A 4-Year-Old Boy With Prolonged Cough and Fever.
J Pediatric Infect Dis Soc. 2020 Jan 22;:
Authors: Handel AS, Davis J, Glass J, Hogan L, Schuval S, Beneri C
PMID: 31967647 [PubMed – as supplied by publisher]
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Allotype-specific processing of the CD16a N45-glycan from primary human natural killer cells and monocytes.
Allotype-specific processing of the CD16a N45-glycan from primary human natural killer cells and monocytes.
Glycobiology. 2020 Jan 21;:
Authors: Patel KR, Roberts JT, Barb AW
Abstract
Fc γ receptor IIIa/CD16a is an activating cell surface receptor with a well-defined role in NK cell and monocyte effector function. The extracellular domain is decorated with five asparagine (N)-linked glycans; N-glycans at N162 and N45 directly contribute to high affinity antibody binding and protein stability. N-glycan structures at N162 showed significant donor-dependent variation in a recent study of CD16a isolated from primary human natural killer (NK) cells, but structures at N45 were relatively homogeneous. In this study we identified variations in N45 glycan structures associated with a polymorphism coding for histidine instead of leucine at position 48 of CD16a from two heterozygous donors. It is known that H48 homozygous individuals suffer from immunodeficiency and recurrent viral infections. An ESI-MS/MS analysis of protein isolated from the primary natural killer cells of individuals expressing both CD16a L48 and H48 variants demonstrated clear processing differences at N45. CD16a H48 displayed a greater proportion of complex-type N45 glycans compared to the more common L48 allotype with predominantly hybrid N45-glycoforms. Structures at the four other N-glycosylation sites showed minimal differences from a data collected on donors expressing only predominant L48 variant. CD16a H48 purified from a pool of monocytes similarly displayed increased processing at N45. Here we provide evidence that CD16a processing is affected by the H48 residue in primary NK cells and monocytes from healthy human donors.
PMID: 31967297 [PubMed – as supplied by publisher]
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“Clinical Aspects of Chronic Granulomatous Disease in Upper Egypt”.
“Clinical Aspects of Chronic Granulomatous Disease in Upper Egypt”.
Immunol Invest. 2020 Jan 22;:1-13
Authors: El-Mokhtar MA, Salama EH, Fahmy EM, Mohamed ME
Abstract
Chronic granulomatous disease (CGD) is a rare inherited primary immunodeficiency disorder that affects phagocytes and is characterized by a marked increased susceptibility to severe bacterial and fungal infections. We aimed to describe the clinical presentations of pediatric patients with CGD in Upper Egypt and to identify the defective component of NADPH oxidase. Pediatric patients diagnosed with CGD within one year from January 2018 to January 2019 were enrolled in the study. Patient history, clinical and laboratory investigations were carried out, including nitroblue tetrazolium test and flow cytometry DHR analysis. Infectious microorganisms were isolated from infected sites to identify the causative agents and their resistance profile. A total of 15 patients were diagnosed with CGD. Failure to thrive and lymphadenopathy were the most common presentations. The median age of clinical onset was 1.17 years of age. The most common gene mutations were observed in the CYBA gene. All cases showed pulmonary infections followed by abscesses. Staphylococcus aureus and Klebsiella pneumoniae were the most frequently isolated bacterial pathogens, Aspergillus spp and Candida spp were isolated from fungal infections. 4/15 (26.7%) children died due to severe serious infections. We concluded that CGD is common in Upper Egypt, and we recommend raising the awareness and testing for CGD in pediatric patients with recurrent or persistent infections, especially those with a familiar history of similar manifestations to avoid delays in proper diagnosis and deterioration of cases.Abbreviations: CGD: chronic granulomatous disease; XL: X-linked; AR: autosomal recessive.
PMID: 31965875 [PubMed – as supplied by publisher]
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T Cell Impairment Is Predictive for a Severe Clinical Course in NEMO Deficiency.
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T Cell Impairment Is Predictive for a Severe Clinical Course in NEMO Deficiency.
J Clin Immunol. 2020 Jan 21;:
Authors: Heller S, Kölsch U, Magg T, Krüger R, Scheuern A, Schneider H, Eichinger A, Wahn V, Unterwalder N, Lorenz M, Schwarz K, Meisel C, Schulz A, Hauck F, von Bernuth H
Abstract
PURPOSE: NEMO-deficient patients present with variable degrees of immunodeficiency. Accordingly, treatment ranges from antibiotic prophylaxis and/or IgG-substitution to allogenic hematopoietic stem cell transplantation (HSCT). The correct estimation of the immunodeficiency is essential to avoid over- as well as under-treatment. We compare the immunological phenotype of a NEMO-deficient patient with a newly-described splice site mutation that causes truncation of the NEMO zinc-finger (ZF) domain and a severe clinical course with the immunological phenotype of three NEMO-deficient patients with missense mutations and milder clinical courses and all previously published patients.
METHODS: Lymphocyte subsets, proliferation, and intracellular NEMO-expression were assessed by FACS. NF-κB signal transduction was determined by measuring IκBα-degradation and the production of cytokines upon stimulation with TNF-α, IL-1β, and TLR-agonists in immortalized fibroblasts and whole blood, respectively.
RESULTS: The patient with truncated ZF-domain of NEMO showed low levels of IgM and IgG, reduced class-switched memory B cells, almost complete skewing towards naïve CD45RA+ T cells, impaired T cell proliferation as well as cytokine production upon stimulation with TNF-α, IL-1β, and TLR-agonists. He suffered from severe infections (sepsis, pneumonia, osteomyelitis) during infancy. In contrast, three patients with missense mutations in IKBKG presented neither skewing of T cells towards naïvety nor impaired T cell proliferation. They are stable on prophylactic IgG-substitution or even off any prophylactic treatment.
CONCLUSION: The loss of the ZF-domain and the impaired T cell proliferation accompanied by almost complete persistence of naïve T cells despite severe infections are suggestive for a profound immunodeficiency. Allogenic HSCT should be considered early for these patients before chronic sequelae occur.
PMID: 31965418 [PubMed – as supplied by publisher]
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Complement deficiencies and dysregulation: Pathophysiological consequences, modern analysis, and clinical management.
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Complement deficiencies and dysregulation: Pathophysiological consequences, modern analysis, and clinical management.
Mol Immunol. 2019 10;114:299-311
Authors: Schröder-Braunstein J, Kirschfink M
Abstract
Complement defects are associated with an enhanced risk of a broad spectrum of infectious as well as systemic or local inflammatory and thrombotic disorders. Inherited complement deficiencies have been described for virtually all complement components but can be mimicked by autoantibodies, interfering with the activity of specific complement components, convertases or regulators. While being rare, diseases related to complement deficiencies are often severe with a frequent but not exclusive manifestation during childhood. Whereas defects of early components of the classical pathway significantly increase the risk of autoimmune disorders, lack of components of the terminal pathway as well as of properdin are associated with an enhanced susceptibility to meningococcal infections. The impaired synthesis or function of C1 inhibitor results in the development of hereditary angioedema (HAE). Furthermore, complement dysregulation causes renal disorders such as atypical hemolytic uremic syndrome (aHUS) or C3 glomerulopathy (C3G) but also age-related macular degeneration (AMD). While paroxysmal nocturnal hemoglobinuria (PNH) results from the combined deficiency of the regulatory complement proteins CD55 and CD59, which is caused by somatic mutation of a common membrane anchor, isolated CD55 or CD59 deficiency is associated with the CHAPLE syndrome and polyneuropathy, respectively. Here, we provide an overview on clinical disorders related to complement deficiencies or dysregulation and describe diagnostic strategies required for their comprehensive molecular characterization – a prerequisite for informed decisions on the therapeutic management of these disorders.
PMID: 31421540 [PubMed – indexed for MEDLINE]
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Primary Immunodeficiency with Severe Multi-Organ Immune Dysregulation.
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Primary Immunodeficiency with Severe Multi-Organ Immune Dysregulation.
Case Reports Immunol. 2019;2019:8746249
Authors: Gavrilova T
Abstract
Polyglandular autoimmune syndrome type 1, also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), is a rare primary immunodeficiency disorder with multi-organ involvement. Besides for being predisposed to severe life-threatening infections, patients with APECED are also prone to organ impairment secondary to severe autoimmunity. As this is an autosomal recessive disorder, a biallelic mutation in the AIRE gene is responsible for APECED. The author presents a case of APECED with a single AIRE mutation. Whole exome sequencing identified a mutation in the BTNL2 gene that the author suggests may have contributed to the patient’s presentation.
PMID: 31956453 [PubMed]
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Fatal Hypogammaglobulinemia 3 Years after Rituximab in a Patient with Immune Thrombocytopenia: An Underlying Genetic Predisposition?
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Fatal Hypogammaglobulinemia 3 Years after Rituximab in a Patient with Immune Thrombocytopenia: An Underlying Genetic Predisposition?
Case Reports Immunol. 2019;2019:2543038
Authors: Viallard JF, Parrens M, Rieux-Laucat F
Abstract
We report the case of a young woman who developed, 3 years after stopping Rituximab (RTX) prescribed for immune thrombocytopenia (ITP), a severe immunodeficiency leading to fatal pulmonary Epstein-Barr virus-positive diffuse large B-cell lymphoma. Genetic analysis led us to identify four missense mutations known to affect immune-deficiency-associated genes (FAS-ligand (FASL) gene (p.G167R); perforin-1 (PRF1 (p.R55C) gene; the Bloom syndrome RecQ-Like helicase (BLM) gene and the Moesin (MSN) (p.A122T) gene). The heterozygous mutation in the FASL gene, not present in the Genome Aggregation Database or ClinVar database, could suggest atypical Autoimmune LymphoProliferative Syndrome and its role in this patient’s immunodepression is discussed. This observation strengthens the role of FASL gene mutation in severe clinical phenotypes of primary immune deficiency and raises new questions about the genetic background of ITP occurring in young people in a context of immunodeficiency.
PMID: 31956452 [PubMed]
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Acquired C1-inhibitor deficiency presenting with nephrotic syndrome.
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Acquired C1-inhibitor deficiency presenting with nephrotic syndrome.
BMJ Case Rep. 2019 Jul 11;12(7):
Authors: Willows J, Wood K, Bourne H, Sayer JA
Abstract
Acquired C1-inhibitor (C1-INH) deficiency is a rare and potentially life-threatening disorder, which presents with recurrent attacks of non-pitting oedema to the face, airway, limbs or gastrointestinal tract. It is often associated with underlying B-cell lymphoproliferative disorders. We describe a case of a 73-year-old man with acquired C1-INH deficiency who presented with nephrotic syndrome due to glomerular IgM deposition, secondary to an underlying secretory lymphoplasmacytic lymphoma. Both the acquired C1-INH deficiency and the nephrotic syndrome resolved when the underlying B-cell lymphoma was treated with rituximab and bendamustine, suggesting the underlying lymphoproliferative malignancy was driving both disorders.
PMID: 31300605 [PubMed – indexed for MEDLINE]
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Hereditary Angio-Oedema for Dermatologists.
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Hereditary Angio-Oedema for Dermatologists.
Dermatology. 2019;235(4):263-275
Authors: Bygum A
Abstract
Among angio-oedema patients, hereditary angio-oedema (HAE) should not be overlooked. Besides skin swellings, these patients might have very painful abdominal attacks and potentially life-threatening angio-oedema of the upper airway. They will not respond to traditional anti-allergic therapy with antihistamines, corticosteroids, and adrenaline, and instead need specific drugs targeting the kallikrein-kinin pathway. Classically, patients with HAE have a quantitative or qualitative deficiency of the C1 inhibitor (C1INH) due to different mutations in SERPING1, although a new subtype with normal C1INH has been recognised more recently. This latter variant is diagnosed based on clinical features, family history, or molecular genetic testing for mutations in F12, ANGPT1,or PLG.The diagnosis of HAE is often delayed due to a general unfamiliarity with this orphan disease. However, undiagnosed patients are at an increased risk of unnecessary surgical interventions or life-threatening laryngeal swellings. Within the last decade, new and effective therapies have been developed and launched for acute and prophylactic therapy. Even more drugs are under evaluation in clinical trials. It is therefore of utmost importance that patients with HAE are diagnosed as soon as possible and offered relevant therapy with orphan drugs to reduce morbidity, prevent mortality, and improve quality of life.
PMID: 31167185 [PubMed – indexed for MEDLINE]
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Flare of IGA glomerulonephritis under G-CSF stimulation regimen for autologous stem cell transplantation in systemic sclerosis.
Flare of IGA glomerulonephritis under G-CSF stimulation regimen for autologous stem cell transplantation in systemic sclerosis.
Rheumatology (Oxford). 2020 Jan 18;:
Authors: Guffroy B, Ingwiller M, Gavand PE, Bouldoires B, Krummel T, Lioure B, Martin T, Guffroy A
PMID: 31953944 [PubMed – as supplied by publisher]
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