Manish Butte

Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome.

J Exp Med. 2020 Jun 01;217(6):

Authors: Béziat V, Tavernier SJ, Chen YH, Ma CS, Materna M, Laurence A, Staal J, Aschenbrenner D, Roels L, Worley L, Claes K, Gartner L, Kohn LA, De Bruyne M, Schmitz-Abe K, Charbonnier LM, Keles S, Nammour J, Vladikine N, Maglorius Renkilaraj MRL, Seeleuthner Y, Migaud M, Rosain J, Jeljeli M, Boisson B, Van Braeckel E, Rosenfeld JA, Dai H, Burrage LC, Murdock DR, Lambrecht BN, Avettand-Fenoel V, Vogel TP, Undiagnosed Diseases Network, Esther CR, Haskologlu S, Dogu F, Ciznar P, Boutboul D, Ouachée-Chardin M, Amourette J, Lebras MN, Gauvain C, Tcherakian C, Ikinciogullari A, Beyaert R, Abel L, Milner JD, Grimbacher B, Couderc LJ, Butte MJ, Freeman AF, Catherinot É, Fieschi C, Chatila TA, Tangye SG, Uhlig HH, Haerynck F, Casanova JL, Puel A

Abstract
Autosomal dominant hyper-IgE syndrome (AD-HIES) is typically caused by dominant-negative (DN) STAT3 mutations. Patients suffer from cold staphylococcal lesions and mucocutaneous candidiasis, severe allergy, and skeletal abnormalities. We report 12 patients from 8 unrelated kindreds with AD-HIES due to DN IL6ST mutations. We identified seven different truncating mutations, one of which was recurrent. The mutant alleles encode GP130 receptors bearing the transmembrane domain but lacking both the recycling motif and all four STAT3-recruiting tyrosine residues. Upon overexpression, the mutant proteins accumulate at the cell surface and are loss of function and DN for cellular responses to IL-6, IL-11, LIF, and OSM. Moreover, the patients’ heterozygous leukocytes and fibroblasts respond poorly to IL-6 and IL-11. Consistently, patients with STAT3 and IL6ST mutations display infectious and allergic manifestations of IL-6R deficiency, and some of the skeletal abnormalities of IL-11R deficiency. DN STAT3 and IL6ST mutations thus appear to underlie clinical phenocopies through impairment of the IL-6 and IL-11 response pathways.

PMID: 32207811 [PubMed – as supplied by publisher]

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Severe phototoxicity associated with concomitant use of methotrexate and voriconazole, an overlooked drug-drug interaction.

Pediatr Blood Cancer. 2020 Mar 24;:e28246

Authors: Bogaert DJ, Verlinden L, Vandecruys E, Laureys G, Verhaeghe E, Bauters T

PMID: 32207558 [PubMed – as supplied by publisher]

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Fever During Anti-integrin Therapy: New Immunodeficiency.

Eur J Case Rep Intern Med. 2020;7(3):001288

Authors: Bonfanti E, Bracco C, Biancheri P, Falcetta A, Martini MB, Melchio R, Fenoglio L

Abstract
Background: The causes of inflammatory bowel disease (IBD) have not yet been clearly elucidated, but it is known that genetic susceptibility, altered gut microbiota and environmental factors are all involved, and that a combination of these factors causes an inappropriate immune response, resulting in impaired intestinal barrier function. With regard to the treatment of IBD, the use of conventional immunosuppressive drugs has been complemented by more specific therapeutic agents, including biological drugs. Systemic immune suppression is a risk factor for cytomegalovirus (CMV) infection, which is associated with considerable morbidity and mortality in immunocompromised hosts.
Case Report: A 33-year-old male patient was admitted to our medical unit complaining of a 10-day history of fever, fatigue and headache. He had been suffering from ulcerative colitis and primary sclerosing cholangitis for five years and was currently being treated with azathioprine and vedolizumab. In the past he had already taken infliximab, adalimumab and golimumab without any clinical response. After the exclusion of systemic infectious diseases, his serology was consistent with a primary CMV infection. This was successfully treated with intravenous ganciclovir therapy.
Conclusion: Vedolizumab is an anti-integrin biological agent approved for IBD treatment. Its gut-selective mechanism of action would appear to increase its safety profile, however data on this are still limited. Moreover, it should always be remembered that IBD patients have an increased risk of CMV infection, both primary and reactivation, because of their concurrent immunosuppression.
LEARNING POINTS: It is important to consider CMV infection (primary and reactivation) in patients affected by IBD.

PMID: 32206635 [PubMed]

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Expanding TREC and KREC Utility in Primary Immunodeficiency Diseases Diagnosis.

Front Immunol. 2020;11:320

Authors: Korsunskiy I, Blyuss O, Gordukova M, Davydova N, Zaikin A, Zinovieva N, Zimin S, Molchanov R, Salpagarova A, Eremeeva A, Filipenko M, Prodeus A, Korsunskiy A, Hsu P, Munblit D

Abstract
Primary immunodeficiency diseases (PID) area heterogeneous group of disorders caused by genetic defects of the immune system, which manifest clinically as recurrent infections, autoimmune diseases or malignancies. Early detection of PID remains a challenge, particularly in older children with milder and less specific symptoms. This study aimed to assess TREC and KREC diagnostic ability in PID. Data from children assessed by clinical immunologists at Speransky Children’s Hospital, Moscow, Russia with suspected immunodeficiencies were analyzed between May 2013 and August 2016. Peripheral blood samples were sent for TREC/KREC, flow cytometry (CD3, CD4, CD8 and CD19), IgA and IgG analysis. A total of 434 children [189 healthy, 97 with group I and II PID (combined T and B cell immunodeficiencies & well-defined syndromes with immunodeficiency) and 148 group III PID (predominantly antibody deficiencies)] were included. Area under the curve (AUC) for TREC in PID groups I and II diagnosis reached 0.82 (CI = 0.75-0.90), with best model providing sensitivity of 65% and specificity of 92%. Neither TREC, nor KREC had added value in PID group III diagnosis. In this study, the predictive value of TREC and KREC in PID diagnosis was examined. We found that the TREC had some diagnostic utility for groups I and II PID. Possibly, addition of TREC measurements to existing clinical diagnostic algorithms may improve their predictive value. Further investigations on a larger cohort are needed to evaluate TREC/KREC abilities to be used as diagnostic tools on a wider scale.

PMID: 32194560 [PubMed – in process]

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Further delineation of primary B cell immunodeficiency caused by novel variants of the BLNK gene in two Chinese patients.

Clin Immunol. 2020 Mar 16;:108387

Authors: Li N, Wu J, Wu Y, Xu Y, Yao R, Li G, Zhang J, Zhou Y, Yin L, Yin Y, Yu T, Wang J

Abstract
Biallelic variants in BLNK cause primary B-cell immunodeficiency that usually results in absence of B cells and immunoglobulin. Here, we identified disease-causing variant(s) in two unrelated Chinese patients with agammaglobulinemia. Patient 1 showed a moderate reduction in total B-cell count but demonstrated both extremely low levels of memory B-cells and lower levels of memory T cells relative to those in healthy controls. Whole-exome sequencing (WES) revealed a novel heterozygous splice variant (c.676+1G>A), and suggested exon 9 deletion from BLNK, which was subsequently validated by quantitative polymerase chain reaction. For Patient 2, WES revealed novel compound heterozygous of a frameshift variant (p.T152Pfs*6) and a synonymous variant (c.525G>A) that resulted in exon 6 skipping, according to cDNA sequencing. These findings represent the first report of a BLNK-deficient patient presenting with impaired memory B-cell and memory T-cell development. Furthermore, this study is the first reporting a pathogenic synonymous splice variant in BLNK.

PMID: 32194234 [PubMed – as supplied by publisher]

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Diapedesis-Induced Integrin Signaling via LFA-1 Facilitates Tissue Immunity by Inducing Intrinsic Complement C3 Expression in Immune Cells.

Immunity. 2020 Mar 17;52(3):513-527.e8

Authors: Kolev M, West EE, Kunz N, Chauss D, Moseman EA, Rahman J, Freiwald T, Balmer ML, Lötscher J, Dimeloe S, Rosser EC, Wedderburn LR, Mayer-Barber KD, Bohrer A, Lavender P, Cope A, Wang L, Kaplan MJ, Moutsopoulos NM, McGavern D, Holland SM, Hess C, Kazemian M, Afzali B, Kemper C

Abstract
Intrinsic complement C3 activity is integral to human T helper type 1 (Th1) and cytotoxic T cell responses. Increased or decreased intracellular C3 results in autoimmunity and infections, respectively. The mechanisms regulating intracellular C3 expression remain undefined. We identified complement, including C3, as among the most significantly enriched biological pathway in tissue-occupying cells. We generated C3-reporter mice and confirmed that C3 expression was a defining feature of tissue-immune cells, including T cells and monocytes, occurred during transendothelial diapedesis, and depended on integrin lymphocyte-function-associated antigen 1 (LFA-1) signals. Immune cells from patients with leukocyte adhesion deficiency type 1 (LAD-1) had reduced C3 transcripts and diminished effector activities, which could be rescued proportionally by intracellular C3 provision. Conversely, increased C3 expression by T cells from arthritis patients correlated with disease severity. Our study defines integrins as key controllers of intracellular complement, demonstrates that perturbations in the LFA-1-C3-axis contribute to primary immunodeficiency, and identifies intracellular C3 as biomarker of severity in autoimmunity.

PMID: 32187519 [PubMed – as supplied by publisher]

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Spectrum of Hepatic Manifestations of Common Variable Immunodeficiency.

Am J Surg Pathol. 2020 Mar 16;:

Authors: Crotty R, Taylor MS, Farmer JR, Kakar S, Ardeniz Ö, Yilmaz F, Patil DT, Deshpande V

Abstract
Common variable immunodeficiency (CVID) has a heterogenous clinical presentation and can be challenging to diagnose. Distinct histologic changes have been linked with CVID in several organ systems, which can help identify the correct diagnosis. In this study we review a cohort of hepatic CVID biopsies, to better define the spectrum of histologic and biochemical alterations. We reviewed 26 liver biopsies from 24 patients with CVID, obtained at 4 institutions between 2010 and 2019. Histologic slides were examined, and pathologic, biochemical, and clinical features were recorded. A control cohort of 21 patients with nodular regenerative hyperplasia (NRH) but lacking CVID was also examined. Liver function tests were frequently abnormal, especially alkaline phosphatase (median: 193 IU/L) and aspartate transaminase (median: 56 U/L), elevated in 23 and 17 of 25 biopsies, respectively. Fifteen patients had CVID involvement of other organs. Histologic features of primary biliary cholangitis were present in 2 patients, with florid duct lesions and prominent bile duct injury, in association with positive antimitochondrial antibodies. Among the other 24 biopsies, mild to moderate portal and lobular inflammation were present in 18 and 17 of 24 biopsies, respectively. Overall, 22 of 24 biopsies showed NRH-like changes. Plasma cell were absent. A distinct pattern of pericellular fibrosis was present in 23 of 26 biopsies overall. Involvement ranged from focal centrizonal fibrosis to bridging fibrosis and was accompanied by increased intrasinusoidal lymphocytes in 13 of 24 biopsies. Pericellular fibrosis was identified in 1 of 21 biopsies in the control cohort. Additional findings included granulomatous inflammation or nonhepatocellular foreign body-type multinucleate giant cells, identified in 4 biopsies. Three of 6 examined biopsies also demonstrated focal hepatocellular copper deposition. Hepatic disease in CVID is often associated with elevated alkaline phosphatase and aspartate transaminase and is characterized histologically by the mild nonspecific portal and lobular hepatitis, absence of plasma cells, NRH-like changes, and less commonly, typical histologic features of primary biliary cholangitis. We have also identified a distinctive pattern of delicate pericellular fibrosis that is a helpful clue to the diagnosis of hepatic disease in CVID, especially when accompanied by NRH-like changes.

PMID: 32187043 [PubMed – as supplied by publisher]

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