Research

WHIM syndrome: Immunopathogenesis, treatment and cure strategies.

Immunol Rev. 2019 Jan;287(1):91-102

Authors: McDermott DH, Murphy PM

Abstract
WHIM syndrome is a rare, autosomal dominant immunodeficiency which is named for the four key manifestations: Warts, Hypogammaglobulinemia, Infections, and Myelokathexis. It results from heterozygous gain-of-function mutations in the chemokine receptor CXCR4 which is widely expressed on leukocytes and has profound influences on immune system homeostasis and organogenesis. New treatments for the disease using drugs to reduce CXCR4 function are excellent examples of precision medicine. Since CXCR4 and its ligand CXCL12 play an important role in a variety of infectious, inflammatory, autoimmune, and malignant diseases, the study of WHIM syndrome provides important insights into both the physiologic and disease roles of these molecules.

PMID: 30565238 [PubMed – in process]

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CHAPLE syndrome uncovers the primary role of complement in a familial form of Waldmann’s disease.

Immunol Rev. 2019 Jan;287(1):20-32

Authors: Ozen A

Abstract
Primary intestinal lymphangiectasia (PIL) or Waldmann’s disease was described in 1961 as an important cause of protein-losing enteropathy (PLE). PIL can be the sole finding in rare individuals or occur as part of a multisystemic genetic syndrome. Although genetic etiologies of many lymphatic dysplasia syndromes associated with PIL have been identified, the pathogenesis of isolated PIL (with no associated syndromic features) remains unknown. Familial cases and occurrence at birth suggest genetic etiologies in certain cases. Recently, CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and PLE (the CHAPLE syndrome) has been identified as a monogenic form of PIL. Surprisingly, loss of CD55, a key regulator of complement system leads to a predominantly gut condition. Similarly to other complement disorders, namely paroxysmal nocturnal and hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS), CHAPLE disease involves pathogenic cross-activation of the coagulation system, predisposing individuals to severe thrombosis. The observation that complement system is overly active in CHAPLE disease introduced a novel concept into the management of PLE; anti-complement therapy. While CD55 deficiency constitutes a treatable subgroup in the larger pool of patients with isolated PIL, the etiology remains to be identified in the remaining patients with intact CD55.

PMID: 30565236 [PubMed – in process]

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An unusual presentation of a patient with severe hypogammaglobulinemia.

Clin Case Rep. 2018 Dec;6(12):2416-2423

Authors: Hoffman TW, van Kessel DA, van Tol MJD, Vidarsson G, Jol-van der Zijde EC, Rijkers GT, van Velzen-Blad H

Abstract
We present a patient who was diagnosed with severe hypogammaglobulinemia after her newborn child presented with two episodes of meningitis. The patient had no history or symptoms suggestive of immunodeficiency. Thus far, a cause for the immunodeficiency has not been found, even after extensive immunological evaluation.

PMID: 30564340 [PubMed]

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Life-Threatening Primary Varicella Zoster Virus Infection With Hemophagocytic Lymphohistiocytosis-Like Disease in GATA2 Haploinsufficiency Accompanied by Expansion of Double Negative T-Lymphocytes.

Front Immunol. 2018;9:2766

Authors: Prader S, Felber M, Volkmer B, Trück J, Schwieger-Briel A, Theiler M, Weibel L, Hambleton S, Seipel K, Vavassori S, Pachlopnik Schmid J

Abstract
Two unrelated patients with GATA2-haploinsufficiency developed a hemophagocytic lymphohistiocytosis (HLH)-like disease during a varicella zoster virus (VZV) infection. High copy numbers of VZV were detected in the blood, and the patients were successfully treated with acyclovir and intravenous immunoglobulins. After treatment with corticosteroids for the HLH, both patients made a full recovery. Although the mechanisms leading to this disease constellation have yet to be characterized, we hypothesize that impairment of the immunoregulatory role of NK cells in GATA2-haploinsufficiency may have accentuated the patients’ susceptibility to HLH. Expansion of a double negative T-lymphocytic population identified with CyTOF could be a further factor contributing to HLH in these patients. This is the first report of VZV-triggered HLH-like disease in a primary immunodeficiency and the third report of HLH in GATA2-haploinsufficiency. Since HLH was part of the presentation in one of our patients, GATA2-haploinsufficiency represents a potential differential diagnosis in patients presenting with the clinical features of HLH-especially in cases of persisting cytopenia after recovery from HLH.

PMID: 30564229 [PubMed – in process]

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Rapid Multiplexed Proteomic Screening for Primary Immunodeficiency Disorders From Dried Blood Spots.

Front Immunol. 2018;9:2756

Authors: Collins CJ, Chang IJ, Jung S, Dayuha R, Whiteaker JR, Segundo GRS, Torgerson TR, Ochs HD, Paulovich AG, Hahn SH

Abstract
Background: Primary immunodeficiency disorders (PIDD) comprise a group of life-threatening congenital diseases characterized by absent or impaired immune responses. Despite the fact that effective, curative treatments are available with optimal clinical outcomes when diagnosed early, newborn screening does not exist for the majority of these diseases due to the lack of detectable, specific biomarkers or validated methods for population-based screening. Peptide immunoaffinity enrichment coupled with selected reaction monitoring mass spectrometry (immuno-SRM) is a sensitive proteomic assay, involving antibody-mediated peptide capture, that allows for concurrent quantification of multiple analytes. This assay has promise for use in potential newborn screening of PIDDs that lead to diminished or absent target proteins in the majority of cases. Objective: To determine and evaluate if a multiplex assay based on immuno-SRM is able to reliably and precisely distinguish affected patients with X-linked agammaglobulinemia (XLA), Wiskott-Aldrich Syndrome (WAS), and CD3ϵ-associated severe combined immunodeficiency (SCID) from one another and from unaffected normal control dried blood spot (DBS) samples. Methods: We performed a blinded, multiplexed analysis of proteolytically-generated peptides from WASp, BTK, and CD3ϵ (for WAS, XLA, and SCID, respectively) in DBS samples from 42 PIDD patients, 40 normal adult controls, and 62 normal newborns. The peptide ATPase copper transporting protein (ATP7B) 1056 was simultaneously monitored for quality assurance purposes. Results: The immuno-SRM assays reliably quantified the target peptides in DBS and accurately distinguished affected patients from normal controls. Analysis of signature peptides found statistically significant reduction or absence of peptide levels in affected patients compared to control groups in each case (WASp and BTK: p = 0.0001, SCID: p = 0.05). Intra and inter-assay precision ranged from 11 to 22% and 11 to 43% respectively; linearity (1.39-2000 fmol peptide), and stability (≤ 0.09% difference in 72 h) showed high precision for the multiplexed assay. Inter-laboratory assay comparison showed high concordance for measured peptide concentrations, with R2 linearity ≥ 0.97 for the WASp 274, CD3ϵ 197, BTK 407, and ATP7B 1056 peptides. Conclusion: Immuno-SRM-based quantification of proteotypic peptides from WASp, BTK, and CD3ϵ in DBS distinguishes relevant PIDD cases from one another and from controls, raising the possibility of employing this approach for large-scale multiplexed newborn screening of selective PIDDs.

PMID: 30564228 [PubMed – in process]

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Concomitant diagnosis of immune deficiency and Pseudomonas sepsis in a 19 month old with ecthyma gangrenosum by host whole-genome sequencing.

Cold Spring Harb Mol Case Stud. 2018 Dec;4(6):

Authors: Sanford E, Farnaes L, Batalov S, Bainbridge M, Laubach S, Worthen HM, Tokita M, Kingsmore SF, Bradley J

Abstract
X-linked agammaglobulinemia (XLA, OMIM#300300) is a rare monogenic primary immunodeficiency caused by mutations in the Bruton tyrosine kinase (BTK) gene. XLA is characterized by insufficient immunoglobulin levels and susceptibility to life-threatening bacterial infections. We report on a patient that presented with ecthyma gangrenosum and septicemia. Rapid trio whole-genome sequencing (rWGS) revealed an apparently de novo hemizygous pathogenic variant (c.726dupT; p.Ile243TyrfsTer15) in the BTK gene. Metagenomic analysis of rWGS sequences that did not align to the human genome revealed 770 aligned to the Pseudomonas aeruginosa PAO1 genome. The patient was diagnosed with XLA and pseudomonal sepsis.

PMID: 30559311 [PubMed – in process]

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Gene co-expression networks from RNA sequencing of dairy cattle identifies genes and pathways affecting feed efficiency.

BMC Bioinformatics. 2018 Dec 17;19(1):513

Authors: Salleh SM, Mazzoni G, Løvendahl P, Kadarmideen HN

Abstract
BACKGROUND: Selection for feed efficiency is crucial for overall profitability and sustainability in dairy cattle production. Key regulator genes and genetic markers derived from co-expression networks underlying feed efficiency could be included in the genomic selection of the best cows. The present study identified co-expression networks associated with high and low feed efficiency and their regulator genes in Danish Holstein and Jersey cows. RNA-sequencing data from Holstein and Jersey cows with high and low residual feed intake (RFI) and treated with two diets (low and high concentrate) were used. Approximately 26 million and 25 million pair reads were mapped to bovine reference genome for Jersey and Holstein breed, respectively. Subsequently, the gene count expressions data were analysed using a Weighted Gene Co-expression Network Analysis (WGCNA) approach. Functional enrichment analysis from Ingenuity® Pathway Analysis (IPA®), ClueGO application and STRING of these modules was performed to identify relevant biological pathways and regulatory genes.
RESULTS: WGCNA identified two groups of co-expressed genes (modules) significantly associated with RFI and one module significantly associated with diet. In Holstein cows, the salmon module with module trait relationship (MTR) = 0.7 and the top upstream regulators ATP7B were involved in cholesterol biosynthesis, steroid biosynthesis, lipid biosynthesis and fatty acid metabolism. The magenta module has been significantly associated (MTR = 0.51) with the treatment diet involved in the triglyceride homeostasis. In Jersey cows, the lightsteelblue1 (MTR = - 0.57) module controlled by IFNG and IL10RA was involved in the positive regulation of interferon-gamma production, lymphocyte differentiation, natural killer cell-mediated cytotoxicity and primary immunodeficiency.
CONCLUSION: The present study provides new information on the biological functions in liver that are potentially involved in controlling feed efficiency. The hub genes and upstream regulators (ATP7b, IFNG and IL10RA) involved in these functions are potential candidate genes for the development of new biomarkers. However, the hub genes, upstream regulators and pathways involved in the co-expressed networks were different in both breeds. Hence, additional studies are required to investigate and confirm these findings prior to their use as candidate genes.

PMID: 30558534 [PubMed – in process]

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Differentiation of Common Variable Immunodeficiency from Igg Deficiency.

J Allergy Clin Immunol Pract. 2018 Dec 14;:

Authors: Filion CA, Taylor-Black S, Maglione PJ, Radigan L, Cunningham-Rundles C

Abstract
BACKGROUND: Common variable immunodeficiency (CVID) and IgG deficiency are two of the more prevalent primary humoral immune defects. Whereas the former is defined by consensus with criteria for quantitative and qualitative antibody defects, the latter is used to describe patients with reduced IgG, who commonly have recurrent sinopulmonary infections but do not fulfill CVID criteria. However, these patients are often given this diagnosis.
OBJECTIVE: We compared immunological findings and clinical manifestations of two large cohorts of patients with CVID or IgG deficient to better delineate differences between those syndromes.
METHODS: We extracted clinical and laboratory data from electronic medical records of patients at our institution who had received International Classification of Disease codes for either CVID, or IgG deficiency. We gathered immunoglobulin levels, lymphocyte sub-population counts, and serological vaccine responses. In some patients, we performed flow cytometry to determine percentages of memory and switched-memory B cells. We compiled and statistically compared clinical data related to infectious manifestations, bronchiectasis, autoimmune diseases, infiltrative inflammatory processes and lymphoid malignancies.
RESULTS: In contrast to IgG deficient patients, we found that CVID patients had lower IgG levels, greater unresponsiveness to most vaccines, lower percentages of memory and isotype switched-memory B cells, and lower CD4 T cell counts. Clinically, CVID patients presented similar rates of sinusitis and pneumonias, but a significantly higher prevalence of bronchiectasis and especially non-infectious complications.
CONCLUSION: CVID and IgG deficiency do not share the same disease spectrum, the former being associated with immunodysregulative manifestations and markers of a more severe immune defect. These data may allow clinicians to distinguish these conditions and the management differences that these patients pose.

PMID: 30557717 [PubMed – as supplied by publisher]

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Efficacy of Ruxolitinib Therapy in a Patient with Severe Enterocolitis Associated with a STAT3 Gain of Function Mutation.

Gastroenterology. 2018 Dec 14;:

Authors: Parlato M, Charbit-Henrion F, Nader EA, Begue B, Guegan N, Bruneau J, Khater S, Macintyre E, Picard C, Rieux-Laucat F, Le Bourhis L, Allez M, Goulet O, Cellier C, Hermine O, Cerf-Bensussan N, Malamut G

PMID: 30557559 [PubMed – as supplied by publisher]

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Central Nervous System Involvement in Common Variable Immunodeficiency: A Case of Acute Unilateral Optic Neuritis in a 26-Year-Old Italian Patient.

Front Neurol. 2018;9:1031

Authors: Abati E, Faravelli I, Magri F, Govoni A, Velardo D, Gagliardi D, Mauri E, Brusa R, Bresolin N, Fabio G, Comi GP, Carrabba M, Corti S

Abstract
Common Variable Immunodeficiency (CVID) is a group of heterogeneous primary immunodeficiencies sharing defective B lymphocytes maturation and dysregulated immune response and resulting in impaired immunoglobulin production. Clinical picture encompasses increased susceptibility to infections, hematologic malignancies, inflammatory, and autoimmune diseases. Neurological manifestations are uncommon and optic neuritis has been previously reported only in one case with bilateral involvement. We hereby report a case of a 26-year-old man affected by CVID undergoing regular immunoglobulin supplementation, who presented with acute unilateral demyelinating optic neuritis and lymphocytic pleocytosis in the cerebrospinal fluid. A variety of infectious, inflammatory, and neoplastic conditions were excluded and a diagnosis of clinically isolated optic neuritis was made. The patient was treated with a short course of intravenous steroids with complete recovery. Overall, this case expands our current knowledge about clinical spectrum of complications in CVID and highlights the need for further research about this complex disease.

PMID: 30555409 [PubMed]

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