Manish Butte

Preclinical Development of Autologous Hematopoietic Stem Cell-Based Gene Therapy for Immune Deficiencies: A Journey from Mouse Cage to Bed Side.

June 18, 2020 By Manish Butte

Preclinical Development of Autologous Hematopoietic Stem Cell-Based Gene Therapy for Immune Deficiencies: A Journey from Mouse Cage to Bed Side.

Pharmaceutics. 2020 Jun 13;12(6):

Authors: Garcia-Perez L, Ordas A, Canté-Barrett K, Meij P, Pike-Overzet K, Lankester A, Staal FJT

Abstract
Recent clinical trials using patient’s own corrected hematopoietic stem cells (HSCs), such as for primary immunodeficiencies (Adenosine deaminase (ADA) deficiency, X-linked Severe Combined Immunodeficiency (SCID), X-linked chronic granulomatous disease (CGD), Wiskott-Aldrich Syndrome (WAS)), have yielded promising results in the clinic; endorsing gene therapy to become standard therapy for a number of diseases. However, the journey to achieve such a successful therapy is not easy, and several challenges have to be overcome. In this review, we will address several different challenges in the development of gene therapy for immune deficiencies using our own experience with Recombinase-activating gene 1 (RAG1) SCID as an example. We will discuss product development (targeting of the therapeutic cells and choice of a suitable vector and delivery method), the proof-of-concept (in vitro and in vivo efficacy, toxicology, and safety), and the final release steps to the clinic (scaling up, good manufacturing practice (GMP) procedures/protocols and regulatory hurdles).

PMID: 32545727 [PubMed]

Monoclonal Gammopathy of Undetermined Significance (MGUS)-Not So Asymptomatic after All.

June 18, 2020 By Manish Butte

Monoclonal Gammopathy of Undetermined Significance (MGUS)-Not So Asymptomatic after All.

Cancers (Basel). 2020 Jun 12;12(6):

Authors: Lomas OC, Mouhieddine TH, Tahri S, Ghobrial IM

Abstract
Monoclonal Gammopathy of Undetermined Significance (MGUS) is considered to be a benign precursor condition that may progress to a lymphoproliferative disease or multiple myeloma. Most patients do not progress to an overt condition, but nevertheless, MGUS is associated with a shortened life expectancy and, in a minority of cases, a number of co-morbid conditions that include an increased fracture risk, renal impairment, peripheral neuropathy, secondary immunodeficiency, and cardiovascular disease. This review aims to consolidate current evidence for the significance of these co-morbidities before considering how best to approach these symptoms and signs, which are often encountered in primary care or within a number of specialties in secondary care.

PMID: 32545521 [PubMed]

RAC2 and primary human immune deficiencies.

June 17, 2020 By Manish Butte

RAC2 and primary human immune deficiencies.

J Leukoc Biol. 2020 Jun 15;:

Authors: Lougaris V, Baronio M, Gazzurelli L, Benvenuto A, Plebani A

Abstract
RAC2 is a GTPase that is exclusively expressed in hematopoietic cells. Animal models have suggested important roles for RAC2 in the biology of different cell types, such as neutrophils and lymphocytes. Primary immunodeficiencies represent “experimentum naturae” and offer priceless insight on the function of the human immune system. Mutations in RAC2 have been identified in a small number of patients giving rise to different forms of primary immunodeficiencies ranging from granulocyte defects caused by dominant negative mutations to combined immunodeficiency due to dominant activating mutations. This review will focus on the clinical and immunologic phenotype of patients with germline mutations in RAC2.

PMID: 32542921 [PubMed – as supplied by publisher]

Interstitial pneumonia as the initial presentation in an infant with a novel mutation of CD40 ligand-associated X-linked hyper-IgM syndrome: A case report.

June 17, 2020 By Manish Butte

Interstitial pneumonia as the initial presentation in an infant with a novel mutation of CD40 ligand-associated X-linked hyper-IgM syndrome: A case report.

Medicine (Baltimore). 2020 Jun 12;99(24):e20505

Authors: Li J, Miao H, Wu L, Fang Y

Abstract
INTRODUCTION: X-linked hyper-IgM syndrome is a type of primary combined immunodeficiency disorder caused by mutations in CD40 ligand. Opportunistic infections caused by P jirovecii, cytomegalovirus (CMV), or fungi are frequently the first presenting symptom of the patients with X-linked hyper-IgM syndrome.
PATIENT CONCERNS: Here, we report a 10-month-old infant who presented with cyanosis and shortness of breath. The infant exhibited no medical or birth history indicating a primary immune deficiency and was first diagnosed with interstitial pneumonia and acute respiratory failure on admission.
DIAGNOSES: The infant was diagnosed with Pneumocystis jirovecii pneumonia combined with CMV and fungal infection through gene sequencing by nasopharyngeal swab and G-test. Whole-exome sequencing from a blood sample was performed and identified a functional mutation across the CD40 ligand gene (NM_000074;exon1;C.86_87del) resulting in an amino acid change (P.T29Sfl*18) attributed to X-linked hyper IgM syndrome.
INTERVENTIONS: The infant received continuous positive airway pressure ventilation treatment combined with trimethoprim-sulfamethoxazole for Pneumocystis jirovecii pneumonia, ganciclovir for CMV, voriconazole for fungal infection and substitution of high-dose immunoglobulin.
OUTCOMES: Six months after discharge from our hospital, the infant remained well.
CONCLUSION: Opportunistic infections should be suspected in infants presenting with severe interstitial pneumonia. Primary immune deficiency diseases should also be considered in infants diagnosed with opportunistic infections.

PMID: 32541472 [PubMed – in process]

Flow-cytometry as an auxiliary in the diagnosis of primary humoral immunodeficiencies.

June 17, 2020 By Manish Butte

Flow-cytometry as an auxiliary in the diagnosis of primary humoral immunodeficiencies.

Gac Med Mex. 2020;156(3):194-200

Authors: Santos-Argumedo L, Berrón-Ruiz L, López-Herrera G, Moreno-Corona NC

Abstract
Background: Antibody deficiencies encompass a wide spectrum of pathologies and constitute approximately 50 % of primary immunodeficiencies; with cytometry, it is possible to evaluate the immune status rapidly, effectively and at low cost.
Objective: To assess, by means of flow cytometry, the cells of patients with three types of primary humoral immunodeficiencies.
Method: Using flow cytometry, blood samples from patients and healthy subjects were analyzed with different monoclonal antibodies.
Results: Using various stains, a severe decrease in B lymphocytes was shown in patients with X-linked agammaglobulinemia, as well as a lack of CD154 expression in patients with hyper-immunoglobulin M syndrome, and heterogeneity of B lymphocyte subpopulations in patients with common variable immunodeficiency.
Conclusion: Flow cytometry enables early diagnosis of primary immunodeficiencies with a high level of confidence and, in many cases, identification of the genes involved.

PMID: 32538998 [PubMed – in process]

A TYK2 Gene Mutation c.2395G>A Leads to TYK2 Deficiency: A Case Report and Literature Review.

June 17, 2020 By Manish Butte

A TYK2 Gene Mutation c.2395G>A Leads to TYK2 Deficiency: A Case Report and Literature Review.

Front Pediatr. 2020;8:253

Authors: Wu P, Chen S, Wu B, Chen J, Lv G

Abstract
Tyrosine kinase 2 (TYK2) deficiency was formerly defined in patients suffering from autosomal recessive hyperimmunoglobulin E syndrome (AR-HIES). In recent years, it was proposed that human TYK2 deficiency is probably not a common cause of the AR-HIES but a distinctive illness object. In the current work, a recessive TYK2 deficiency is reported in a patient suffering from BCG disease and recurrent respiratory infection. It was implied that this patient carried novel missense homozygous mutation (c.2395G>A, p. G799R) in the TYK2. Both the in vivo and in vitro experiments indicated the inhibition effects of the c.2395G>A homozygous mutation on the TYK2 gene and protein expression. By literature review, we summarized the clinical manifestations, gene mutations, and related cytokine responses of formerly reported patients possessing TYK2 deficiency. The core manifestation of these patients is infected by intracellular pathogens, such as mycobacteria and/or viruses. Therefore, the possibility of TYK2 deficiency should be considered when a patient has repeated intracellular bacteria (including tuberculosis bacillus infection), repeated viral infection or eczema.

PMID: 32537443 [PubMed]

Specific Antibody Immunodeficiency Presenting With Streptococcal pneumonia-Induced Spontaneous Bacterial Peritonitis.

June 17, 2020 By Manish Butte

Specific Antibody Immunodeficiency Presenting With Streptococcal pneumonia-Induced Spontaneous Bacterial Peritonitis.

Allergy Rhinol (Providence). 2020 Jan-Dec;11:2152656720928065

Authors: Jeskey J, Parida A, Graven K, Hostoffer R

Abstract
Specific antibody immunodeficiency (SAD) is a primary immunodeficiency disorder characterized by normal levels of serum immunoglobulins (IgG, IgA, and IgM) associated with a dysfunctional immune response. SAD is associated with recurrent infections in the setting of an insufficient response to polysaccharide vaccinations. Streptococcus pneumoniae is a well-established cause of respiratory infections in SAD. However, there has been a paucity of evidence of pneumococcal peritonitis in SAD patients, being reported as spontaneous in acquired immunodeficiency such as AIDS. We report the first case of S. pneumoniae-induced peritonitis as the presenting sign for SAD.

PMID: 32537259 [PubMed]

A curious case of delayed hemolytic transfusion reaction with evanescent antibodies in a patient with hereditary hemorrhagic telangiectasia.

June 17, 2020 By Manish Butte

A curious case of delayed hemolytic transfusion reaction with evanescent antibodies in a patient with hereditary hemorrhagic telangiectasia.

Transfusion. 2019 12;59(12):3570-3574

Authors: Lemay AS, Faughnan M, Krok E, Pavenski K

Abstract
BACKGROUND: Delayed hemolytic reactions are potential complications of incompatible transfusions and are usually associated with the identification of a new antibody on serologic studies, following a second immunization event. However, in rare cases, the antibody investigation remains negative even if the clinical presentation would lead one to suspect otherwise.
CASE REPORT: A 44-year-old woman with hereditary hemorrhagic telangiectasia presented to the emergency department with hematuria and low back pain after she had received three units of RBCs 2 weeks earlier. Hematology and biochemistry results were consistent with delayed hemolytic transfusion reaction, but surprisingly, serologic antibody investigations were negative. It was only when her plasma was tested with enzyme (ficin)-treated panel cells that anti-e was finally detected, with a 3+ reaction with all homozygous e+ cells. No reaction was seen with heterozygous e+ cells. Four months later, an anti-K was also detected on standard panels, while the anti-e remained detectable only with ficin-treated panel cells. Three years later, both antibodies had vanished and remained undetectable. The weakness of anti-e reaction, combined with the quick evanescence of both antibodies led to the suspicion of a potential underlying immunodeficiency disorder, which was confirmed by low immunoglobulin levels on two occasions.
CONCLUSION: To our knowledge, this is the first case of immunodeficiency disorder diagnosed after the identification of evanescent antibody reactions. This case also outlines the importance of a good clinical history that should lead to further investigations when a hemolytic transfusion reaction is suspected.

PMID: 31710384 [PubMed – indexed for MEDLINE]

Oral plasma kallikrein inhibitor BCX7353 for treatment of hereditary angioedema.

June 17, 2020 By Manish Butte

Oral plasma kallikrein inhibitor BCX7353 for treatment of hereditary angioedema.

Immunotherapy. 2019 12;11(17):1439-1444

Authors: Hwang JR, Hwang G, Johri A, Craig T

Abstract
Hereditary angioedema (HAE) is rare disorder caused by a SERPING1 gene mutation that triggers severe swelling of the skin and upper airway. Treatment options for HAE with deficient and dysfunctional C1-inhibitor are expanding to include small-molecule drugs that inhibit protein interactions in the kallikrein-kinin system. Discovered by BioCryst Pharmaceuticals, BCX7353 is a synthetic, once-daily, small molecule drug that can be taken as an oral capsule to treat HAE attacks and for prophylaxis. This article will summarize recent and current BCX7353 clinical trials. Overall, results indicate BCX7353 is a promising form of therapy with a rapid 1 h onset of action, long duration of action, and acceptable tolerance.

PMID: 31635497 [PubMed – indexed for MEDLINE]

Dedicator of cytokinesis protein 2 couples with lymphoid enhancer-binding factor 1 to regulate expression of CD21 and B-cell differentiation.

June 17, 2020 By Manish Butte

Dedicator of cytokinesis protein 2 couples with lymphoid enhancer-binding factor 1 to regulate expression of CD21 and B-cell differentiation.

J Allergy Clin Immunol. 2019 11;144(5):1377-1390.e4

Authors: Jing Y, Kang D, Liu L, Huang H, Chen A, Yang L, Jiang P, Li N, Miller H, Liu Z, Zhu X, Yang J, Wang X, Sun J, Liu Z, Liu W, Zhou X, Liu C

Abstract
BACKGROUND: B-cell receptor (BCR) signaling, combined with CD19 and CD21 signals, imparts specific control of B-cell responses. Dedicator of cytokinesis protein 2 (DOCK2) is critical for the migration and motility of lymphocytes. Although absence of DOCK2 leads to lymphopenia, little is known about the signaling mechanisms and physiologic functions of DOCK2 in B cells.
OBJECTIVE: We sought to determine the underlying molecular mechanism of how DOCK2 regulates BCR signaling and peripheral B-cell differentiation.
METHODS: In this study we used genetic models for DOCK2, Wiskott-Aldrich syndrome protein (WASP), and lymphoid enhancer-binding factor 1 deficiency to study their interplay in BCR signaling and B-cell differentiation.
RESULTS: We found that the absence of DOCK2 led to downregulation of proximal and distal BCR signaling molecules, including CD19, but upregulation of SH2-containing inositol 5 phosphatase 1, a negative signaling molecule. Interestingly, DOCK2 deficiency reduced CD19 and CD21 expression at the mRNA and/or protein levels and was associated with reduced numbers of marginal zone B cells. Additionally, loss of DOCK2 reduced activation of WASP and accelerated degradation of WASP, resulting into reduced actin accumulation and early activation of B cells. Mechanistically, the absence of DOCK2 upregulates the expression of lymphoid enhancer-binding factor 1. These differences were associated with altered humoral responses in the absence of DOCK2.
CONCLUSIONS: Overall, our study has provided a novel underlying molecular mechanism of how DOCK2 deficiency regulates surface expression of CD21, which leads to downregulation of CD19-mediated BCR signaling and marginal zone B-cell differentiation.

PMID: 31405607 [PubMed – indexed for MEDLINE]