not associated with a defect in MyD88/IRAK4-pathway.

Background: Beta-hemolytic Group A Streptococcus invasive disease (iGASd) has been subject to intense research since its re-emergence in the late 1980s. In Quebec, an increase in the number of severe iGASd cases has recently been observed. Because of the inter-individual variability in the severity of iGASd, a hereditary predisposition to invasive disease can be suspected.

Whole-exome sequencing reveals a rapid change in the frequency of rare functional variants in a founding population of humans.

Whole-exome or gene targeted resequencing in hundreds to thousands of individuals has shown that the majority of genetic variants are at low frequency in human populations. Rare variants are enriched for functional mutations and are expected to explain an important fraction of the genetic etiology of human disease, therefore having a potential medical interest. In this work, we analyze the whole-exome sequences of French-Canadian individuals, a founder population with a unique demographic history that includes an original population bottleneck less than 20 generations ago, followed by a demographic explosion, and the whole exomes of French individuals sampled from France.

Cord blood-derived and peripheral blood-derived cytokine-induced killer cells are sensitive to Fas-mediated apoptosis.

Fas-mediated apoptosis is one of the mechanisms used by tumor cells to escape the cytotoxicity of tumor-infiltrating lymphocytes. It has been suggested that cytokine-induced killer (CIK) cells are resistant to Fas-mediated apoptosis, thereby rendering them more attractive for use in cellular immunotherapy. Unlike what was observed by others, here we show that CIK cells are sensitive to Fas-mediated apoptosis.

A homozygous mucosa-associated lymphoid tissue 1 (MALT1) mutation in a family with combined immunodeficiency.

Background: Combined immunodeficiency (CID) is characterized by severe recurrent infections with normal numbers of T and B lymphocytes but with deficient cellular and humoral immunity. Most cases are sporadic, but autosomal recessive inheritance has been described. In most cases, the cause of CID remains unknown.

Exome sequencing identifies mutations in the gene TTC7A in French-Canadian cases with hereditary multiple intestinal atresia.

Background: Congenital multiple intestinal atresia (MIA) is a severe, fatal neonatal disorder, involving the occurrence of obstructions in the small and large intestines ultimately leading to organ failure. Surgical interventions are palliative but do not provide long-term survival. Severe immunodeficiency may be associated with the phenotype.

Fatal Mycobacterium colombiense/cytomegalovirus coinfection associated with acquired immunodeficiency due to autoantibodies against interferon gamma: a case report.

Background: Reports of acquired immunodeficiency due to autoantibodies against interferon gamma in the adult population are increasing. The interleukin-12-dependent interferon-gamma axis is a major regulatory pathway of cell-mediated immunity and is critical for protection against a few intracellular organisms, including non-tuberculous mycobacteria and Salmonella spp. We report the first case of a fatal disseminated Mycobacterium colombiense/cytomegalovirus coinfection in an adult woman associated with the acquisition of autoantibodies against interferon-gamma.

Inflammatory bowel disease and T cell lymphopenia in G6PC3 deficiency.

Purpose: G6PC3 deficiency presents as a complex and heterogeneous syndrome that classically associates severe congenital neutropenia with cardiac and urogenital developmental defects. Here we investigate the findings of T cell lymphopenia and inflammatory bowel disease in a child with G6PC3 deficiency due to compound heterozygous mutations in intron 3 (c.IVS3-1 G>A) and exon 6 (c.

Cord-blood-derived mesenchymal stromal cells downmodulate CD4+ T-cell activation by inducing IL-10-producing Th1 cells.

The mechanisms by which mesenchymal stromal cells (MSCs) induce immunomodulation are still poorly understood. In the current work, we show by a combination of polymerase chain reaction (PCR) array, flow cytometry, and multiplex cytokine data analysis that during the inhibition of an alloantigen-driven CD4+ T-cell response, MSCs induce a fraction of CD4+ T-cells to coexpress interferon-γ (IFNγ) and interleukin-10 (IL-10). This CD4+ IFNγ+ IL-10+ cell population shares properties with recently described T-cells originating from switched Th1 cells that start producing IL-10 and acquire a regulatory function.

Reconstitution of maturating and regulatory lymphocyte subsets after cord blood and BMT in children.

Some clinical characteristics of cord blood transplantation (CBT) might be explained by specificities in the reconstitution of immune subsets differing by their maturation stage or their implication in GVHD, tolerance or immune responses against tumor or infectious agents. Here, we compare the immune reconstitution of several of these subsets after CBT and BMT. B-cell count recovery was faster after CBT.

Reconstitution of protective immune responses against cytomegalovirus and varicella zoster virus does not require disease development in pediatric recipients of umbilical cord blood transplantation.

CMV and varicella zoster virus (VZV) are significant causes of morbidity and mortality following umbilical cord blood transplantation (UCBT). However, the kinetics of reconstitution and protective potential of antiviral cell-mediated immune responses following UCBT remain poorly characterized. In this study, the reconstitution of CMV- and VZV-specific T cell responses was assessed using IFN-γ ELISPOT in 28 children who underwent UCBT to treat hematological or inherited disorders.

Human interferon-alpha increases the cytotoxic effect of CD56(+) cord blood-derived cytokine-induced killer cells on human B-acute lymphoblastic leukemia cell lines.

Background Aims: Cytokine-induced killer (CIK) cells may represent a promising immunotherapy for the treatment of children with relapsing B-lineage acute lymphoblastic leukemia (B-ALL) following hematopoietic stem cell transplantation (HSCT). Therefore, we investigated the possibility of combining adoptive immunotherapy with CIK cells and human interferon-alpha (hIFN-α) in order to potentiate the cytotoxicity of CIK cells against B-ALL.

Methods: Cord blood- derived CIK (CB-CIK) cells were differentiated, stimulated with phosphate-buffered saline (PBS) or hIFN-α, and tested for cytotoxic activity.

Ataxia-telangiectasia presenting with a novel immunodeficiency.

Ataxia-telangiectasia is a rare autosomal recessive disorder characterized by progressive cerebellar ataxia, oculocutaneous telangiectasias, and variable degrees of immunodeficiency. Immunologic evaluations of affected patients often reveal anomalies of humoral and cell-mediated immunity. We describe a case of ataxia-telangiectasia with an atypical immunodeficiency and a novel mutation in the ATM gene.