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Old vaccines, new diseases: when BCG meets SPPL2a

Sergio D. Rosenzweig
2018 Nature Immunology  
Sergio D.  ...  Rosenzweig I n the current issue of Nature Immunology, a study from the Casanova laboratory provides yet another surprise by adding a new metabolic pathway associated with Mendelian susceptibility to mycobacterial  ... 
doi:10.1038/s41590-018-0193-0 pmid:30127437 fatcat:cf7dwt4rebby3o7t6u5zkp6zzi

News from the CIS Executive Committee

Sergio D. Rosenzweig
2014 Journal of Clinical Immunology  
doi:10.1007/s10875-013-9984-0 pmid:24402622 fatcat:7ah2kcrbs5fzbhq6wc7r25f2m4

Bacille Calmette–Guerin Complications in Newly Described Primary Immunodeficiency Diseases: 2010–2017

Cristiane de Jesus Nunes-Santos, Sergio D. Rosenzweig
2018 Frontiers in Immunology  
Less than a year later, Nunes-Santos and Rosenzweig BCG in New PIDD Frontiers in Immunology | www.frontiersin.org  ...  2 Nunes-Santos and Rosenzweig BCG in New PIDD Frontiers in Immunology | www.frontiersin.org June 2018 | Volume 9 | Article 1423 Activated phosphoinositide 3-kinase δ syndrome (APDS) in an immunodeficiency  ... 
doi:10.3389/fimmu.2018.01423 pmid:29988375 pmcid:PMC6023996 fatcat:flq22yzsqfczdendunrb5gvrg4

Bacillus Calmette-Guérin (BCG) complications associated with primary immunodeficiency diseases

Sayna Norouzi, Asghar Aghamohammadi, Setareh Mamishi, Sergio D. Rosenzweig, Nima Rezaei
2012 Journal of Infection  
Primary immunodeficiency diseases (PIDs) are a group of inherited disorders, characterized by defects of the immune system predisposing individuals to variety of manifestations, including recurrent infections and unusual vaccine complications. There are a number of PIDs prone to Bacillus Calmette-Guérin (BCG) complications. This review presents an update on our understanding about the BCGosis-susceptible PIDs, including severe combined immunodeficiency, chronic granulomatous disease, and
more » ... an susceptibility to mycobacterial diseases. Also in practice, vaccination with attenuated M. bovis BCG vaccine could result in BCGosis in these patients. 35,37 These patients are sacrifice to the BCG vaccination to show up their Norouzi et al.
doi:10.1016/j.jinf.2012.03.012 pmid:22430715 pmcid:PMC4792288 fatcat:azaj7cle6nccjhqscrl6iylu4y

Glycans Instructing Immunity: The Emerging Role of Altered Glycosylation in Clinical Immunology

Jonathan J. Lyons, Joshua D. Milner, Sergio D. Rosenzweig
2015 Frontiers in Pediatrics  
Protein glycosylation is an important epigenetic modifying process affecting expression, localization, and function of numerous proteins required for normal immune function. Recessive germline mutations in genes responsible for protein glycosylation processes result in congenital disorders of glycosylation and can have profound immunologic consequences. Genetic mutations in immune signaling pathways that affect glycosylation sites have also been shown to cause disease. Sugar supplementation and
more » ... in vivo alteration of glycans by medication holds therapeutic promise for some of these disorders. Further understanding of how changes in glycosylation alter immunity may provide novel treatment approaches for allergic disease, immune dysregulation, and immunodeficiency in the future.
doi:10.3389/fped.2015.00054 pmid:26125015 pmcid:PMC4463932 fatcat:byv3vxz42zhwvkk5l3uhbvnqse

Targeted NGS: A Cost-Effective Approach to Molecular Diagnosis of PIDs

Jennifer L. Stoddard, Julie E. Niemela, Thomas A. Fleisher, Sergio D. Rosenzweig
2014 Frontiers in Immunology  
Primary immunodeficiencies (PIDs) are a diverse group of disorders caused by multiple genetic defects. Obtaining a molecular diagnosis for PID patients using a phenotype-based approach is often complex, expensive, and not always successful. Nextgeneration sequencing (NGS) methods offer an unbiased genotype-based approach, which can facilitate molecular diagnostics. Objective: To develop an efficient NGS method to identify variants in PID-related genes. Methods:We performed HaloPlex custom
more » ... enrichment and NGS using the IonTorrent PGM to screen 173 genes in 11 healthy controls, 13 PID patients previously evaluated with either an identified mutation or SNP, and 120 patients with undiagnosed PIDs. Sensitivity and specificity were determined by comparing NGS and Sanger sequencing results for 33 patients. Run metrics and coverage analyses were done to identify systematic deficiencies. Results: A molecular diagnosis was identified for 18 of 120 patients who previously lacked a genetic diagnosis, including 9 who had atypical presentations and extensive previous genetic and functional studies. Our NGS method detected variants with 98.1% sensitivity and >99.9% specificity. Uniformity was variable (72-89%), and we were not able to reliably sequence 45 regions (45/2455 or 1.8% of total regions) due to low (<20) average read depth or <90% region coverage; thus, we optimized probe hybridization conditions to improve read-depth and coverage for future analyses, and established criteria to help identify true positives. Conclusion: While NGS methods are not as sensitive as Sanger sequencing for individual genes, targeted NGS is a cost-effective, first-line genetic test for the evaluation of patients with PIDs. This approach decreases time to diagnosis, increases diagnostic rate, and provides insight into the genotype-phenotype correlation of PIDs in a cost-effective way.
doi:10.3389/fimmu.2014.00531 pmid:25404929 pmcid:PMC4217515 fatcat:25y7cvhyszaftect42iv5fkhju

Class-Switch Recombination (CSR)/Hyper-IgM (HIGM) Syndromes and Phosphoinositide 3-Kinase (PI3K) Defects

Rekha D. Jhamnani, Cristiane J. Nunes-Santos, Jenna Bergerson, Sergio D. Rosenzweig
2018 Frontiers in Immunology  
Antibody production and function represent an essential part of the immune response, particularly in fighting bacterial and viral infections. Multiple immunological phenotypes can result in dysregulation of the immune system humoral compartment, including class-switch recombination (CSR) defects associated with hyper-IgM (HIGM) syndromes. The CSR/HIGM syndromes are defined by the presence of normal or elevated plasma IgM levels in the context of low levels of switched IgG, IgA, and IgE
more » ... Recently described autosomal dominant gain-of-function (GOF) mutations in PIK3CD and PIK3R1 cause combined immunodeficiencies that can also present as CSR/HIGM defects. These defects, their pathophysiology and derived clinical manifestations are described in depth. Previously reported forms of CSR/HIGM syndromes are briefly reviewed and compared to the phosphoinositide 3-kinase (PI3K) pathway defects. Diseases involving the PI3K pathway represent a distinctive subset of CSR/HIGM syndromes, presenting with their own characteristic clinical and laboratory attributes as well as individual therapeutic approaches.
doi:10.3389/fimmu.2018.02172 pmid:30319630 pmcid:PMC6168630 fatcat:ssq5sboh6jfrdjoiohrrp2o4qy

Ataxia telangiectasia associated with nodular regenerative hyperplasia

Ki L. Milligan, Karen Schirm, Stephanie Leonard, Ashleigh A. Hussey, Anahita Agharahimi, David E. Kleiner, Ivan Fuss, Shilpa Lingala, Theo Heller, Sergio D. Rosenzweig
2016 Journal of Clinical Immunology  
doi:10.1007/s10875-016-0334-x pmid:27671921 pmcid:PMC5097878 fatcat:6mrp5hjmmjhvpifabg3j736wja

Bone Marrow Findings at Diagnosis in Patients with Multisystem Langerhans Cell Histiocytosis

Maria Laura Galluzzo, Jorge Braier, Sergio D. Rosenzweig, M.aria T. Garcia de Davila, Diego Rosso
2010 Pediatric and Developmental Pathology  
This study was designed to describe the bone marrow features of multisystem Langerhans cell histiocytosis (LCH) at diagnosis in patients with or without hematologic dysfunction. A retrospective review of bone marrow biopsies from patients with multisystem LCH was performed. Cases were diagnosed at the Garrahan Hospital between 1987 and 2004. Routine and immunohistochemistry techniques (hemaloxylin-eosin, periodic acid-Schiff, Giemsa, Gomori reticulin, and CD1a, CD68, and CD61) were evaluated.
more » ... inical outcome and laboratory data were obtained from the medical charts. Twenty-two bone marrow biopsies from patients with multisystem LCH were reviewed at onset of disease. Four patients had no hematologic dysfunction and the other 18 patients had monocytopenia (9), bicytopenia (7), or tricytopenia (2). Increased number and dysplasia of megakaryocytes were evident in 22/22 samples and emperipolesis was present in 21/22 (95%). Aggregates of histiocytes and hemophagocytosis were seen in 9/22 samples. Myelofibrosis was found in 16/17 (94%) evaluable samples at diagnosis. No association of myelofibrosis and cytopenias or clinical outcome was found. Positive CD1a confirmed the presence of LCH cells in 3/22 (14%) samples. Hemophagocytosis and poor outcome were significantly more common in patients with bilineage and trilineage cytopenias. Langerhans cell histiocytosis cells were rarely seen in the bone marrow of these patients (14%); increased histiocytes and hemophagocytosis were more commonly found (41 %). Hemophagocytosis was associated with severe cytopenias. Bicytopenia and tricytopenia were associated with poor outcome (death). Myelofibrosis, megakaryocytic dysplasia, and emperipolesis were common findings.
doi:10.2350/09-05-0651-oa.1 pmid:19863448 pmcid:PMC3740343 fatcat:nao2ysimnfa45g2uuuydg7zf2i

N-Glycan Modification in Covid-19 Pathophysiology: In vitro Structural Changes with Limited Functional Effects

Cristiane J. Nunes-Santos, Hye Sun Kuehn, Sergio D. Rosenzweig
2020 Journal of Clinical Immunology  
In 2014, we reported two siblings with a rare congenital disorder of glycosylation due to mutations in mannosyl-oligosaccharide glucosidase (MOGS). The glycan alteration derived from this disease resulted in an in vitro infection resistance to particular enveloped, N-glycosylation-dependent viruses as influenza and HIV. As part of the global effort to find safe and effective antiviral therapies for Covid-19, we assessed the in vitro activity of the FDA-approved α-glucosidase inhibitor miglustat
more » ... against SARS-CoV-2. Expression plasmids encoding SARS-CoV-2 spike (S) and human ACE2 glycoproteins (GP) were tested to evaluate N-glycan modifications induced by α-glucosidase inhibition. Immunoprecipitation was used to assess binding between these two GP. Cell-to-cell fusion was assessed by immunofluorescence of cocultures of SARS-CoV-2 S and ACE2-expressing cells. Miglustat effect on immune response was tested by measuring cytokine release from PBMC exposed to purified SARS-CoV-2 S. In our overexpression system, miglustat successfully and specifically modified N-glycans in both SARS-CoV-2 S and its main receptor ACE2. Binding between these two GP was not affected by glycan modifications. A surrogate marker for viral cytopathic effect, measured as receptor-dependent SARS-CoV-2 S-driven cell-to-cell fusion, was not disrupted by miglustat treatment. This observation was further confirmed in MOGS-null transfected cells. Miglustat produced no statistically significant effects on cytokine production following SARS-CoV-2 S glycoprotein stimulation of PBMC. Our work shows that despite clear N-glycan alteration in the presence of miglustat, the functions of the Covid-19-related glycoproteins studied were not affected, making it unlikely that miglustat can change the natural course of the disease.
doi:10.1007/s10875-020-00905-4 pmid:33245474 pmcid:PMC7691692 fatcat:rfkbiqgzyjhu7mkhyzxy7twop4

Case Report: Ocular toxoplasmosis in a WHIM syndrome immunodeficiency patient

David H. McDermott, Lauren E. Heusinkveld, Wadih M. Zein, H. Nida Sen, Martha M. Marquesen, Mark Parta, Sergio D. Rosenzweig, Gary A. Fahle, Michael D. Keller, Henry E. Wiley, Philip M. Murphy
2019 F1000Research  
A patient with WHIM syndrome immunodeficiency presented with sudden painless right eye blindness associated with advanced retinal and optic nerve damage. Toxoplasma gondii was detected by PCR in vitreous fluid but not serum. The patient was treated with pyrimethamine/sulfadiazine for 6 weeks due to evidence of active ocular inflammation and then received prophylaxis with trimethoprim-sulfamethoxazole due to his immunosuppression. Vision did not return; however, the infection did not spread to
more » ... volve other sites. Toxoplasmosis is rare in primary immunodeficiency disorders and is the first protozoan infection reported in WHIM syndrome.
doi:10.12688/f1000research.16825.2 fatcat:an6izprhofbbfn66iy3bg7jiia

Case Report: Ocular toxoplasmosis in a WHIM syndrome immunodeficiency patient

David H. McDermott, Lauren E. Heusinkveld, Wadih M. Zein, H. Nida Sen, Martha M. Marquesen, Mark Parta, Sergio D. Rosenzweig, Gary A. Fahle, Michael D. Keller, Henry E. Wiley, Philip M. Murphy
2019 F1000Research  
A patient with WHIM syndrome immunodeficiency presented with sudden painless right eye blindness associated with advanced retinal and optic nerve damage. Toxoplasma gondii was detected by PCR in vitreous fluid but not serum. The patient was treated with trimethoprim-sulfamethoxazole. Vision did not return; however, the infection did not spread to involve other sites. Toxoplasmosis is rare in primary immunodeficiency disorders and is the first protozoan infection reported in WHIM syndrome.
doi:10.12688/f1000research.16825.1 pmid:31249677 pmcid:PMC6587139 fatcat:n665hlqy3fcqddxai6di3yogom

Decreased lymphocytes and increased risk for infection are common in endogenous pediatric Cushing syndrome

Christina Tatsi, Rebecca Boden, Ninet Sinaii, Meg Keil, Charalampos Lyssikatos, Elena Belyavskaya, Sergio D Rosenzweig, Constantine A Stratakis, Maya B Lodish
2017 Pediatric Research  
Recurrence (%) 13 (6.6) No follow-up (%) 34 (17.2) Articles | Tatsi et al.
doi:10.1038/pr.2017.278 pmid:29211058 pmcid:PMC5866174 fatcat:klnopyglqbcstejcspil75ibfa

A Novel Mutation in IKBKG/NEMO Leads to Ectodermal Dysplasia with Severe Immunodeficiency (EDA-ID)

Alicia M. Johnston, Julie Niemela, Sergio D. Rosenzweig, Ari J. Fried, Ottavia Maria Delmonte, Thomas A. Fleisher, Hyesun Kuehn
2016 Journal of Clinical Immunology  
doi:10.1007/s10875-016-0309-y pmid:27368913 pmcid:PMC5007618 fatcat:rfha5rp4nvbvtcugtik2pmbofu

Gain of Function Mutations of PIK3CD as a Cause of Primary Sclerosing Cholangitis

Heather N. Hartman, Julie Niemela, Mary K. Hintermeyer, Mary Garofalo, Jennifer Stoddard, James W. Verbsky, Sergio D. Rosenzweig, John M. Routes
2014 Journal of Clinical Immunology  
Gain of function (GOF) mutation in the p110δ catalytic subunit of the phosphatidylinositol-3-OH kinase (PIK3CD) is the cause of a primary immunodeficiency (PID) characterized by recurrent sinopulmonary infections and lymphoproliferation. We describe a family of two adults and three children with GOF mutation in PIK3CD, all with recurrent sinopulmonary infections and varied infectious and non-infectious complications. The two adults have primary sclerosing cholangitis (PSC) without evidence of
more » ... yptosporidium parvum infection and have required liver transplantation. PSC is a novel phenotype of GOF mutation in PI3CKD.
doi:10.1007/s10875-014-0109-1 pmid:25352054 pmcid:PMC4769101 fatcat:gmlq36z7u5htdbmufjljubecqm
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