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CD8+ T-cell senescence and skewed lymphocyte subsets in young Dyskeratosis Congenita patients with PARN and DKC1 mutations.

J Clin Lab Anal. 2020 May 25;:e23375

Authors: Zeng T, Lv G, Chen X, Yang L, Zhou L, Dou Y, Tang X, Yang J, An Y, Zhao X

Abstract
BACKGROUND: Dyskeratosis congenita (DC) is a syndrome resulting from defective telomere maintenance. Immunodeficiency associated with DC can cause significant morbidity and lead to premature mortality, but the immunological characteristics and molecular hallmark of DC patients, especially young patients, have not been described in detail.
METHODS: We summarize the clinical data of two juvenile patients with DC. Gene mutations were identified by whole-exome and direct sequencing. Swiss-PdbViewer was used to predict the pathogenicity of identified mutations. The relative telomere length was determined by QPCR, and a comprehensive analysis of lymphocyte subsets and CD57 expression was performed by flow cytometry.
RESULTS: Both patients showed typical features of DC without severe infection. In addition, patient 1 (P1) was diagnosed with Hoyeraal-Hreidarsson syndrome due to cerebellar hypoplasia. Gene sequencing showed P1 had a compound heterozygous mutation (c.204G > T and c.178-245del) in PARN and P2 had a novel hemizygous mutation in DKC1 (c.1051A > G). Lymphocyte subset analysis showed B and NK cytopenia, an inverted CD4:CD8 ratio, and decreased naïve CD4 and CD8 cells. A significant increase in CD21low B cells and skewed numbers of helper T cells (Th), regulatory T cells (Treg), follicular regulatory T cells (Tfr), and follicular helper T cells (Tfh) were also detected. Short telomere lengths, increased CD57 expression, and an expansion of CD8 effector memory T cells re-expressing CD45RA (TEMRA) were also found in both patients.
CONCLUSION: Unique immunologic abnormalities, CD8 T-cell senescence, and shortened telomere together as a hallmark occur in young DC patients before progression to severe disease.

PMID: 32452087 [PubMed – as supplied by publisher]

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A Phased Approach to Resuming Suspended Allergy/Immunology Clinical Services.

J Allergy Clin Immunol Pract. 2020 May 22;:

Authors: Searing DA, Dutmer CM, Fleischer DM, Shaker MS, Oppenheimer J, Grayson MH, Stukus D, Hartog N, Hsieh EWY, Rider NL, Vander Leek TK, Kim H, Chan ES, Mack D, Ellis AK, Abrams EM, Bansal P, Lang DM, Lieberman J, Golden DB, Wallace D, Portnoy J, Mosnaim G, Greenhawt M

Abstract
In early 2020, the first US and Canadian cases of the novel SARS-CoV-2 infection were detected. In the ensuing months, there has been rapid spread of the infection. In March 2020, in response to the virus, state/provincial and local governments instituted shelter-in-place orders, and non-essential ambulatory care was significantly curtailed, including allergy/immunology services. With rates of new infections and fatalities potentially reaching a plateau and/or declining, restrictions on provision of routine ambulatory care are lifting, and there is a need to help guide the allergy/immunology clinician on how to re-initiate services. Given COVID-19 will circulate within our communities for months or longer, we present a flexible, algorithmic best-practices planning approach on how to prioritize services, in 4 stratified phases of re-opening according to community risk level, as well highlight key considerations for how to safely do so. The decisions on what services to offer and how fast to proceed are left to the discretion of the individual clinician and practice, operating in accordance with state and local ordinances with respect to the level of non-essential ambulatory care that can be provided. Clear communication with staff and patients before and after all changes should be incorporated into this new paradigm on continual change, given the movement may be forward and even backward through the phases as this is an evolving situation.

PMID: 32450236 [PubMed – as supplied by publisher]

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A Novel X-Linked Inhibitor of Apoptosis Deficient Variant Showing Attenuated Epstein-Barr Virus Response.

J Pediatric Infect Dis Soc. 2020 May 25;:

Authors: Zhong Y, Huang CH, Soe WM, Chan KW, Isa MS, Soh J, Yap M, MacAry PA, Lau YL, Chai LYA, Shek LP, Lee BW

Abstract
We report on 2 Asian siblings with X-linked inhibitor of apoptosis deficiency that arose from a novel deletion that presented with Epstein-Barr virus disease and hemophagocytic lymphohistiocytosis. This disease is ascribed to dysfunction in the nucleotide binding and oligomerization domain receptor pathway, tested using a modified muramyl dipeptide-mediated assay.

PMID: 32448891 [PubMed – as supplied by publisher]

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An IL17RA frameshift variant in a Holstein cattle family with psoriasis-like skin alterations and immunodeficiency.

BMC Genet. 2020 May 24;21(1):55

Authors: Häfliger IM, Sickinger M, Holsteg M, Raeder LM, Henrich M, Marquardt S, Drögemüller C, Lühken G

Abstract
BACKGROUND: Skin lesions and dermatoses in cattle are often associated with infections due to bacteria, fungi or environmental risk factors. Dermatoses with genetic etiology have been described in cattle. Among these rare disorders, there are primary congenital dermatoses that are associated with inherited nutritional deficiencies, such as bovine hereditary zinc deficiency or zinc deficiency-like syndrome. This study presents three cases of Holstein cattle with congenital skin lesions observed on a single farm that resemble zinc deficiency-like syndrome. Close clinical and pathological examinations took place in two cases. Pedigree analysis indicated autosomal recessive inheritance and whole-genome sequencing of both affected calves was performed.
RESULTS: The two calves showed retarded growth and suffered from severe ulcerative dermatitis with hyperkeratosis, alopecia furunculosis and subcutaneous abscess formation. Blood analysis showed correspondent leukocytosis with neutrophilia whereas minerals, macro- and micronutrients were within the reference ranges. Variant calling and filtering against the 1000 Bull Genomes variant catalogue resulted in the detection of a single homozygous protein-changing variant exclusively present in both sequenced genomes. This single-nucleotide deletion in exon 3 of IL17RA on bovine chromosome 5 was predicted to have a deleterious impact on the encoded protein due to a frameshift leading to a truncated gene product. Genotyping of the affected cattle family confirmed recessive inheritance.
CONCLUSIONS: A loss-of-function mutation of the IL17RA transmembrane protein could be identified as most likely pathogenic variant for the psoriasis-like skin alterations observed in the two affected Holstein calves. In man, rare recessive diseases associated with IL17RA include immunodeficiency 51 and chronic mucocutaneous candidiasis. This supports the observed immunodeficiency of the presented cases. This study reports the first naturally occurring IL17RA-associated animal model.

PMID: 32448141 [PubMed – in process]

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[Chronic kidney disease in adults with primary immunodeficiency diseases in treatment with intravenous immunoglobulin].

Rev Alerg Mex. 2020 Jan-Mar;67(1):25-33

Authors: O’Farrill-Romanillos PM, Luna-Mújica RF, Contreras-García CE, Anda JC

Abstract
BACKGROUND: Intravenous immunoglobulin (IVIG) is the treatment of choice for humoral primary immunodeficiency diseases (PIDs). A third of the patients who receive intravenous immunoglobulin have adverse reactions, such as osmotic nephrosis.
OBJECTIVE: To assess the presence of kidney disease in adults with humoral PIDs, in treatment with intravenous immunoglobulin.
METHODS: A cross-sectional, descriptive, and observational study of patients who belong to the PID Clinic of the Specialties Hospital of the National Medical Center “Siglo XXI”, Mexico City, who receive treatment with intravenous immunoglobulin. A questionnaire with demographic information, 24h urine creatinine clearance, serum creatinine, urea, and BUN (Blood Urea Nitrogen) was applied.
RESULTS: 35 patients were surveyed; 65.7 % were women; the average age was 34 years; 51.4 % of the patients presented kidney damage. Those with > 5 years of treatment with intravenous immunoglobulin presented chronic kidney disease (CKD) with more frequency (55.6 %) according to the KDOQI scale.
CONCLUSIONS: Chronic kidney disease occurs in 51 % of adult patients with PID who have been treated with intravenous immunoglobulin for more than 5 years; which is why these patients require periodic evaluations of their kidney function, and the use of sugar-free immunoglobulin in order to reduce the risk.

PMID: 32447865 [PubMed – as supplied by publisher]

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Tspan18 is a novel regulator of thrombo-inflammation.

Med Microbiol Immunol. 2020 May 23;:

Authors: Gavin RL, Koo CZ, Tomlinson MG

Abstract
The interplay between thrombosis and inflammation, termed thrombo-inflammation, causes acute organ damage in diseases such as ischaemic stroke and venous thrombosis. We have recently identified tetraspanin Tspan18 as a novel regulator of thrombo-inflammation. The tetraspanins are a family of 33 membrane proteins in humans that regulate the trafficking, clustering, and membrane diffusion of specific partner proteins. Tspan18 partners with the store-operated Ca2+ entry channel Orai1 on endothelial cells. Orai1 appears to be expressed in all cells and is critical in health and disease. Orai1 mutations cause human immunodeficiency, resulting in chronic and often lethal infections, while Orai1-knockout mice die at around the time of birth. Orai1 is a promising drug target in autoimmune and inflammatory diseases, and Orai1 inhibitors are in clinical trials. The focus of this review is our work on Tspan18 and Orai1 in Tspan18-knockout mice and Tspan18-knockdown primary human endothelial cells. Orai1 trafficking to the cell surface is partially impaired in the absence of Tspan18, resulting in impaired Ca2+ signaling and impaired release of the thrombo-inflammatory mediator von Willebrand factor following endothelial stimulation. As a consequence, Tspan18-knockout mice are protected in ischemia-reperfusion and deep vein thrombosis models. We provide new evidence that Tspan18 is relatively highly expressed in endothelial cells, through the analysis of publicly available single-cell transcriptomic data. We also present new data, showing that Tspan18 is required for normal Ca2+ signaling in platelets, but the functional consequences are subtle and restricted to mildly defective platelet aggregation and spreading induced by the platelet collagen receptor GPVI. Finally, we generate structural models of human Tspan18 and Orai1 and hypothesize that Tspan18 regulates Orai1 Ca2+ channel function at the cell surface by promoting its clustering.

PMID: 32447449 [PubMed – as supplied by publisher]

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