Research

Multigene sequencing reveals heterogeneity of NLRP12-related autoinflammatory disorders.

Rheumatol Int. 2018 Mar 02;:

Authors: Kostik MM, Suspitsin EN, Guseva MN, Levina AS, Kazantseva AY, Sokolenko AP, Imyanitov EN

Abstract
NLRP12-related autoinflammatory disease (NLRP12-AID) is an exceptionally rare autosomal dominant disorder caused by germline mutations in NLRP12 gene. Very few patients with NLRP12-AD have been identified worldwide; therefore, there is a scarcity of data on phenotypic presentation of this syndrome. Here we provide evidence that NLRP12-AID may have clinical manifestations characteristic for primary immune deficiencies (PID). 246 children with periodic fever (PF) of unknown origin were subjects to the next generation sequencing (NGS) analysis; 213 of these patients had signs of primary immunodeficiency (PID) manifested by recurrent infections, while 33 kids had isolated PF. The NGS panel was composed of 302 genes implicated in PID and/or AID. 15 patients (9 girls and 6 boys) with NLRP12-AID were identified. Median age of first AID-related fever episode was 12 months, ranging from 2 months to 13 years. Main clinical features of NLRP12-related AID were periodic fever (100%), abdominal pain and diarrhea (47%), arthralgia (20%), headache (20%) and failure to thrive (33%). Nine patients demonstrated increased susceptibility to infection and two children suffered from Crohn’s disease. Administration of short courses of NSAID or corticosteroids resulted in resolution of the disease flare. In one severe case, canakinumab (anti-interleukin-1β antibody) was successfully used. Significant number of patients with genetically assigned diagnosis of NLPR12-AID has clinical features which close resemble primary immune deficiency. This phenotypic overlap may result in underdiagnosis of NLPR12-AID among patients with PID.

PMID: 29500522 [PubMed – as supplied by publisher]

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Increased risk of hematologic malignancies in primary immunodeficiency disorders: opportunities for immunotherapy.

Clin Immunol. 2018 Feb 27;:

Authors: Verhoeven D, Stoppelenburg AJ, Meyer-Wentrup F, Boes M

Abstract
Primary immunodeficiency disorders (PIDs) convey increased susceptibility to infections and sometimes to malignancies, particularly lymphomas. Such cancer development can be contributed by immune impairments resulting in weakened immunological surveillance against (pre)malignant cells and oncogenic viruses. Molecular defects in PID-patients are therefore being clarified, identifying new targets for innovative immunotherapy. Particularly pediatric cancers are being scrutinized, where over one third of cancer-related deaths is accounted for by leukemia and lymphomas. Here we review how immunopathogenic mechanisms of several PIDs might associate with lymphoma development. We furthermore delineate existing immunotherapy strategies in adults for potential therapeutic application in childhood leukemia and lymphomas.

PMID: 29499421 [PubMed – as supplied by publisher]

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Molecular control of B-cell homeostasis in health and malignancy.

Immunol Cell Biol. 2018 Mar 02;:

Authors: Garcillán B, Figgett WA, Infantino S, Lim EX, Mackay F

Abstract
Altered B-cell homeostasis underlies a wide range of pathologies, from cancers, to autoimmunity, and immunodeficiency. The molecular safeguards against those disorders, which also allow effective immune responses, are therefore particularly critical. Here, we review recent findings detailing the fine control of B-cell homeostasis, during B-cell development, maturation in the periphery and, during activation and differentiation into antibody-producing cells. This article is protected by copyright. All rights reserved.

PMID: 29499091 [PubMed – as supplied by publisher]

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StatPearls

Book. 2018 01

Authors:

Abstract
Pulmonary alveolar proteinosis (PAP) was first described in 1958 by Samuel H. Rosen et al. Since that time, clinicians’ understanding of this rare lung disease has improved dramatically. Initial reports of this disease described it as respiratory failure secondary to over-production of surfactant proteins within the alveoli. It was believed to be a consequence of inhaled environmental irritants or infectious agents and was called acquired or idiopathic PAP. Practitioners now understand that there are 3 separate pathological pathways to the development of surfactant accumulation within alveoli: congenital, secondary, and autoimmune. All 3 of these pathways end with decreased clearance of surfactant, rather than increased production. Autoimmune PAP is the most common pathological type accounting for 90% of documented cases. Autoimmune PAP is initiated by immunoglobulin (Ig)-G anti-granulocyte macrophage colony stimulating factor (anti-GM-CSF) antibodies, which decrease functional alveolar macrophages. Secondary PAP lacks anti-GM-CSF antibodies but has decreased functional macrophages secondary to hematological malignancies (myelodysplastic syndrome, chronic myelogenous leukemia, among others) or primary immunodeficiency diseases (common variable immunodeficiency, DiGeorge syndrome, among others). Congenital PAP is the least common and results from genetic mutations in GM-CSF receptor proteins or surfactant proteins.

PMID: 29493933

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Minimum effective betamethasone dosage on the neurological phenotype in patients with Ataxia-Telangiectasia: a multicenter observer-blind study.

Eur J Neurol. 2018 Feb 28;:

Authors: Cirillo E, Del Giudice E, Micheli R, Cappellari AM, Soresina A, Dellepiane RM, Pietrogrande MC, Dell’Era L, Specchia F, Pession A, Plebani A, Pignata C

Abstract
BACKGROUND AND PURPOSE: Ataxia-Telangiectasia (A-T) is a rare neurodegenerative disease, due to A-T Mutated (ATM) gene mutations, which typically presents with signs of progressive neurological dysfunction, cerebellar ataxia and uncoordinated movements. A-T severely affects patients’ quality of life (QoL). Successful treatment options are still not available. Aim of this multicenter study, performed with a blind evaluation procedure, was to define the minimal effective dosage of oral betamethasone, thus preventing the occurrence of side effects.
METHODS: Nine A-T patients were enrolled to receive betamethasone at increasing dosages of 0.001, 0.005 and 0.01 mg/kg/day. Neurological assessment and the evaluation of QoL were performed through the Scale for the Assessment and Rating of Ataxia (SARA) and the Italian version of the Children Health Assessment Questionnaire (CHAQ) at each time-point. Drug safety profile was evaluated. Patients were categorized as responders, partial responders and non-responders.
RESULTS: Four out 9 patients had a benefit at the dose of 0.005 mg/kg/day of oral betamethasone. Using the higher dosage, only 1 additional patient had a positive response. Conversely, a daily dose of 0.001 mg/kg was ineffective. A correlation between the serum ACTH levels and the clinical response was observed. Five of 30 CHAQ items improved in 4 patients.
CONCLUSIONS: These data suggest that a short-term betamethasone oral treatment, at a daily dosage of 0.005 mg/kg, is effective in some patients. Pre-existing risk factors for side-effects should be taken into account before therapy. This article is protected by copyright. All rights reserved.

PMID: 29489040 [PubMed – as supplied by publisher]

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Locally Ablative Radiation Therapy of a Primary Human Small Cell Lung Cancer Tumor Decreases the Number of Spontaneous Metastases in Two Xenograft Models.

Int J Radiat Oncol Biol Phys. 2018 Mar 15;100(4):1044-1056

Authors: Frenzel T, Siekmann J, Grohmann C, Valentiner U, Schmitz R, Riecken K, Fehse B, Schumacher U, Lange T, Krüll A

Abstract
PURPOSE: To investigated the influence of radiation therapy (RT), surgery (OP), radio-chemotherapy (RChT), or chemotherapy (ChT) on small cell lung cancer metastases in 2 xenograft models.
METHODS AND MATERIALS: A total of 1 × 106 human small cell lung cancer cells (OH1, H69) were subcutaneously injected into severe combined immunodeficiency mice to form a local primary tumor node at the lower trunk. Radiation therapy, OP, RChT, or ChT were started after development of palpable tumors. Chemotherapy was given as a single intraperitoneal injection of cisplatin. Radiation therapy was 5 × 10 Gy on the local tumor node. Two additional groups were implemented to assess primary tumors and distant metastases in untreated mice at the beginning (control group A) and at the end of the experiment (control group B). Proapoptotic, antiproliferative, antiangiogenic, and hypoxic effects were assessed by Feulgen, Ki67, S1P1 receptor, and hypoxia-inducible factor 1α staining, respectively. Quantitative Alu-polymerase chain reaction was used to determine circulating tumor cells in the blood, and disseminated tumor cells in the lungs, bone marrow, liver, and brain.
RESULTS: In both xenograft models, RT and RChT abrogated local tumor growth, indicated by increased apoptosis, decreased cell proliferation, and reduced microvessel density (equally affecting vessels of all diameters). Regarding metastases, RT and RChT not only counteracted the time-dependent increase of dissemination but also decreased the metastatic load pre-existing at therapy induction in the blood, lungs, and liver. Only in the case of relapse-free surgery could similar effects be achieved by OP.
CONCLUSIONS: Our models provide evidence that RT and RChT ablate the primary tumor and inhibit metastasis development over time. Upon local recurrence, RT showed beneficial effects compared with OP with regard to suppression of circulating tumor cells and disseminated tumor cells.

PMID: 29485046 [PubMed – in process]

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Genetic and Structural Analysis of a SKIV2L Mutation Causing Tricho-hepato-enteric Syndrome.

Dig Dis Sci. 2018 Feb 26;:

Authors: Vardi I, Barel O, Sperber M, Schvimer M, Nunberg M, Field M, Ouahed J, Marek-Yagel D, Werner L, Haberman Y, Lahad A, Anikster Y, Rechavi G, Barshack I, McElwee JJ, Maranville J, Somech R, Snapper SB, Weiss B, Shouval DS

Abstract
BACKGROUND: Advances in genomics have facilitated the discovery of monogenic disorders in patients with unique gastro-intestinal phenotypes. Syndromic diarrhea, also called tricho-hepato-enteric (THE) syndrome, results from deleterious mutations in SKIV2L or TTC37 genes. The main features of this disorder are intractable diarrhea, abnormal hair, facial dysmorphism, immunodeficiency and liver disease.
AIM: To report on a patient with THE syndrome and present the genetic analysis that facilitated diagnosis.
METHODS: Whole-exome sequencing (WES) was performed in a 4-month-old female with history of congenital diarrhea and severe failure to thrive but without hair anomalies or dysmorphism. Since the parents were first-degree cousins, the analysis focused on an autosomal recessive model. Sanger sequencing was used to validate suspected variants. Mutated protein structure was modeled to assess the effect of the mutation on protein function.
RESULTS: We identified an autosomal recessive C.1891G > A missense mutation (NM_006929) in SKIV2L gene that was previously described only in a compound heterozygous state as causing THE syndrome. The mutation was determined to be deleterious in multiple prediction models. Protein modeling suggested that the mutation has the potential to cause structural destabilization of SKIV2L, either through conformational changes, interference with the protein’s packing, or changes at the protein’s interface.
CONCLUSIONS: THE syndrome can present with a broad range of clinical features in the neonatal period. WES is an important diagnostic tool in patients with congenital diarrhea and can facilitate diagnosis of various diseases presenting with atypical features.

PMID: 29484573 [PubMed – as supplied by publisher]

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Novel CARMIL2 Mutations in Patients with Variable Clinical Dermatitis, Infections, and Combined Immunodeficiency.

Front Immunol. 2018;9:203

Authors: Alazami AM, Al-Helale M, Alhissi S, Al-Saud B, Alajlan H, Monies D, Shah Z, Abouelhoda M, Arnaout R, Al-Dhekri H, Al-Numair NS, Ghebeh H, Sheikh F, Al-Mousa H

Abstract
Combined immunodeficiencies are a heterogeneous collection of primary immune disorders that exhibit defects in T cell development or function, along with impaired B cell activity even in light of normal B cell maturation. CARMIL2 (RLTPR) is a protein involved in cytoskeletal organization and cell migration, which also plays a role in CD28 co-signaling of T cells. Mutations in this protein have recently been reported to cause a novel primary immunodeficiency disorder with variable phenotypic presentations. Here, we describe seven patients from three unrelated, consanguineous multiplex families that presented with dermatitis, esophagitis, and recurrent skin and chest infections with evidence of combined immunodeficiency. Through the use of whole exome sequencing and autozygome-guided analysis, we uncovered two mutations not previously reported (p.R50T and p.L846Sfs) in CARMIL2. Real-time PCR analysis revealed that the biallelic frameshift mutation is under negative selection, likely due to nonsense-mediated RNA decay and leading to loss of detectable protein upon immunoblotting. Protein loss was also observed for the missense mutation, and 3D modeling suggested a disturbance in structural stability due to an increase in the electrostatic energy for the affected amino acid and surrounding residues. Immunophenotyping revealed that patient Treg counts were significantly depressed, and that CD4+ T cells were heavily skewed towards the naïve status. CD3/CD28 signaling impairment was evidenced by reduced proliferative response to stimulation. This work broadens the allelic heterogeneity associated with CARMIL2 and highlights a deleterious missense alteration located outside the leucine-rich repeat of the protein, where all other missense mutations have been reported to date.

PMID: 29479355 [PubMed]

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Evaluation of infectious and non-infectious complications in patients with primary immunodeficiency.

Cent Eur J Immunol. 2017;42(4):336-341

Authors: Bazregari S, Azizi G, Tavakol M, Asgardoon MH, Kiaee F, Tavakolinia N, Valizadeh A, Abolhassani H, Aghamohammadi A

Abstract
Introduction: Primary immunodeficiency diseases (PIDs) are a heterogeneous group of genetic immune disorders. PID patients suffer from a variety of complications. The aim of this study was to determine the infectious and non-infectious complications among PID patients.
Material and methods: This retrospective cohort study was performed on recorded data of 202 PID patients who were diagnosed with eight major categories: common variable immunodeficiency (CVID), X-linked agammaglobulinemia, hyper-IgM syndrome, hyper IgE syndrome, chronic granulomatous disease (CGD), ataxia telangiectasia, hereditary angioedema and leukocyte adhesion deficiency. For all patients, infectious and non-infectious manifestations and laboratory data were collected in a comprehensive questionnaire.
Results: Infectious complications were more frequent than non-infectious complications. Pneumonia and otitis media were the main infectious problems in PID patients, especially in patients with antibody deficiencies. Among the non-infectious complications, splenomegaly and hepatomegaly were the most common complications in PID patients, and were more commonly seen in CGD patients than others. Splenomegaly, hepatomegaly and autoimmunity were the most common findings in CVID patients. A significant correlation was observed between diagnostic delay and bronchiectasis in CVID patients (p = 0.042).
Conclusions: PID patients are at risk of multiple infectious and non-infectious problems. Timely diagnosis of PIDs not only improves their outcome and quality of life, but also helps prevent these troubling complications.

PMID: 29479289 [PubMed]

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