Manish Butte

Immunodeficiency in the differential diagnosis of interstitial lung diseases.

January 8, 2020 By Manish Butte

Immunodeficiency in the differential diagnosis of interstitial lung diseases.

Vnitr Lek. 2019;65(11):685-693

Authors: Doubková M, Špeldová J, Chovancová Z

Abstract
Interstitial lung processes (IPP), or diffuse parenchymal lung diseases, are a broad group of diseases characterized by varying degrees of pulmonary fibrosis and inflammation affecting predominantly, but not exclusively, pulmonary interstitium. IPP mostly occur in adulthood with maximum manifestation between 40 and 70 years of age. Although IPP mostly present as a primary diagnosis, they also belong to the portfolio of pulmonary disorders in patients with primary immunodeficiencies. The authors present case reports of patients with interstitial lung involvement and primary immunodeficiencies [particularly those manifesting also in adulthood, such as common variable immunodeficiency (CVID), and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) deficiency]. In addition, we report the case of silico-sis patient with severe lymphopenia. Therefore, in patients with newly diagnosed interstitial lung disease, congenital immune system disorder should be considered. Basic immunological laboratory examination of humoral and cellular immunity should be an essential part of the differential diagnosis algorithm for interstitial lung disease.

PMID: 31906674 [PubMed – in process]

BLM Potentiates c-Jun Degradation and Alters Its Function as an Oncogenic Transcription Factor.

January 8, 2020 By Manish Butte

BLM Potentiates c-Jun Degradation and Alters Its Function as an Oncogenic Transcription Factor.

Cell Rep. 2018 07 24;24(4):947-961.e7

Authors: Priyadarshini R, Hussain M, Attri P, Kaur E, Tripathi V, Priya S, Dhapola P, Saha D, Madhavan V, Chowdhury S, Sengupta S

Abstract
Mutations in BLM helicase predispose Bloom syndrome (BS) patients to a wide spectrum of cancers. We demonstrate that MIB1-ubiquitylated BLM in G1 phase functions as an adaptor protein by enhancing the binding of transcription factor c-Jun and its E3 ligase, Fbw7α. BLM enhances the K48/K63-linked ubiquitylation on c-Jun, thereby enhancing the rate of its subsequent degradation. Functionally defective Fbw7α mutants prevalent in multiple human cancers are reactivated by BLM. However, BS patient-derived BLM mutants cannot potentiate Fbw7α-dependent c-Jun degradation. The decrease in the levels of c-Jun in cells expressing BLM prevents effective c-Jun binding to 2,584 gene promoters. This causes decreases in the transcript and protein levels of c-Jun targets in BLM-expressing cells, resulting in attenuated c-Jun-dependent effects during neoplastic transformation. Thus, BLM carries out its function as a tumor suppressor by enhancing c-Jun turnover and thereby preventing its activity as a proto-oncogene.

PMID: 30044990 [PubMed – indexed for MEDLINE]

Lymphocyte Subset Abnormalities in Pediatric-Onset Common Variable Immunodeficiency.

January 7, 2020 By Manish Butte

Lymphocyte Subset Abnormalities in Pediatric-Onset Common Variable Immunodeficiency.

Int Arch Allergy Immunol. 2020 Jan 03;:1-10

Authors: Ogulur I, Kiykim A, Baser D, Karakoc-Aydiner E, Ozen A, Baris S

Abstract
INTRODUCTION: Common variable immunodeficiency (CVID) is characterized by recurrent infections, autoimmunity, lymphoproliferation, hypogammaglobulinemia, and defective antibody production. In CVID, B-cell abnormalities were described to predict end organ involvement and prognosis. Pediatric-onset CVID is much rarer than adult CVID, and lymphocyte subset abnormalities have not been thoroughly evaluated.
OBJECTIVE: We sought to determine lymphocyte subset abnormalities and their association with end organ involvement in pediatric-onset CVID patients.
METHODS: The clinical manifestations and laboratory findings including absolute numbers and percentages of B-, T-, and NK cell populations were assessed in pediatric-onset CVID patients and compared to age-matched healthy controls. The patients were divided into 2 groups according to age at assessment (pediatric CVID patients: 10-16 years, n = 9; and adult CVID patients: >16 years, n = 13). The comparisons between lymphocyte subsets and organ involvement were also evaluated.
RESULTS: Mean age at symptom onset was 18 (3-204) months. All CVID patients with pediatric onset had decreased levels of total and memory B cells, CD4+ T cells, CD4+CD45RA+ naive T cells, and recent thymic emigrant (RTE) cells. On the other hand, they had increases in CD8+CD45RO+ memory T cells. Interestingly, adult CVID patients demonstrated high frequencies of activated and double-negative T cells, which were unique only for this group of patients. Specific cellular abnormalities associated with the reduction in B and NK cells and increase in CD8+ T cells were found in patients with bronchiectasis. Moreover, in pediatric CVID patients, low serum IgA levels and decreased numbers of naive T and RTE cells were determined as risk factors for chronic diarrhea.
CONCLUSIONS: Specific abnormalities in B- and T-lymphocyte compartments were identified in pediatric-onset CVID patients and appear to be associated with end organ manifestations.

PMID: 31901904 [PubMed – as supplied by publisher]

Mutations in topoisomerase IIβ result in a B cell immunodeficiency.

January 7, 2020 By Manish Butte

Mutations in topoisomerase IIβ result in a B cell immunodeficiency.

Nat Commun. 2019 08 13;10(1):3644

Authors: Broderick L, Yost S, Li D, McGeough MD, Booshehri LM, Guaderrama M, Brydges SD, Kucharova K, Patel NC, Harr M, Hakonarson H, Zackai E, Cowell IG, Austin CA, Hügle B, Gebauer C, Zhang J, Xu X, Wang J, Croker BA, Frazer KA, Putnam CD, Hoffman HM

Abstract
B cell development is a highly regulated process involving multiple differentiation steps, yet many details regarding this pathway remain unknown. Sequencing of patients with B cell-restricted immunodeficiency reveals autosomal dominant mutations in TOP2B. TOP2B encodes a type II topoisomerase, an essential gene required to alleviate topological stress during DNA replication and gene transcription, with no previously known role in B cell development. We use Saccharomyces cerevisiae, and knockin and knockout murine models, to demonstrate that patient mutations in TOP2B have a dominant negative effect on enzyme function, resulting in defective proliferation, survival of B-2 cells, causing a block in B cell development, and impair humoral function in response to immunization.

PMID: 31409799 [PubMed – indexed for MEDLINE]

Anesthetic Management of a Patient With Hereditary Angioedema for Oral Surgery.

January 7, 2020 By Manish Butte

Anesthetic Management of a Patient With Hereditary Angioedema for Oral Surgery.

Anesth Prog. 2019;66(1):30-32

Authors: Hosokawa R, Tsukamoto M, Nagano S, Yokoyama T

Abstract
Hereditary angioedema (HAE) is a rare genetic disease that results from deficiency or dysfunction of C1 inhibitor (C1-INH). This disease is characterized by sudden attacks of angioedema. When edema occurs in the pharynx or larynx, it can lead to serious airway compromise, including death. Physical and/or psychological stress can trigger an attack. Dental treatment, including tooth extraction, is also a recognized trigger. We report a case of a 20-year-old male with HAE who required impacted third molar extractions. C1-INH concentrate was administered 1 hour before surgery, which was completed under deep intravenous sedation. This report describes the anesthetic management of a patient with HAE and reviews treatment options and concerns.

PMID: 30883234 [PubMed – indexed for MEDLINE]

Diagnostic utility of a targeted next-generation sequencing gene panel in the clinical suspicion of systemic autoinflammatory diseases: a multi-center study.

January 7, 2020 By Manish Butte

Diagnostic utility of a targeted next-generation sequencing gene panel in the clinical suspicion of systemic autoinflammatory diseases: a multi-center study.

Rheumatol Int. 2019 05;39(5):911-919

Authors: Karacan İ, Balamir A, Uğurlu S, Aydın AK, Everest E, Zor S, Önen MÖ, Daşdemir S, Özkaya O, Sözeri B, Tufan A, Yıldırım DG, Yüksel S, Ayaz NA, Ömeroğlu RE, Öztürk K, Çakan M, Söylemezoğlu O, Şahin S, Barut K, Adroviç A, Seyahi E, Özdoğan H, Kasapçopur Ö, Turanlı ET

Abstract
Systemic autoinflammatory diseases (sAIDs) are a heterogeneous group of disorders, having monogenic inherited forms with overlapping clinical manifestations. More than half of patients do not carry any pathogenic variant in formerly associated disease genes. Here, we report a cross-sectional study on targeted Next-Generation Sequencing (NGS) screening in patients with suspected sAIDs to determine the diagnostic utility of genetic screening. Fifteen autoinflammation/immune-related genes (ADA2-CARD14-IL10RA-LPIN2-MEFV-MVK-NLRC4-NLRP12-NLRP3-NOD2-PLCG2-PSTPIP1-SLC29A3-TMEM173-TNFRSF1A) were used to screen 196 subjects from adult/pediatric clinics, each with an initial clinical suspicion of one or more sAID diagnosis with the exclusion of typical familial Mediterranean fever (FMF) patients. Following the genetic screening, 140 patients (71.4%) were clinically followed-up and re-evaluated. Fifty rare variants in 41 patients (20.9%) were classified as pathogenic or likely pathogenic and 32 of those variants were located on the MEFV gene. We detected pathogenic or likely pathogenic variants compatible with the final diagnoses and inheritance patterns in 14/140 (10%) of patients for the following sAIDs: familial Mediterranean fever (n = 7), deficiency of adenosine deaminase 2 (n = 2), mevalonate kinase deficiency (n = 2), Muckle-Wells syndrome (n = 1), Majeed syndrome (n = 1), and STING-associated vasculopathy with onset in infancy (n = 1). Targeted NGS panels have impact on diagnosing rare monogenic sAIDs for a group of patients. We suggest that MEFV gene screening should be first-tier genetic testing especially in regions with high carrier rates. Clinical utility of multi-gene testing in sAIDs was as low as expected, but extensive genome-wide familial analyses in combination with exome screening would enlighten additional genetic factors causing disease.

PMID: 30783801 [PubMed – indexed for MEDLINE]

NASPGHAN Position Paper on The Evaluation and Management for Patients with Very Early-Onset Inflammatory Bowel Disease (VEO-IBD).

January 4, 2020 By Manish Butte

NASPGHAN Position Paper on The Evaluation and Management for Patients with Very Early-Onset Inflammatory Bowel Disease (VEO-IBD).

J Pediatr Gastroenterol Nutr. 2019 Dec 30;:

Authors: Kelsen JR, Sullivan KE, Rabizadeh S, Singh N, Snapper S, Elkadri A, Grossman AB

Abstract
The rate of pediatric inflammatory bowel disease (IBD) has been increasing over the last decade and this increase has occurred most rapidly in the youngest children diagnosed <6 year, known as very early-onset inflammatory bowel disease (VEO-IBD). 1-5 These children can present with more extensive and severe disease than older children and adults. The contribution of host genetics in this population is underscored by the young age of onset and the distinct, aggressive phenotype. In fact, monogenic defects, often involving primary immunodeficiency genes, have been identified in children with VEO-IBD and have led to targeted and life-saving therapy. 4,6-10 This position paper will discuss the phenotype of VEO-IBD and outline the approach and evaluation for these children and what factors should trigger concern for an underlying immunodeficiency. We will then review the immunological assays and genetic studies that can facilitate the identification of the underlying diagnosis in patients with VEO-IBD and how this evaluation may lead to directed therapies. The position paper will also aid the pediatric gastroenterologist in recognizing when a patient should be referred to a center specializing in the care of these patients. These guidelines are intended for pediatricians, allied health professionals caring for children, pediatric gastroenterologists, pediatric pathologists and immunologists.

PMID: 31899730 [PubMed – as supplied by publisher]

Rubella Vaccine Persistence Within Cutaneous Granulomas in Common Variable Immunodeficiency Disorder.

January 4, 2020 By Manish Butte

Rubella Vaccine Persistence Within Cutaneous Granulomas in Common Variable Immunodeficiency Disorder.

Am J Dermatopathol. 2020 Jan 02;:

Authors: Bender NR, Cardwell LA, Siegel D, Sokumbi O

Abstract
Common variable immunodeficiency disorder is a primary immunodeficiency disorder characterized by reduced levels of serum immunoglobulins and impaired antibody response. This condition may be associated with development of noninfectious granulomatous dermatitis of the skin which may be disfiguring and destructive. There are no published guidelines for the treatment of cutaneous granulomas in this patient population. In recent studies, rubella virus-positive cells in granulomas were localized to M2 macrophages which have an important role in wound healing and the secretion of immunoregulatory cytokines. We present a case of treatment-refractory, disfiguring common variable immunodeficiency disorder-associated granulomatous dermatitis. Immunofluorescence microscopy of the biopsy specimen confirmed the presence of rubella vaccine capsid proteins in M2 macrophages within the granuloma, a newly recognized phenomenon in this patient population. This knowledge may serve to identify future therapeutic targets or preventative strategies for granulomatous dermatitis in patients with primary immunodeficiency disorder.

PMID: 31899704 [PubMed – as supplied by publisher]

Eczematous dermatitis in primary immunodeficiencies: A review of cutaneous clues to diagnosis.

January 4, 2020 By Manish Butte

Eczematous dermatitis in primary immunodeficiencies: A review of cutaneous clues to diagnosis.

Clin Immunol. 2019 Dec 30;:108330

Authors: Hoskins S, Skoda-Smith S, Torgerson TR, Boos MD

Abstract
Primary immunodeficiency Disorders (PIDD) are a varied group of heritable disorders characterized by defects in components of the innate and/or adaptive arms of the immune system. Although diagnosing these disorders is often challenging, the skin is a readily accessible and easily assessable organ that may provide clues to a diagnosis of PIDD. Specifically, many immunodeficiencies are associated with characteristic cutaneous eruptions that, based on their morphology, distribution and symptomatology, may suggest a specific underlying diagnosis. This review will discuss an approach to identifying and managing PIDDs that typically present with eczematous dermatitis.

PMID: 31899331 [PubMed – as supplied by publisher]

A Novel, Heterozygous Three Base-Pair Deletion in CARD11 Results in B Cell Expansion with NF-κB and T Cell Anergy Disease.

January 4, 2020 By Manish Butte

A Novel, Heterozygous Three Base-Pair Deletion in CARD11 Results in B Cell Expansion with NF-κB and T Cell Anergy Disease.

J Clin Immunol. 2020 Jan 02;:

Authors: Shields AM, Bauman BM, Hargreaves CE, Pollard AJ, Snow AL, Patel SY

Abstract
Germline gain-of-function mutations in CARD11 lead to the primary immunodeficiency, B cell expansion with NF-κB, and T cell anergy (BENTA). Herein, we report the case of a girl, presenting at 2 years of age with lymphocytosis and splenomegaly in whom a novel, in-frame, three base pair deletion in CARD11 was identified resulting in the deletion of a single lysine residue (K215del) from the coiled-coil domain. In vitro functional assays demonstrated that this variant leads to a subtle increase in baseline NF-κB signaling and impaired proliferative responses following T cell receptor and mitogenic stimulation. Previously reported immunological defects associated with BENTA appear mild in our patient who is now 6 years of age; a B cell lymphocytosis and susceptibility to upper respiratory tract infections persist; however, she has broad, sustained responses to protein-polysaccharide conjugate vaccines and displays normal proliferative responses to ex vivo T cell stimulation.

PMID: 31897776 [PubMed – as supplied by publisher]