Manish Butte

Primary immunodeficiencies caused by mutations in actin regulatory proteins.

December 4, 2019 By Manish Butte

Primary immunodeficiencies caused by mutations in actin regulatory proteins.

Immunol Rev. 2019 01;287(1):121-134

Authors: Janssen E, Geha RS

Abstract
The identification of patients with monogenic gene defects have illuminated the function of different proteins in the immune system, including proteins that regulate the actin cytoskeleton. Many of these actin regulatory proteins are exclusively expressed in leukocytes and regulate the formation and branching of actin filaments. Their absence or abnormal function leads to defects in immune cell shape, cellular projections, migration, and signaling. Through the study of patients’ mutations and generation of mouse models that recapitulate the patients’ phenotypes, our laboratory and others have gained a better understanding of the role these proteins play in cell biology and the underlying pathogenesis of immunodeficiencies and immune dysregulatory syndromes.

PMID: 30565251 [PubMed – indexed for MEDLINE]

Primary immunodeficiencies reveal the essential role of tissue neutrophils in periodontitis.

December 4, 2019 By Manish Butte

Primary immunodeficiencies reveal the essential role of tissue neutrophils in periodontitis.

Immunol Rev. 2019 01;287(1):226-235

Authors: Silva LM, Brenchley L, Moutsopoulos NM

Abstract
Periodontitis is a common human inflammatory disease. In this condition, microbiota trigger excessive inflammation in oral mucosal tissues surrounding the dentition, resulting in destruction of tooth-supporting structures (connective tissue and bone). While susceptibility factors for common forms of periodontitis are not clearly understood, studies in patients with single genetic defects reveal a critical role for tissue neutrophils in disease susceptibility. Indeed, various genetic defects in the development, egress from the bone marrow, chemotaxis, and extravasation are clearly linked to aggressive/severe periodontitis at an early age. Here, we provide an overview of genetic defects in neutrophil biology that are linked to periodontitis. In particular, we focus on the mechanisms underlying Leukocyte Adhesion Deficiency-I, the prototypic Mendelian defect of impaired neutrophil extravasation and severe periodontitis.

PMID: 30565245 [PubMed – indexed for MEDLINE]

Lessons from primary immunodeficiencies: Autoimmune regulator and autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.

December 4, 2019 By Manish Butte

Lessons from primary immunodeficiencies: Autoimmune regulator and autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.

Immunol Rev. 2019 01;287(1):103-120

Authors: Constantine GM, Lionakis MS

Abstract
The discovery of the autoimmune regulator (AIRE) protein and the delineation of its critical contributions in the establishment of central immune tolerance has significantly expanded our understanding of the immunological mechanisms that protect from the development of autoimmune disease. The parallel identification and characterization of patient cohorts with the monogenic disorder autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), which is typically caused by biallelic AIRE mutations, has underscored the critical contribution of AIRE in fungal immune surveillance at mucosal surfaces and in prevention of multiorgan autoimmunity in humans. In this review, we synthesize the current clinical, genetic, molecular and immunological knowledge derived from basic studies in Aire-deficient animals and from APECED patient cohorts. We also outline major advances and research endeavors that show promise for informing improved diagnostic and therapeutic approaches for patients with APECED.

PMID: 30565240 [PubMed – indexed for MEDLINE]

Pathogenic CARD11 mutations affect B cell development and differentiation through a noncanonical pathway.

December 1, 2019 By Manish Butte

Pathogenic CARD11 mutations affect B cell development and differentiation through a noncanonical pathway.

Sci Immunol. 2019 Nov 29;4(41):

Authors: Wei Z, Zhang Y, Chen J, Hu Y, Jia P, Wang X, Zhao Q, Deng Y, Li N, Zang Y, Qin J, Wang X, Lu W

Abstract
Pathogenic CARD11 mutations cause aberrant nuclear factor κB (NF-κB) activation, which is presumably responsible for multiple immunological disorders. However, whether there is an NF-κB-independent regulatory mechanism contributing to CARD11 mutations related to pathogenesis remains undefined. Using three distinct genetic mouse models, the Card11 knockout (KO) mouse model mimicking primary immunodeficiency, the CARD11 E134G point mutation mouse model representing BENTA (B cell expansion with NF-κB and T cell anergy) disease, and the mouse model bearing oncogenic K215M mutation, we show that CARD11 has a noncanonical function as a negative regulator of the AKT-FOXO1 signal axis, independent of NF-κB activation. Although BENTA disease-related E134G mutant elevates NF-κB activation, we find that E134G mutant mice phenotypically copy Card11 KO mice, in which NF-κB activation is disrupted. Mechanistically, the E134G mutant causes exacerbated AKT activation and reduced FOXO1 protein in B cells similar to that in Card11 KO cells. Moreover, the oncogenic CARD11 mutant K215M reinforces the importance of the noncanonical function of CARD11. In contrast to the E134G mutant, K215M shows a stronger inhibitory effect on AKT activation and more stabilized FOXO1. Likewise, E134G and K215M mutants have converse impacts on B cell development and differentiation. Our results demonstrate that, besides NF-κB, CARD11 also governs the AKT/FOXO1 signaling pathway in B cells. The critical role of CARD11 is further revealed by the effects of pathogenic CARD11 mutants on this noncanonical regulatory function on the AKT-FOXO1 signaling axis.

PMID: 31784498 [PubMed – in process]

Computational Analysis of nsSNPs of ADA Gene in Severe Combined Immunodeficiency Using Molecular Modeling and Dynamics Simulation.

November 30, 2019 By Manish Butte

Computational Analysis of nsSNPs of ADA Gene in Severe Combined Immunodeficiency Using Molecular Modeling and Dynamics Simulation.

J Immunol Res. 2019;2019:5902391

Authors: Essadssi S, Krami AM, Elkhattabi L, Elkarhat Z, Amalou G, Abdelghaffar H, Rouba H, Barakat A

Abstract
Severe combined immunodeficiency (SCID) is the most severe form of primary immunodeficiency (PID), characterized by fatal opportunistic infections. The ADA gene encodes adenosine deaminase, an enzyme that catalyzes the irreversible deamination of adenosine and deoxyadenosine in the catabolic pathway of purine. Mutations of the ADA gene have been identified in patients with severe combined immunodeficiency. In this study, we performed a bioinformatics analysis of the human ADA gene to identify potentially harmful nonsynonymous SNPs and their effect on protein structure and stability. Using eleven prediction tools, we identified 15 nsSNPs (H15D, H15P, H17Q, H17Y, D19N, T26I, G140E, C153F, A183D, G216R, H258Y, C262Y, S291L, S291W, and K34OE) as harmful. The results of ConSurf’s analysis revealed that all these nsSNPs are localised in the highly conserved positions and affect the structure of the native proteins. In addition, our computational analysis showed that the H15D, G140E, G216R, and S291L mutations identified as being associated with severe combined immunodeficiency affect protein structure. Similarly, the results of the analyses of Rmsd, Rmsf, and Rg showed that all these factors influence protein stability, flexibility, and compaction with different levels of impact. This study is the first comprehensive computational analysis of nsSNPs of the ADA gene. However, functional analyses are needed to elucidate the biological mechanisms of these polymorphisms in severe combined immunodeficiency.

PMID: 31781678 [PubMed – in process]

Conditioning Perspectives for Primary Immunodeficiency Stem Cell Transplants.

November 30, 2019 By Manish Butte

Conditioning Perspectives for Primary Immunodeficiency Stem Cell Transplants.

Front Pediatr. 2019;7:434

Authors: Shaw P, Shizuru J, Hoenig M, Veys P, IEWP-EBMT

Abstract
The majority of children undergoing Hematopoietic Stem cell Transplantation (HSCT) require conditioning therapy to make space and prevent rejection of the donor stem cells. The exception is certain children with Severe Combined immune deficiency, who have limited or no ability to reject the donor graft. Transplant conditioning is associated with significant morbidity and mortality from both direct toxic effects of chemotherapy as well as opportunistic infections associated with profound immunosuppression. The ultimate goal of transplant practice is to achieve sufficient engraftment of donor cells to correct the underlying disease with minimal short- and long-term toxicity to the recipient. Traditional combinations, such as busulfan and cyclophosphamide, achieve a high rate of full donor engraftment, but are associated with significant acute transplant-related-mortality and late effects such as infertility. Less “intensive” approaches, such as combinations of treosulfan or melphalan with fludarabine, are less toxic, but may be associated with rejection or low level chimerism requiring the need for re-transplantation. The major benefit of these novel approaches, however, which we hope will be realized in the decades to come, may be the preservation of fertility. Future approaches look to replace chemotherapy with non-toxic antibody conditioning. The lessons learnt in refining conditioning for HSCT are likely to be equally applicable to gene therapy protocols for the same diseases.

PMID: 31781522 [PubMed]

Defining the biological responses of IL-6 by the study of a novel IL-6 receptor chain (IL6R) immunodeficiency.

November 29, 2019 By Manish Butte

Defining the biological responses of IL-6 by the study of a novel IL-6 receptor chain (IL6R) immunodeficiency.

J Allergy Clin Immunol. 2019 Nov 25;:

Authors: Nahum A, Sharfe N, Broides A, Dadi H, Naghdi Z, Mandola AB, Vong L, Arbiv A, Dalal I, Levy J, Brami I, Wormser O, Roifman CM

Abstract
We describe immunodeficiency arising from ablation of IL6R expression that is characterized by recurrent infections, eczema, high IgE titers, and absent CRP acute-phase response.

PMID: 31778705 [PubMed – as supplied by publisher]

NEUROENDOCRINE TUMOR IN A CHILD WITH COMMON VARIABLE IMMUNODEFICIENCY.

November 29, 2019 By Manish Butte

NEUROENDOCRINE TUMOR IN A CHILD WITH COMMON VARIABLE IMMUNODEFICIENCY.

Rev Paul Pediatr. 2019;38:e2018146

Authors: Antunes PSL, Tersariol HG, Veiga MMB, Menezes MCS, Bernardi FDC, Forte WCN

Abstract
OBJECTIVE: To report a case of a child with primary immunodeficiency who at eight years developed digestive symptoms, culminating with the diagnosis of a neuroendocrine tumor at ten years of age.
CASE DESCRIPTION: One-year-old boy began to present recurrent pneumonias in different pulmonary lobes. At four years of age, an immunological investigation showed a decrease in IgG and IgA serum levels. After the exclusion of other causes of hypogammaglobinemia, he was diagnosed with a Common Variable Immunodeficiency and started to receive monthly replacement of human immunoglobulin. The patient evolved well, but at 8 years of age began with epigastrium pain and, at 10 years, chronic persistent diarrhea and weight loss. After investigation, a neuroendocrine tumor was diagnosed, which had a rapid progressive evolution to death.
COMMENTS: Medical literature has highlighted the presence of gastric tumors in adults with Common Variable Immunodeficiency, emphasizing the importance of early diagnosis and the investigation of digestive neoplasms. Up to now there is no description of neuroendocrine tumor in pediatric patients with Common Variable Immunodeficiency. We believe that the hypothesis of digestive neoplasm is important in children with Common Variable Immunodeficiency and with clinical manifestations similar to the case described here in the attempt to improve the prognosis for pediatric patients.

PMID: 31778409 [PubMed – in process]

Atopic dermatitis without serum immunoglobulin E elevation or loss-of-function filaggrin gene mutation in a patient with X-linked agammaglobulinemia.

November 28, 2019 By Manish Butte

Atopic dermatitis without serum immunoglobulin E elevation or loss-of-function filaggrin gene mutation in a patient with X-linked agammaglobulinemia.

J Dermatol. 2019 Nov 27;:

Authors: Yamazaki E, Kikuchi K, Sasahara Y, Kono M, Akiyama M, Aiba S

Abstract
A case of atopic dermatitis (AD) with X-linked agammaglobulinemia (XLA), which is one of the primary immunodeficiency diseases, is reported. A 12-year-old boy had suffered from dry skin and recurrent itchy eruptions since he was 2 years old, and he was diagnosed as having XLA at the age of 4 years. His total immunoglobulin (Ig)E level was 7 IU/mL, even with regular Ig replacement therapy. Furthermore, filaggrin (FLG) mutations known in the Japanese population were not found. His skin lesions were well controlled by the application of a mild-class topical steroid and a moisturizer, though he developed folliculitis due to Staphylococcus aureus infection during treatment with a strong-class topical steroid. This case suggests that the FLG mutation and IgE-mediated sensitization are not necessary to induce AD skin manifestation.

PMID: 31773767 [PubMed – as supplied by publisher]

The screening of pivotal gene expression signatures and biomarkers in renal carcinoma.

November 28, 2019 By Manish Butte

The screening of pivotal gene expression signatures and biomarkers in renal carcinoma.

J Cancer. 2019;10(25):6384-6394

Authors: Ruan H, Li S, Tong J, Cao Q, Song Z, Wang K, Huang Y, Bao L, Chen X, Yang H, Chen K, Zhang X

Abstract
Renal cell carcinoma (RCC) is one of the most common malignancies in the urinary system, among which the proportion of clear cell RCC (ccRCC) is over 80%. This study aims to explore potential signaling pathways and key biomarkers that drive RCC progression. The RCC GEO Datasets GSE15641 was featured to screen differentially expressed genes (DEGs). The pathway enrichment and functional annotation of differentially expressed genes were analyzed using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and the Gene Ontology (GO). We screened Hub genes from DEGs using protein-protein interaction (PPI) networks and Cytoscape software. The survival and diagnostic analysis of these hub genes was performed to evaluate their potential prognostic and diagnostic value for ccRCC. In GSE15641 dataset, 598 DEGs were captured according to screening criteria (406 up-regulated genes and 192 down-regulated genes). Meanwhile, 15 hub genes were screened out from DEGs using PPI and Cytoscape. Kaplan Meier and ROC curve analysis identified three potential prognostic and diagnostic biomarkers (TGFB1, TIMP1 and VIM) for ccRCC from 15 hub genes. Gene set enrichment analysis (GSEA) revealed that these three dysregulated genes are mainly enriched in primary immunodeficiency, ECM receptor interaction, cytokine receptor interaction and natural killer cell-mediated cytotoxicity pathway. In summary, our findings discovered pivotal gene expression signatures and signaling pathways in the progression of ccRCC. TGFB1, TIMP1 and VIM might contribute to the progression of ccRCC, which could have potential as biomarkers or therapeutic targets for ccRCC.

PMID: 31772671 [PubMed]