Manish Butte

Homeostatic and pathogenic roles of PI3Kδ in the human immune system.

April 25, 2020 By Manish Butte

Homeostatic and pathogenic roles of PI3Kδ in the human immune system.

Adv Immunol. 2020;146:109-137

Authors: Sogkas G, Adriawan IR, Dubrowinskaja N, Atschekzei F, Schmidt RE

Abstract
Phosphoinositide 3-kinase delta (PI3Kδ) mediates signaling transduction downstream of diverse immune receptors, including the T cell receptor (TCR), the B cell receptor (BCR), costimulatory molecules and cytokine receptors. Our understanding of the role of PI3Kδ in the immune system comes primarily from mice, and especially from the consequences of pharmacological inhibition of PI3Kδ in mouse models of human disease as well as the consequences of genetic manipulation, resulting in hyperactivation or loss of PI3Kδ function. In case of humans, in vitro studies with PI3Kδ-specific inhibitors, the consequences of treatment of hematologic malignancies with the PI3Kδ-specific inhibitor idelalisib and primary immunodeficiency disorders due to germline variants hyper- or underactivating PI3Kδ provide most of our knowledge on the role of PI3Kδ in immunity and immune regulation. In this review, we summarize the physiological and pathophysiological roles of PI3Kδ in the human immune system, focusing on immunodeficiency due to defects in PI3Kδ signaling and especially on the recently reported cases with mutations resulting in loss of PI3Kδ activity.

PMID: 32327151 [PubMed – in process]

Defective SEC61α1 underlies a novel cause of autosomal dominant severe congenital neutropenia.

April 24, 2020 By Manish Butte

Defective SEC61α1 underlies a novel cause of autosomal dominant severe congenital neutropenia.

J Allergy Clin Immunol. 2020 Apr 20;:

Authors: Van Nieuwenhove E, Barber JS, Neumann J, Smeets E, Willemsen M, Pasciuto E, Prezzemolo T, Lagou V, Seldeslachts L, Malengier-Devlies B, Metzemaekers M, Haßdenteufel S, Kerstens A, van der Kant R, Rousseau F, Schymkowitz J, Di Marino D, Lang S, Zimmermann R, Schlenner S, Munck S, Proost P, Matthys P, Devalck C, Boeckx N, Claessens F, Wouters C, Humblet-Baron S, Meyts I, Liston A

Abstract
BACKGROUND: The molecular cause of severe congenital neutropenia (SCN) is unknown in 30-50% of patients. SEC61A1 encodes the α subunit of the SEC61 complex, which governs endoplasmic reticulum protein transport and passive calcium leakage. Recently, mutations in SEC61A1 were reported to be pathogenic in common variable immunodeficiency and glomerulocystic kidney disease.
OBJECTIVE: To expand the spectrum of SEC61A1- mediated disease to include autosomal dominant SCN.
METHODS: WES findings were validated and reported mutations compared by western blotting, Ca+2 flux assays, differentiation of transduced HL-60 cells, in vitro differentiation of primary CD34 cells, qPCR for unfolded protein response genes and single-cell RNA-sequencing on whole bone marrow.
RESULTS: We identified a novel de novo missense mutation in SEC61A1 (c.A275G;p.Q92R) in a patient with SCN born to non-consanguineous Belgian parents. The mutation results in diminished protein expression, disturbed protein translocation and an increase in calcium leakage from the ER. In vitro differentiation of CD34+ cells recapitulated the patient’s clinical arrest in granulopoiesis. The impact of Q92R-SEC61α1 on neutrophil maturation was validated using HL-60 cells, where transduction reduced differentiation into CD11b+CD16+ cells. A potential mechanism for this defect is the uncontrolled initiation of the unfolded protein stress response, with single-cell analysis of primary bone-marrow revealing perturbed UPR in myeloid precursors, and in vitro differentiation of primary CD34+ cells revealing upregulation of CHOP and BiP UPR-response genes.
CONCLUSION: Specific mutations in SEC61A1 cause SCN through dysregulation of the UPR.

PMID: 32325141 [PubMed – as supplied by publisher]

Hemophagocytic Lymphohistiocytosis in Patients With Primary Immunodeficiency.

April 24, 2020 By Manish Butte

Hemophagocytic Lymphohistiocytosis in Patients With Primary Immunodeficiency.

J Pediatr Hematol Oncol. 2020 Apr 21;:

Authors: Cetinkaya PG, Ayvaz D, Gumruk F, Tezcan I

Abstract
Hemophagocytic lymphohistiocytosis (HLH) is characterized by uncontrolled and excessive immune responses with high mortality. We aimed to define mortality-related parameters in HLH secondary to primary immunodeficiency (PID). A total of 28 patients with HLH between the years 2013 and 2017 were enrolled in the study. The patients were evaluated in 2 groups including PID with hypopigmentation (n=7) (Chédiak-Higashi syndrome [CHS] and Griscelli syndrome type 2 [GS2]) and other PIDs (n=21). The median age of the study population was 23 (4.3 to 117.0) months at the time of the diagnosis of HLH. Central nervous system involvement was recorded in 7 (GS2/CHS patients [n=4], other PIDs [n=3], P=0.026), and death was observed in 9 patients (GS2/CHS patients [n=1], other PIDs [n=8], P=0.371). Five patients (3 GS2/CHS and 2 other PID patients) underwent hematopoietic stem cell transplantation. Low serum albumin level was the only variable associated with the mortality and albumin levels less than the cut-off value of 3.07 g/dL increased mortality 5.8 times in patients with HLH secondary to PID. We presented a single-center experience consisting of patients with HLH secondary to PID with a mortality rate of 32.1%. Hypoalbuminemia was the only risk factor to increase the overall mortality rate of HLH.

PMID: 32324696 [PubMed – as supplied by publisher]

Primary Antibody Deficiencies.

April 24, 2020 By Manish Butte

Primary Antibody Deficiencies.

Adv Exp Med Biol. 2020;1254:117-144

Authors: Min Q, Meng X, Wang JY

Abstract
Primary antibody deficiencies (PADs) are the most common types of inherited primary immunodeficiency diseases (PIDs) presenting at any age, with a broad spectrum of clinical manifestations including susceptibility to infections, autoimmunity and cancer. Antibodies are produced by B cells, and consequently, genetic defects affecting B cell development, activation, differentiation or antibody secretion can all lead to PADs. Whole exome and whole genome sequencing approaches have helped identify genetic defects that are involved in the pathogenesis of PADs. Here, we summarize the clinical manifestations, causal genes, disease mechanisms and clinical treatments of different types of PADs.

PMID: 32323274 [PubMed – in process]

Immunosuppressive Activity of Artemisia argyi Extract and Isolated Compounds.

April 24, 2020 By Manish Butte

Immunosuppressive Activity of Artemisia argyi Extract and Isolated Compounds.

Front Pharmacol. 2020;11:402

Authors: Zimmermann-Klemd AM, Reinhardt JK, Morath A, Schamel WW, Steinberger P, Leitner J, Huber R, Hamburger M, Gründemann C

Abstract
The need for novel drugs for the treatment of autoimmune diseases is high, since available pharmaceuticals often have substantial side effects and limited efficacy. Natural products are a good starting point in the development of immunosuppressive leads. Since enhanced T cell proliferation is a common feature of autoimmune diseases, we investigated the T cell proliferation inhibitory potential of an extract library of plants used in traditional Chinese medicine. Using a newly established cell-based screening platform, an ethyl acetate extract of Artemisia argyi H.Lév. & Vaniot (Asteraceae, A. argyi) was found to suppress the proliferation of human primary T lymphocytes in vitro in an IL-2-dependent manner. Flow cytometry- and ELISA-based techniques further demonstrated that the A. argyi extract reduced the activation and function of T cells. Transcription factor analysis and flow cytometric calcium influx investigations indicated that the immunomodulatory effect was based on specific modification of T cell signaling in a non-cytotoxic manner which is mediated via the NFAT pathway and a non-sequestrant inhibition of the calcium influx. A series of guaianolide and seco-guaianolide sesquiterpene lactones, as well as a flavonoid, were identified in a previous study as the bioactive compounds in the A. argyi extract. The effects of these bioactive compounds were compared to those of the crude extract. The tested sesquiterpene lactones act via the transcription factor NFAT and NF-κB, thereby exhibiting their immunosuppressive potential, but have an overall effect on T cell biology on a more-downstream level than the crude A. argyi extract.

PMID: 32322200 [PubMed]

Recurrent swelling and pain in the abdomen and joints in a patient with hereditary angioedema and Ehlers-Danlos syndrome.

April 24, 2020 By Manish Butte

Recurrent swelling and pain in the abdomen and joints in a patient with hereditary angioedema and Ehlers-Danlos syndrome.

BMJ Case Rep. 2019 Nov 27;12(11):

Authors: Dang MT, Ambort A, Arrey-Mensah A

Abstract
A 23-year-old woman was referred to the allergy and immunology clinic for recurrent abdominal, cutaneous and joint swelling and pain with a history of mucosal infections since childhood. Her history and clinical findings were suggestive of two rare and complex disorders, hereditary angioedema (HAE) and Ehlers-Danlos syndrome (EDS). Her recurrent episodes of abdominal and joint pain were initially misattributed to more common diagnoses such as esophagitis, depression and chronic pain syndrome. However, the coexistence of HAE and EDS likely contributed to a delay in diagnoses as the combination of these two rare but overlapping disorders is less understood by physicians. She had persistently low levels of C4 and C1-esterase inhibitor (C1-INH) with low to low-normal C1-esterase function, normal C1Q and no C1Q antibodies. In the setting of recurrent abdominal pain with cutaneous swelling, this supported the diagnosis of HAE type I. The increase in joint extensibility with recurrent shoulder subluxations since childhood was a manifestation of EDS. Although no known genetic mutations were identified for EDS, her diagnosis was confirmed by a geneticist based on her clinical phenotype. Before the diagnosis of HAE and EDS, our patient had at least 100 visits/year to the emergency department/hospitalisations for these recurrent symptoms. After starting on C1-INH replacement therapy, the frequency has decreased 10-fold. She also noted a 70% improvement in her quality of life. Familiarity with these rare disorders will assist healthcare providers in recognising HAE and EDS and include them as part of their differential diagnoses. Early diagnosis is important for a patient’s well-being as both these chronic disorders have been associated with poor quality of life. Additionally, proper diagnoses will reduce healthcare costs by preventing unnecessary procedures due to misdiagnoses. Proper treatment will help to decrease hospitalisations and avoidance of life-threatening consequences (such as asphyxiation from fatal laryngeal attacks of HAE and rupture of aneurysms in EDS).

PMID: 31780602 [PubMed – indexed for MEDLINE]

Functionally meaningful rating scales in progressive pediatric movement disorders.

April 24, 2020 By Manish Butte

Functionally meaningful rating scales in progressive pediatric movement disorders.

Dev Med Child Neurol. 2020 02;62(2):157

Authors: Perlman S

PMID: 31583682 [PubMed – indexed for MEDLINE]

A newly found homozygous mutation in recombination activating gene 1 in a patient with leaky severe combined immunodeficiency disorder.

April 24, 2020 By Manish Butte

A newly found homozygous mutation in recombination activating gene 1 in a patient with leaky severe combined immunodeficiency disorder.

Mol Biol Rep. 2019 Dec;46(6):6571-6575

Authors: Salari F, Zaremehrjardi F, Arshi S, Bemanian MH, Fallahpour M, Shokri S, Seif F, Movahedi M, Nabavi M

Abstract
The recombination activating genes, including RAG1 and RAG2, are essential for V(D)J somatic recombination in lymphocytes. Leaky severe combined immunodeficiency disorder (SCID) is characterized by normal or intermediate T cells and normal to absent B cells associated with partial T cell and B cell dysfunction. We present a newly found RAG1 deficiency in a 21-year-old boy with leaky SCID. Immunoglobulin levels, flow cytometry, and whole exome sequencing (WES) were evaluated. Flow cytometric analysis revealed a decreased number of CD3+, CD4+, and CD8+ T cells, and B cells whereas NK cell counts were normal. Immunoglobulin levels were also decreased. The WES revealed a newly found homozygous mutation of RAG1 gene (NM_000448: exon 2: c.C2275T). Atypical features, including leukopenia, candidiasis, and low lymphocyte counts in patients with late-onset combined immunodeficiency disorders (CID) such as leaky SCID due to RAG1 deficiency may result in misdiagnosis and inadequate therapy instead of adopting the curative hematopoietic stem cell transplantation in these patients.

PMID: 31520268 [PubMed – indexed for MEDLINE]

Managing childhood allergies and immunodeficiencies during respiratory virus epidemics – the 2020 COVID-19 pandemic.

April 23, 2020 By Manish Butte

Managing childhood allergies and immunodeficiencies during respiratory virus epidemics – the 2020 COVID-19 pandemic.

Pediatr Allergy Immunol. 2020 Apr 22;:

Authors: Brough HA, Kalayci O, Sediva A, Untersmayr E, Munblit D, Rodriquez Del Rio P, Vazquez-Ortiz M, Arasi S, Alvaro-Lozano M, Tsabouri S, Galli E, Beken B, Eigenmann PA

Abstract
While the world is facing an unprecedented pandemic with COVID-19, patients with chronic diseases need special attention and if warranted adaptation of their regular treatment plan. In children, allergy and asthma are among the most prevalent non-communicable chronic diseases, and health care providers taking care of these patients need guidance. At the current stage of knowledge, children have less severe symptoms of COVID-19, and severe asthma and immunodeficiency are classified as risk factors. In addition, there is no evidence that currently available asthma and allergy treatments, including antihistamines, corticosteroids, bronchodilators increase the risk of severe disease from COVID-19. Most countries affected by COVID-19 have opted for nationwide confinement, which means that communication with the primary clinician is often performed by telemedicine. Optimal disease control of allergic, asthmatic and immunodeficient children should be sought according to usual treatment guidelines. This statement of the EAACI Section on Pediatrics puts forward six recommendations for the management of childhood allergies and immunodeficiencies based on six underlying facts and existing evidence.

PMID: 32319129 [PubMed – as supplied by publisher]

Cytological diagnosis of primary cutaneous histoplasmosis with hemophagocytosis in immunocompetent patient – A rare case from non endemic region.

April 23, 2020 By Manish Butte

Cytological diagnosis of primary cutaneous histoplasmosis with hemophagocytosis in immunocompetent patient – A rare case from non endemic region.

Indian J Pathol Microbiol. 2020 Apr-Jun;63(2):309-311

Authors: Chandra S, Raina MK, Gaur DS, Agarwal VK

Abstract
Histoplasma capsulatum is an opportunistic dimorphic fungus caused by inhalation of spores present in the soil. It is extremely rare in the northern Himalayan region of India and is usually asymptomatic. It may rarely progress to disseminated histoplasmosis which is usually observed in immunocompromised patients associated with malignancy, acquired immunodeficiency syndrome or diabetes. The present case is being reported because of unusual cutaneous presentation of disseminated histoplasmosis in an immunocompetent patient of non-endemic region. The case also highlights the importance of fine needle aspiration cytology for its precise early diagnosis and avoiding of further complications.

PMID: 32317542 [PubMed – in process]