Research

The microbiome and immunodeficiencies: Lessons from rare diseases.

February 2, 2019 By Manish Butte

The microbiome and immunodeficiencies: Lessons from rare diseases.

J Autoimmun. 2019 Jan 28;:

Authors: Pellicciotta M, Rigoni R, Falcone EL, Holland SM, Villa A, Cassani B

Abstract
Primary immunodeficiencies (PIDs) are inherited disorders of the immune system, associated with a considerable increase in susceptibility to infections. PIDs can also predispose to malignancy, inflammation and autoimmunity. There is increasing awareness that some aspects of the immune dysregulation in PIDs may be linked to intestinal microbiota. Indeed, the gut microbiota and its metabolites have been shown to influence immune functions and immune homeostasis both locally and systemically. Recent studies have indicated that genetic defects causing PIDs lead to perturbations in the conventional mechanisms underlying homeostasis in the gut, resulting in poor immune surveillance at the intestinal barrier, which associates with altered intestinal permeability and bacterial translocation. Consistently, a substantial proportion of PID patients presents with clinically challenging IBD-like pathology. Here, we describe the current body of literature reporting on dysbiosis of the gut microbiota in different PIDs and how this can be either the result or cause of immune dysregulation. Further, we report how infections in PIDs enhance pathobionts colonization and speculate how, in turn, pathobionts may be responsible for increased disease susceptibility and secondary infections in these patients. The potential relationship between the microbial composition in the intestine and other sites, such as the oral cavity and skin, is also highlighted. Finally, we provide evidence, in preclinical models of PIDs, for the efficacy of microbiota manipulation to ameliorate disease complications, and suggest that the potential use of dietary intervention to correct dysbiotic flora in PID patients may hold promise.

PMID: 30704941 [PubMed – as supplied by publisher]

AWARENESS OF PRIMARY IMMUNODEFICIENCY DISEASES AMONG MEDICAL STUDENTS.

February 1, 2019 By Manish Butte

AWARENESS OF PRIMARY IMMUNODEFICIENCY DISEASES AMONG MEDICAL STUDENTS.

Georgian Med News. 2018 Dec;(285):124-130

Authors: Boyarchuk O, Volyanska L, Kosovska T, Lewandowicz-Uszynska A, Kinash M

Abstract
Primary immunodeficiency diseases (PID) are a group of more than 300 rare, chronic disorders in which a part of the body’s immune system is missing or functions improperly. The issue of early diagnosis, timely and effective treatment, prevention of complications and improved prognosis remains extremely relevant. The aim of this study was to assess the awareness of graduating medical university students about the signs of primary immunodeficiency in children and adults. A survey on awareness of primary immunodeficiencies was conducted among sixth year (graduating) students of the Faculty of Medicine of I.Horbachevsky Ternopil State Medical University, Ukraine. Questionnaires were offered to 271 students. The questionnaire consisted of 25 questions. The average percentage of correct answers given by the surveyed students for each question was 59.2% (ranging from 22.5% to 82.3%). The percentage of correct answers to the questions about warning signs of PID in children was 64.4%, and in adults was 54.2% (p=0.0491). The percentage of correct answers to the questions about general signs of PID was 61.6% and about specific signs of PID 51.7% (p=0.0016). The percentages of correct answers among surveyed students ranged from 26 to 88%. 223 (82.3%) medical students gave more than 50% of correct answers to all questions, but only 21 surveyed students (7.7%) gave more than 75% of correct answers. This study has revealed the lack of awareness for PID among medical students. The lowest knowledge was about PID warning signs in adults and the specific signs of PID, especially those concerning verification and management of Nijmegan breakage syndrome and common variable immunodeficiency. This study indicates a significant need to increase knowledge of medical students about primary immunodeficiencies, taking into account low levels of diagnosis of these diseases in Ukraine and the need to raise knowledge and awareness about PID among physicians of all specialties.

PMID: 30702085 [PubMed – in process]

Progress and history of the 10th Federation of African Immunological Societies Congress.

February 1, 2019 By Manish Butte

Progress and history of the 10th Federation of African Immunological Societies Congress.

J Leukoc Biol. 2019 Feb;105(2):229-232

Authors: Sibanda E, Barbouche MR

Abstract
The 10th Federation of African Immunological Societies (FAIS) Congress, held in Tunisia in November 2017, marked a significant scientific milestone. It enabled scientists from across the continent to promote immunology research and to showcase major achievements made by immunologists throughout Africa. This issue of the Journal of Leukocyte Biology (JLB) features manuscripts from the FAIS Congress. As noted in these papers, research in infectious diseases remains the focus of the African immunology community; however, increasingly noncommunicable diseases-such as autoimmunity, allergy, primary immunodeficiency, cancer and transplantation immunology-are also an emerging priority. This overview gives a brief history of the FAIS meeting, which also commemorated the 25th anniversary of the FAIS. It describes the current activities of the organization, as well as its history and the future opportunities for this Federation.

PMID: 30702767 [PubMed – in process]

In vitro study of HAX1 gene therapy by retro viral transduction as a therapeutic target in severe congenital neutropenia.

January 31, 2019 By Manish Butte

In vitro study of HAX1 gene therapy by retro viral transduction as a therapeutic target in severe congenital neutropenia.

Eur Cytokine Netw. 2019 Jan 28;:

Authors: Farajifard H, Zavvar M, Rajaei T, Noorbakhsh F, Nikougoftar-Zarif M, Azadmanesh K, Kompani F, Rezaei N

Abstract
Severe congenital neutropenia (SCN) is a primary immunodeficiency disease in which a number of underlying gene defects are responsible for abnormalities in neutrophil development. The HCLS1-associated protein X1 (HAX1) mutation is associated with an autosomal-recessive form of SCN. Considering the potential of gene therapy approaches for the treatment of monogenic disorders, in this study we aimed to develop retroviral vectors expressing coding sequences (CDS) to be used for the removal of the genetic blockade in deficient hematopoietic cells. Following amplification of CDS with primers containing appropriate restriction sites, HAX1 CDS was cloned into an intermediate vector using TA-cloning. The sequence was transferred into a retroviral vector, followed by retroviral packaging in Plat-A cells. To show HAX1 protein expression, HEK293T cells were exposed to 10 multiplicity of infection (MOI) of retroviral particles and HAX1 expression was confirmed in these cells, using indirect intracellular flow cytometry. This vector was applied for in vitro transduction of hematopoietic stem cell with HAX1 mutation; after 11 days, cultured cells were analyzed for CD66acde and CD177 (neutrophil surface markers) and the expression was compared to that in the control groups. Increased neutrophil production in HAX1 viral vector-expressing hematopoietic cells was observed as compared to control vector transduced cells. Hence, according to the results, this type of therapy could be considered a potential treatment protocol for the disease.

PMID: 30698159 [PubMed – as supplied by publisher]

Primary immune regulatory disorders for the pediatric hematologist and oncologist: A case-based review.

January 31, 2019 By Manish Butte

Primary immune regulatory disorders for the pediatric hematologist and oncologist: A case-based review.

Pediatr Blood Cancer. 2019 Jan 29;:e27619

Authors: Chandrakasan S, Chandra S, Davila Saldana BJ, Torgerson TR, Buchbinder D

Abstract
An array of monogenic immune defects marked by autoimmunity, lymphoproliferation, and hyperinflammation rather than infections have been described. Primary immune regulatory disorders pose a challenge to pediatric hematologists and oncologists. This paper focuses on primary immune regulatory disorders including autoimmune lymphoproliferative syndrome (ALPS) and ALPS-like syndromes, immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) and IPEX-like disorders, common variable immunodeficiency (CVID), CVID-like, and late-onset combined immunodeficiency (CID) disorders. Hyperinflammatory disorders and those associated with increased susceptibility to lymphoid malignancies are also discussed. Using a case-based approach, a review of clinical pearls germane to the clinical and laboratory evaluation as well as the treatment of these disorders is provided.

PMID: 30697957 [PubMed – as supplied by publisher]

Toll-like receptors pathway in common variable immune deficiency (CVID) and X-linked agammaglobulinemia (XLA).

January 31, 2019 By Manish Butte

Toll-like receptors pathway in common variable immune deficiency (CVID) and X-linked agammaglobulinemia (XLA).

Eur Cytokine Netw. 2019 Jan 28;:

Authors: Tavasolian P, Sharifi L, Aghamohammadi A, Noorbakhsh F, Sanaei R, Shabani M, Rezaei N

Abstract
Common variable immunodeficiency (CVID) and X-linked agammaglobulinemia (XLA) are two major humoral immunodeficiencies, causing a high rate of early age mortality in children. In order to identifiy the possible factors involved in the pathogenesis of CVID and XLA, recent studies have focused on Toll-like receptors (TLRs) and demonstrate the defects in different TLR pathways in immune cells of CVID and XLA patients. Herein, we measured TLR-4 and TLR-9 RNA levels and consequently TNF-α and IFN-α production in peripheral blood mononuclear cells (PBMCs) of patients with CVID and XLA. Contrary to healthy individuals, TLR-9 expression was not significantly increased after ligand stimulation, whereas ligand-induced TLR-4 expression was not significantly different from that in healthy control PBMCs. Lipopolysaccharide (LPS)-stimulated TNF-α production was significantly reduced in patients compared to controls, whereas IFN-α production was increased in all groups after CpG stimulation without any significant inter-group difference. Our data suggest that defects in TLR-9 activated pathways may be a result of the decreased TLR-9 expression, although TLR-9 is not the only modulator of IFN-α production in these patients. On the other hand, impaired signaling in TLR-4 activated pathways which results in significant reduction in TNF-α production are not related to a defect in TLR-4 expression.

PMID: 30698158 [PubMed – as supplied by publisher]

Comprehensive Genetic Results for Primary Immunodeficiency Disorders in a Highly Consanguineous Population.

January 31, 2019 By Manish Butte

Comprehensive Genetic Results for Primary Immunodeficiency Disorders in a Highly Consanguineous Population.

Front Immunol. 2018;9:3146

Authors: Al-Herz W, Chou J, Delmonte OM, Massaad MJ, Bainter W, Castagnoli R, Klein C, Bryceson YT, Geha RS, Notarangelo LD

Abstract
Objective: To present the genetic causes of patients with primary immune deficiencies (PIDs) in Kuwait between 2004 and 2017. Methods: The data was obtained from the Kuwait National Primary Immunodeficiency Disorders Registry. Genomic DNA from patients with clinical and immunological features of PID was sequenced using Sanger sequencing (SS), next generation sequencing (NGS) of targeted genes, whole exome sequencing (WES), and/or whole genome sequencing (WGS). Functional assays were utilized to assess the biologic effect of identified variants. Fluorescence in situ hybridization (FISH) for 22q11.2 deletion and genomic hybridizations arrays were performed when thymic defects were suspected. Results: A total of 264 patients were registered during the study period with predominance of patients with immunodeficiencies affecting cellular and humoral immunity (35.2%), followed by combined immunodeficiencies with associated syndromic features (24%). Parental consanguinity and family history suggestive of PID were reported in 213 (81%) and 145 patients (55%), respectively. Genetic testing of 206 patients resulted in a diagnostic yield of 70%. Mutations were identified in 46 different genes and more than 90% of the reported genetic defects were transmitted by in an autosomal recessive pattern. The majority of the mutations were missense mutations (57%) followed by deletions and frame shift mutations. Five novel disease-causing genes were discovered. Conclusions: Genetic testing should be an integral part in the management of primary immunodeficiency patients. This will help the delivery of precision medicine and facilitate proper genetic counseling. Studying inbred populations using sophisticated diagnostic methods can allow better understanding of the genetics of primary immunodeficiency disorders.

PMID: 30697212 [PubMed – in process]

Granulomatous-Lymphocytic Interstitial Lung Disease in 22q11.2 Deletion Syndrome: a Case Report and Literature Review.

January 31, 2019 By Manish Butte

Granulomatous-Lymphocytic Interstitial Lung Disease in 22q11.2 Deletion Syndrome: a Case Report and Literature Review.

Curr Allergy Asthma Rep. 2018 02 22;18(3):14

Authors: Sood AK, Funkhouser W, Handly B, Weston B, Wu EY

Abstract
PURPOSE OF REVIEW: Granulomatous-lymphocytic interstitial lung disease (GLILD) has classically been associated with common variable immune deficiency (CVID), but is increasingly being reported in other immunodeficiencies. We describe the second reported case of GLILD in a patient with 22q11.2 deletion syndrome (22q11.2DS) and review the recent literature surrounding GLILD.
RECENT FINDINGS: GLILD is characterized by granulomata and lymphoproliferation. Consensus statements and retrospective and case-control studies have better elucidated the clinicopathological and radiographic manifestations of GLILD, allowing for its differentiation from similar conditions like sarcoidosis. Gaps of knowledge remain, however, particularly regarding optimal management strategies. Combination therapies targeting T and B cell populations have recently shown favorable results. GLILD is associated with poorer outcomes in CVID. Its recognition as a rare complication of 22q11.2DS and other immunodeficiencies therefore has important therapeutic and prognostic implications. Additional research is needed to better understand the natural history and pathogenesis of GLILD and to develop evidence-based practice guidelines.

PMID: 29470661 [PubMed – indexed for MEDLINE]

Ibuprofen prevents progression of ataxia telangiectasia symptoms in ATM-deficient mice.

January 30, 2019 By Manish Butte

Ibuprofen prevents progression of ataxia telangiectasia symptoms in ATM-deficient mice.

J Neuroinflammation. 2018 Nov 06;15(1):308

Authors: Hui CW, Song X, Ma F, Shen X, Herrup K

Abstract
BACKGROUND: Inflammation plays a critical role in accelerating the progression of neurodegenerative diseases, such as Alzheimer’s disease (AD) and ataxia telangiectasia (A-T). In A-T mouse models, LPS-induced neuroinflammation advances the degenerative changes found in cerebellar Purkinje neurons both in vivo and in vitro. In the current study, we ask whether ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), can have the opposite effect and delay the symptoms of the disease.
METHODS: We tested the beneficial effects of ibuprofen in both in vitro and in vivo models. Conditioned medium from LPS stimulated primary microglia (LM) applied to cultures of dissociated cortical neurons leads to numerous degenerative changes. Pretreatment of the neurons with ibuprofen, however, blocked this damage. Systemic injection of LPS into either adult wild-type or adult Atm-/- mice produced an immune challenge that triggered profound behavioral, biochemical, and histological effects. We used a 2-week ibuprofen pretreatment regimen to investigate whether these LPS effects could be blocked. We also treated young presymptomatic Atm-/- mice to determine if ibuprofen could delay the appearance of symptoms.
RESULTS: Adding ibuprofen directly to neuronal cultures significantly reduced LM-induced degeneration. Curiously, adding ibuprofen to the microglia cultures before the LPS challenge had little effect, thus implying a direct effect of the NSAID on the neuronal cultures. In vivo administration of ibuprofen to Atm-/- animals before a systemic LPS immune challenge suppressed cytological damage. The ibuprofen effects were widespread as microglial activation, p38 phosphorylation, DNA damage, and neuronal cell cycle reentry were all reduced. Unfortunately, ibuprofen only slightly improved the LPS-induced behavioral deficits. Yet, while the behavioral symptoms could not be reversed once they were established in adult Atm-/- animals, administration of ibuprofen to young mutant pups prevented their symptoms from appearing.
CONCLUSION: Inflammatory processes impact the normal progression of A-T implying that modulation of the immune system can have therapeutic benefit for both the behavioral and cellular symptoms of this neurodegenerative disease.

PMID: 30400801 [PubMed – indexed for MEDLINE]

Phytochrome-Based Extracellular Matrix with Reversibly Tunable Mechanical Properties.

January 29, 2019 By Manish Butte

Phytochrome-Based Extracellular Matrix with Reversibly Tunable Mechanical Properties.

Adv Mater. 2019 Jan 27;:e1806727

Authors: Hörner M, Raute K, Hummel B, Madl J, Creusen G, Thomas OS, Christen EH, Hotz N, Gübeli RJ, Engesser R, Rebmann B, Lauer J, Rolauffs B, Timmer J, Schamel WWA, Pruszak J, Römer W, Zurbriggen MD, Friedrich C, Walther A, Minguet S, Sawarkar R, Weber W

Abstract
Interrogation and control of cellular fate and function using optogenetics is providing revolutionary insights into biology. Optogenetic control of cells is achieved by coupling genetically encoded photoreceptors to cellular effectors and enables unprecedented spatiotemporal control of signaling processes. Here, a fast and reversibly switchable photoreceptor is used to tune the mechanical properties of polymer materials in a fully reversible, wavelength-specific, and dose- and space-controlled manner. By integrating engineered cyanobacterial phytochrome 1 into a poly(ethylene glycol) matrix, hydrogel materials responsive to light in the cell-compatible red/far-red spectrum are synthesized. These materials are applied to study in human mesenchymal stem cells how different mechanosignaling pathways respond to changing mechanical environments and to control the migration of primary immune cells in 3D. This optogenetics-inspired matrix allows fundamental questions of how cells react to dynamic mechanical environments to be addressed. Further, remote control of such matrices can create new opportunities for tissue engineering or provide a basis for optically stimulated drug depots.

PMID: 30687975 [PubMed – as supplied by publisher]