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High Rates of Positive Severe Combined Immunodeficiency Screening Among Newborns with Severe Intestinal Failure.

February 26, 2020 By Manish Butte

High Rates of Positive Severe Combined Immunodeficiency Screening Among Newborns with Severe Intestinal Failure.

JPEN J Parenter Enteral Nutr. 2018 Jan;42(1):239-246

Authors: Fullerton BS, Velazco CS, Hong CR, Carey AN, Jaksic T

Abstract
PURPOSE: Severe combined immunodeficiency (SCID) screening by T-cell receptor excision circles (TREC) has been part of Massachusetts routine newborn screening since 2009. Tetratricopeptide repeat domain 7A gene (TTC7A) mutations responsible for hereditary multiple intestinal atresia with combined immunodeficiency (MIA-CID) were also recently identified. We reviewed newborn SCID screening among infants with intestinal failure and correlated results with patient characteristics and outcomes.
METHODS: Records of infants with severe intestinal failure and available newborn screen results treated at a single center 2009-2016 were reviewed retrospectively. Patients with 1 or more positive SCID screens (<252 TREC copies/μL) were compared with those without positive screens. TREC copies/μL were compared with population norms.
RESULTS: Of 70 included infants, 34% had newborn screens with TREC <252 copies/μL, compared with 0.3% of the general population; TREC levels for the cohort were lower than the general population (p<0.001). Of those with positive screens, 42% had prior or subsequent negative screening, 8% had no further workup, and 50% had flow cytometry showing: severe T-cell lymphopenia (absolute CD3+ <1500 cells/mcL) in 8, 3 of whom had TTC7A mutation-associated MIA-CID. Four had CD3+ >1500 cells/mcL. MIA-CID patients had the lowest serum citrulline in the cohort; 4 of the 8 patients with CD3+ <1500 cells/mcL on flow cytometry had newborn screening notable for severe hypocitrullinemia (<3 μM).
CONCLUSION: Infants with intestinal failure have lower TREC copies/μL than the general population; one-third had levels concerning for SCID, and 11% were diagnosed with severe T-cell lymphopenia. The clinical implications and etiology of this phenomenon remain unknown, but may be related to hypocitrullinemia.

PMID: 29505141 [PubMed – indexed for MEDLINE]

Unusual phenotype in patients with a hypomorphic mutation in the DCLRE1C gene: IgG hypergammaglobulinemia with IgA and IgE deficiency.

February 25, 2020 By Manish Butte

Unusual phenotype in patients with a hypomorphic mutation in the DCLRE1C gene: IgG hypergammaglobulinemia with IgA and IgE deficiency.

Clin Immunol. 2020 Feb 21;:108366

Authors: Nahum A, Somech R, Shubinsky G, Levy J, Broides A

Abstract
The nuclease Artemis is a enzyme for V(D)J recombination allowing for the creation of T and B lymphocytes as well as for the repair of radiation-induced DNA double strand breaks encoded by the DCLRE1C gene. Artemis-null mutations are a known cause of severe combined immunodeficiencies (SCIDs) with radiosensitivity. Hypomorphic mutations in Artemis have been reported to cause a “leaky SCID” phenotype, typically with hypogammaglobulinemia. We present four patients, all harboring the same unique hypomorphic mutation in the DCLRE1C gene, an 8-base pair insertion (c.1299_1306dup, p.Cys436*) presenting with a relatively mild phenotype including pulmonary infectious EBV-related lymphoproliferative diseases, an autoimmune phenomenon. Non-typical findings of IgG hypergammaglobulinemia accompanied by IgA and IgE deficiency were recorded in all patients. The typical viral, fungal, and opportunistic infections were absent, and patients reached a relatively old age.

PMID: 32092471 [PubMed – as supplied by publisher]

Gut microbiota in Mexican patients with common variable immunodeficiency.

February 25, 2020 By Manish Butte

Gut microbiota in Mexican patients with common variable immunodeficiency.

Gac Med Mex. 2019;155(5):447-452

Authors: Franco-Esquivias AP, Peña CG, Torres-Lozano C, Vaca-Paniagua F, Díaz-Velásquez C, Ortega-Cisneros M, Quintero-Ramos A

Abstract
Introduction: Common variable immunodeficiency (CVID) is the main symptomatic primary immunodeficiency and is associated with complex immune disorders. Gut microbiota interacts closely with the immune system, and intestinal dysbiosis is related to multiple diseases.
Objective: To describe for the first time the composition of gut microbiota in Mexican patients with CVID.
Methods: Fecal samples from five patients with CVID were collected and massive sequencing of the V3-V4 region of 16S rRNA gene was carried out using illumina technology.
Results: Bacterial relative abundance was observed at all taxonomic levels. Firmicutes, Actinobacteria and Verrucomicrobia were the predominant phyla. The Clostridia class and the Clostridial order were the most common in their respective taxon; the Ruminococcaceae family predominated. A total of 166 genera were reported, with the most abundant being Faecalibacterium. Five species were identified, but only Bifidobacterium longum was present in all patients.
Conclusions: Unlike healthy subjects’ gut microbiota, where Firmicutes and Bacteroidetes predominate, the microbiota of the patients with CVID considered in this study was abundant in Firmicutes, Actinobacteria and Verrucomicrobia. The low presence of Bacteroidetes and high abundance of Firmicutes might indicate the existence of intestinal dysbiosis in these patients.

PMID: 32091022 [PubMed – in process]

Neutralization capacity of highly divergent type 2 vaccine-derived polioviruses from immunodeficient patients.

February 25, 2020 By Manish Butte

Neutralization capacity of highly divergent type 2 vaccine-derived polioviruses from immunodeficient patients.

Vaccine. 2020 Feb 20;:

Authors: McDonald SL, Weldon WC, Wei L, Chen Q, Shaw J, Zhao K, Jorba J, Kew OM, Pallansch MA, Burns CC, Steven Oberste M

Abstract
The use of the oral poliovirus vaccine (OPV) in developing countries has reduced the incidence of poliomyelitis by >99% since 1988 and is the primary tool for global polio eradication. Spontaneous reversions of the vaccine virus to a neurovirulent form can impede this effort. In persons with primary B-cell immunodeficiencies, exposure to OPV can result in chronic infection, mutation, and excretion of immunodeficiency-associated vaccine-derived polioviruses, (iVDPVs). These iVDPVs may have the potential for transmission in a susceptible population and cause paralysis. The extent to which sera from OPV recipients are able to neutralize iVDPVs with varying degrees of antigenic site substitutions is investigated here. We tested sera from a population immunized with a combination vaccine schedule (both OPV and inactivated polio vaccine) against a panel of iVDPVs and found that increases in amino acid substitution in the P1 capsid protein resulted in a decrease in the neutralizing capacity of the sera. This study underscores the importance of maintaining high vaccine coverage in areas of OPV use as well as active surveillance of those known to be immunocompromised.

PMID: 32089462 [PubMed – as supplied by publisher]

Non-infectious granulomatous dermatoses.

February 25, 2020 By Manish Butte

Non-infectious granulomatous dermatoses.

J Dtsch Dermatol Ges. 2019 May;17(5):518-533

Authors: Schmitt A, Volz A

Abstract
Granulomatous dermatoses comprise a wide range of etiologically and clinically distinct skin diseases that share a common histology characterized by the accumulation of histiocytes include macrophages. While the pathogenesis of these disorders is not fully understood, the underlying mechanism is thought to involve a reaction pattern caused by an immunogenic stimulus. Antigen-presenting cells and the effect of various cytokines play a key role. Our understanding of granulomatous reaction patterns has been advanced by insights drawn from observations of such reactions in patients on immunomodulatory therapy and in individuals with genetic immunodeficiency. Traditionally, a distinction is made between infectious and non-infectious granulomatous dermatoses. The present CME article addresses granulomatous skin diseases for which there is no evidence of a causative infectious agent. Common representatives include granuloma annulare, necrobiosis lipoidica and cutaneous sarcoidosis. Granulomatous dermatoses may be part of the clinical spectrum of various systemic disorders or may be associated therewith. Some neoplastic disorders may mimic granulomatous dermatoses histologically. Given the pathogenetic diversity involved, the clinical presentation, too, is quite varied. Overall, however, each disorder is characterized by typical clinical features. The diagnosis always requires thorough clinicopathologic correlation. Treatment is preferably based on the underlying pathogenesis and frequently involves anti-inflammatory agents. In most cases, however, there is insufficient study data. The dermal nature of these disorders frequently poses a therapeutic challenge, especially with respect to topical treatment.

PMID: 31115996 [PubMed – indexed for MEDLINE]

Survival of human cadaver skin on severe combined immune deficiency pigs: Proof of concept.

February 25, 2020 By Manish Butte

Survival of human cadaver skin on severe combined immune deficiency pigs: Proof of concept.

Wound Repair Regen. 2019 07;27(4):426-430

Authors: Singer AJ, Tuggle C, Ahrens A, Sauer M, McClain SA, Tredget E, Rosenberg L

Abstract
Transplantation of human xenografts onto immunocompromised mice is a powerful research tool for studying wound healing. However, differences in healing between humans and mice and their small size limit this model. We determined whether human cadaver skin xenografts transplanted onto pigs with severe combined immune deficiency (SCID) would survive and not be rejected. Meshed (1:1.5), cryopreserved human cadaver skin was transplanted onto 10 partial thickness dermatome wounds in each of two normal domestic pigs and two SCID pigs. Autografts (n = 2/animal) from the four animals were used as controls. In normal pigs, all autografts were engrafted and healed with a minimal, if any, inflammation and scarring. All human xenografts were rejected by the normal pigs within 5-11 days and associated with an intense T-cell inflammatory response. In contrast, both autografts and xenografts were engrafted and survived the 28-day study in the SCID pigs with a minimal inflammation and no gross scarring.

PMID: 30843296 [PubMed – indexed for MEDLINE]

Genetic analysis in Egyptian patients with Chediak-Higashi syndrome reveals new LYST mutations.

February 25, 2020 By Manish Butte

Genetic analysis in Egyptian patients with Chediak-Higashi syndrome reveals new LYST mutations.

Clin Exp Dermatol. 2019 Oct;44(7):814-817

Authors: Gomaa NS, Lee JYW, El Sharkawy A, El Chazli YF, Hassab HMA, Doghaim NN, McGrath JA, Onoufriadis A

PMID: 30815890 [PubMed – indexed for MEDLINE]

Loss of ARHGEF1 causes a human primary antibody deficiency.

February 25, 2020 By Manish Butte

Icon for American Society for Clinical Investigation

Loss of ARHGEF1 causes a human primary antibody deficiency.

J Clin Invest. 2019 03 01;129(3):1047-1060

Authors: Bouafia A, Lofek S, Bruneau J, Chentout L, Lamrini H, Trinquand A, Deau MC, Heurtier L, Meignin V, Picard C, Macintyre E, Alibeu O, Bras M, Molina TJ, Cavazzana M, André-Schmutz I, Durandy A, Fischer A, Oksenhendler E, Kracker S

Abstract
ARHGEF1 is a RhoA-specific guanine nucleotide exchange factor expressed in hematopoietic cells. We used whole-exome sequencing to identify compound heterozygous mutations in ARHGEF1, resulting in the loss of ARHGEF1 protein expression in 2 primary antibody-deficient siblings presenting with recurrent severe respiratory tract infections and bronchiectasis. Both ARHGEF1-deficient patients showed an abnormal B cell immunophenotype, with a deficiency in marginal zone and memory B cells and an increased frequency of transitional B cells. Furthermore, the patients’ blood contained immature myeloid cells. Analysis of a mediastinal lymph node from one patient highlighted the small size of the germinal centers and an abnormally high plasma cell content. On the molecular level, T and B lymphocytes from both patients displayed low RhoA activity and low steady-state actin polymerization (even after stimulation of lysophospholipid receptors). As a consequence of disturbed regulation of the RhoA downstream target Rho-associated kinase I/II (ROCK), the patients’ lymphocytes failed to efficiently restrain AKT phosphorylation. Enforced ARHGEF1 expression or drug-induced activation of RhoA in the patients’ cells corrected the impaired actin polymerization and AKT regulation. Our results indicate that ARHGEF1 activity in human lymphocytes is involved in controlling actin cytoskeleton dynamics, restraining PI3K/AKT signaling, and confining B lymphocytes and myelocytes within their dedicated functional environment.

PMID: 30521495 [PubMed – indexed for MEDLINE]

Recurrent Campylobacter Enteritis in Patients with Hypogammaglobulinemia: Review of the Literature.

February 23, 2020 By Manish Butte

Recurrent Campylobacter Enteritis in Patients with Hypogammaglobulinemia: Review of the Literature.

J Clin Med. 2020 Feb 18;9(2):

Authors: Najjar I, Paluca F, Loukidis K, Tarr PE

Abstract
Recurrent Campylobacter enteritis is a well-recorded complication of primary hypogammaglobulinemia but has only rarely been reported with other types of immunodeficiency, and no cases have been reported after rituximab-associated secondary hypogammaglobulinemia. We therefore reviewed our local microbiology laboratory databases and conducted a literature search, to provide a detailed characterization of the immunodeficiency states associated with recurrent Campylobacter enteritis. Published cases had primary hypogammaglobulinemia, most frequently in the setting of common variable immunodeficiency, x-linked agammaglobulinemia, and Good syndrome. No cases were identified in the literature after rituximab or secondary hypogammaglobulinemia. We report a 73-year-old patient with recurrent Campylobacter enteritis and hypogammaglobulinemia in the setting of non-Hodgkin lymphoma, chemotherapy, and maintenance rituximab. Physicians should be aware of the association of recurrent Campylobacter enteritis and immunodeficiency, most commonly in primary hypogammaglobulinemia. Rituximab alone may not be sufficiently immunosuppressive for recurrent campylobacteriosis to occur; additional factors, including hematological malignancy and its treatment, appear necessary. Patients with recurrent Campylobacter enteritis and those starting rituximab should be investigated for hypogammaglobulinemia and B-lymphopenia.

PMID: 32085573 [PubMed – as supplied by publisher]

Structural insights into CpG-specific DNA methylation by human DNA methyltransferase 3B.

February 22, 2020 By Manish Butte

Structural insights into CpG-specific DNA methylation by human DNA methyltransferase 3B.

Nucleic Acids Res. 2020 Feb 21;:

Authors: Lin CC, Chen YP, Yang WZ, Shen JCK, Yuan HS

Abstract
DNA methyltransferases are primary enzymes for cytosine methylation at CpG sites of epigenetic gene regulation in mammals. De novo methyltransferases DNMT3A and DNMT3B create DNA methylation patterns during development, but how they differentially implement genomic DNA methylation patterns is poorly understood. Here, we report crystal structures of the catalytic domain of human DNMT3B-3L complex, noncovalently bound with and without DNA of different sequences. Human DNMT3B uses two flexible loops to enclose DNA and employs its catalytic loop to flip out the cytosine base. As opposed to DNMT3A, DNMT3B specifically recognizes DNA with CpGpG sites via residues Asn779 and Lys777 in its more stable and well-ordered target recognition domain loop to facilitate processive methylation of tandemly repeated CpG sites. We also identify a proton wire water channel for the final deprotonation step, revealing the complete working mechanism for cytosine methylation by DNMT3B and providing the structural basis for DNMT3B mutation-induced hypomethylation in immunodeficiency, centromere instability and facial anomalies syndrome.

PMID: 32083663 [PubMed – as supplied by publisher]