88 results on '"Hyper-IgM Immunodeficiency Syndrome, Type 1"'
Search Results
2. Allogeneic Hematopoietic Stem Cell Transplant for Patients With Primary Immune Deficiencies
- Published
- 2024
3. Studies of Disorders in Antibody Production and Related Primary Immunodeficiency States
- Published
- 2017
4. Bioequivalence Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of Gammaplex® 10 and Gammaplex® 5% in Primary Immunodeficiency Diseases (GMX07)
- Published
- 2017
5. Intramural Duodenal Hematoma in a Case of Hyper IgM Syndrome.
- Author
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Chandola S, Prabhakar P, Seth R, and Jana M
- Subjects
- Male, Humans, Duodenum diagnostic imaging, Duodenum pathology, Gastrointestinal Hemorrhage, Hematoma diagnostic imaging, Hematoma etiology, Hematoma pathology, Hyper-IgM Immunodeficiency Syndrome, Type 1, Hyper-IgM Immunodeficiency Syndrome, Duodenal Diseases etiology, Duodenal Diseases pathology
- Abstract
Three-year-old boy who presented with colicky abdominal pain, diarrhoea and vomiting was investigated with computed tomography which revealed a mass in the peripancreatic region. An imaging possibility of duodenal intramural hematoma was considered after reassessment with ultrasound which was subsequently confirmed by magnetic resonance imaging. The development of a spontaneous duodenal hematoma lead to further evaluation of the patient and revealed X linked hyper IgM syndrome., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2024
- Full Text
- View/download PDF
6. A Study to Find Out How Safe and Effective Gammaplex® is in Young People With Primary Immunodeficiency
- Published
- 2014
7. Late-Onset Lymphopenia and ITP in a Patient with Hyper IgM Syndrome Due to a Homozygous Variant in AICDA.
- Author
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Adatia A and Ritchie B
- Subjects
- Humans, Homozygote, Cytidine Deaminase genetics, Immunoglobulin M, Hyper-IgM Immunodeficiency Syndrome complications, Hyper-IgM Immunodeficiency Syndrome diagnosis, Hyper-IgM Immunodeficiency Syndrome genetics, Hyper-IgM Immunodeficiency Syndrome, Type 1, Lymphopenia diagnosis, Lymphopenia genetics
- Published
- 2023
- Full Text
- View/download PDF
8. Allogeneic Bone Marrow Transplantation in Patients With Primary Immunodeficiencies
- Published
- 2009
9. Study of Immune Responses and Safety of Recombinant Human CD40 Ligand in Patients With X-Linked Hyper-IgM Syndrome
- Published
- 2008
10. Study of Genetic and Molecular Defects in Primary Immunodeficiency Disorders
- Author
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University of Washington
- Published
- 2005
11. CD40L Activates Platelet Integrin αIIbβ3 by Binding to the Allosteric Site (Site 2) in a KGD-Independent Manner and HIGM1 Mutations Are Clustered in the Integrin-Binding Sites of CD40L.
- Author
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Takada YK, Shimoda M, and Takada Y
- Subjects
- Humans, Platelet Glycoprotein GPIIb-IIIa Complex metabolism, CD40 Ligand genetics, CD40 Ligand metabolism, Allosteric Site, Binding Sites, Mutation genetics, Integrin alpha5beta1 metabolism, Hyper-IgM Immunodeficiency Syndrome, Type 1, Thrombosis
- Abstract
CD40L is expressed in activated T cells, and it plays a major role in immune response and is a major therapeutic target for inflammation. High IgM syndrome type 1 (HIGM1) is a congenital functional defect in CD40L/CD40 signaling due to defective CD40L. CD40L is also stored in platelet granules and transported to the surface upon platelet activation. Platelet integrin αIIbβ3 is known to bind to fibrinogen and activation of αIIbβ3 is a key event that triggers platelet aggregation. Also, the KGD motif is critical for αIIbβ3 binding and the interaction stabilizes thrombus. Previous studies showed that CD40L binds to and activates integrins αvβ3 and α5β1 and that HIGM1 mutations are clustered in the integrin-binding sites. However, the specifics of CD40L binding to αIIbβ3 were unclear. Here, we show that CD40L binds to αIIbβ3 in a KGD-independent manner using CD40L that lacks the KGD motif. Two HIGM1 mutants, S128E/E129G and L155P, reduced the binding of CD40L to the classical ligand-binding site (site 1) of αIIbβ3, indicating that αIIbβ3 binds to the outer surface of CD40L trimer. Also, CD40L bound to the allosteric site (site 2) of αIIbβ3 and allosterically activated αIIbβ3 without inside-out signaling. Two HIMG1 mutants, K143T and G144E, on the surface of trimeric CD40L suppressed CD40L-induced αIIbβ3 activation. These findings suggest that CD40L binds to αIIbβ3 in a manner different from that of αvβ3 and α5β1 and induces αIIbβ3 activation. HIGM1 mutations are clustered in αIIbβ3 binding sites in CD40L and are predicted to suppress thrombus formation and immune responses through αIIbβ3.
- Published
- 2023
- Full Text
- View/download PDF
12. Variants Disrupting CD40L Transmembrane Domain and Atypical X-Linked Hyper-IgM Syndrome: A Case Report With Leishmaniasis and Review of the Literature
- Author
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Boaz Palterer, Lorenzo Salvati, Manuela Capone, Valentina Mecheri, Laura Maggi, Alessio Mazzoni, Lorenzo Cosmi, Nila Volpi, Lucia Tiberi, Aldesia Provenzano, Sabrina Giglio, Paola Parronchi, Giandomenico Maggiore, Oreste Gallo, Alessandro Bartoloni, Francesco Annunziato, Lorenzo Zammarchi, and Francesco Liotta
- Subjects
Adult ,Male ,Immunoglobulin M ,Agammaglobulinemia ,Hyper-IgM Immunodeficiency Syndrome, Type 1 ,CD40 Ligand ,Immunology ,Cryptosporidiosis ,Cryptosporidium ,Humans ,Immunology and Allergy ,Hyper-IgM Immunodeficiency Syndrome ,Leishmaniasis - Abstract
X-linked hyper-IgM (XHIGM) syndrome is caused by mutations of the CD40LG gene, encoding the CD40L protein. The clinical presentation is characterized by early-onset infections, with profound hypogammaglobulinemia and often elevated IgM, susceptibility to opportunistic infections, such asPneumocystis jiroveciipneumonia, biliary tract disease due toCryptosporidium parvum, and malignancy. We report a 41-year-old male presenting with recurrent leishmaniasis, hypogammaglobulinemia, and myopathy. Whole-exome sequencing (WES) identified a missense variant in the CD40LG gene (c.107T>A, p.M36K), involving the transmembrane domain of the protein and a missense variant in the carnitine palmitoyl-transferase II (CPT2; c.593C>G; p.S198C) gene, leading to the diagnosis of hypomorphic XHIGM and CPT2 deficiency stress-induced myopathy. A review of all the previously reported cases of XHIGM with variants in the transmembrane domain showcased that these patients could present with atypical clinical features. Variants in the transmembrane domain of CD40LG act as hypomorphic generating a protein with a lower surface expression. Unlike large deletions or extracellular domain variants, they do not abolish the interaction with CD40, therefore preserving some biological activity.
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- 2022
13. X-linked hyper-IgM syndrome complicated with interstitial pneumonia and liver injury: a new mutation locus in the CD40LG gene
- Author
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Wen Zhu, Tian-Jiao Wang, Hua Wang, Li-Fang Wu, Yi-Qun Teng, Junguo Chen, and Xiao-Lin Liu
- Subjects
Male ,Liver injury ,Pathology ,medicine.medical_specialty ,X-Linked Hyper IgM Syndrome ,Hyper-IgM Immunodeficiency Syndrome, Type 1 ,business.industry ,Hyper-IgM Immunodeficiency Syndrome ,CD40LG gene ,CD40 Ligand ,Immunology ,Mutation, Missense ,Infant ,Locus (genetics) ,medicine.disease ,Amino Acid Substitution ,Genetic Loci ,New mutation ,medicine ,Hepatic Insufficiency ,Humans ,Missense mutation ,Interstitial pneumonia ,Lung Diseases, Interstitial ,business - Published
- 2019
14. CD40LG mutations in Vietnamese patients with X‐linked hyper‐IgM syndrome; catastrophic anti‐phospholipid syndrome as a new complication
- Author
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Linh Thi Truc Pham, Xinh Thi Phan, Thuy Thi Thanh Pham, Vy Nguyen, Tuan Minh Nguyen, Anh Tran, Anh Nguyen Lien Phan, Sigrid M. A. Swagemakers, Petrus Martinus van Hagen, Khanh Thi Xuan Luong, Nghia Huynh, Tam Thi Minh Nguyen, Chi-Bao Bui, Cuc Tran Thu Cao, Duong Thuy Nguyen, Pathology, Internal Medicine, and Immunology
- Subjects
0301 basic medicine ,Adult ,Male ,Hyper IgM syndrome ,anti‐phospholipid syndrome ,Adolescent ,CD40 Ligand ,QH426-470 ,030105 genetics & heredity ,medicine.disease_cause ,primary immunodeficiency ,Clinical Reports ,03 medical and health sciences ,Western blot ,Genotype ,Genetics ,medicine ,Humans ,Child ,Molecular Biology ,CD40 ligand ,Genetics (clinical) ,Exome sequencing ,Mutation ,Clinical Report ,medicine.diagnostic_test ,business.industry ,Hyper-IgM Immunodeficiency Syndrome, Type 1 ,hyper‐IgM syndrome ,medicine.disease ,Antiphospholipid Syndrome ,030104 developmental biology ,Otitis ,Phenotype ,Immunology ,Primary immunodeficiency ,whole‐exome sequencing ,medicine.symptom ,Complication ,business - Abstract
Background X‐linked hyper‐IgM syndrome (XHIGM) is a rare primary immunodeficiency caused by CD40 ligand defects. Methods We identified three patients with XHIGM in Ho Chi Minh City, Vietnam. Whole‐exome sequencing, immunological analyses and western blot were performed to investigate phenotypic and genotypic features. Results Despite showing symptoms typical of XHIGM, including recurrent sinopulmonary infections, oral ulcers and otitis media, the diagnosis was significantly delayed. One patient developed anti‐phospholipid syndrome, which has been documented for the first time in XHIGM syndrome. Two patients had elevated IgM levels and all of them had low IgG levels. Exome sequencing revealed mutations in the CD40LG gene: one novel splicing mutation c.156+2T>A and two previously characterised mutations (non‐frameshift deletion c.436_438delTAC, stop‐gain c.654C>A). Due to these mutations, the CD40 ligand was not expressed in any of the three patients, as demonstrated by western blot analysis. Conclusion This is the first report of XHIGM syndrome in Vietnam indicates that an effective diagnostic strategy, such as sequencing analysis, contributes to reliable diagnosis and subsequent therapy., X‐linked hyper‐IgM syndrome (XHIGM) is a rare primary immunodeficiency caused by CD40 ligand defects. Exome sequencing revealed mutations in the CD40LG gene: one novel splicing mutation c.156+2T>A and two previously characterised mutations (non‐frameshift deletion c.436_438delTAC, stop‐gain c.C654A). This first is the first report of XHIGM syndrome in Vietnam indicates that an effective diagnostic strategy, such as sequencing analysis, contributes to reliable diagnosis and subsequent therapy.
- Published
- 2021
15. Mitochondrial DNA insert into CD40 ligand gene‐associated X‐linked hyper‐IgM syndrome
- Author
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Dan Xu, Yunlian Zhou, Yingshuo Wang, Xuejing Li, Beilei Cheng, and Zhimin Chen
- Subjects
Male ,0301 basic medicine ,Mitochondrial DNA ,CD40 Ligand ,QH426-470 ,030105 genetics & heredity ,Biology ,DNA, Mitochondrial ,Genome ,03 medical and health sciences ,Exon ,symbols.namesake ,Genetics ,Humans ,Molecular Biology ,Gene ,Genetics (clinical) ,Sanger sequencing ,CD40LG ,Hyper-IgM Immunodeficiency Syndrome, Type 1 ,Breakpoint ,Infant ,Chromosome ,Original Articles ,Mutagenesis, Insertional ,030104 developmental biology ,nuclear mitochondrial DNA sequences ,symbols ,Original Article ,Numt ,X‐linked hyper‐IgM syndrome ,insertional mutation - Abstract
Background X‐linked hyper‐IgM (X‐HIGM), which results from mutations in the CD40LG gene located on chromosome Xq26.3, is the most common form of HIGM. To date, more than 130 variants of the CD40L gene have been reported. We described a patient with novel de novo nuclear mitochondrial DNA sequences (NUMTs) in the CD40LG gene that have resulted in X‐HIGM. Methods Whole‐exome sequencing (WES) analysis was used to screen for causal variants in the genome, and the candidate breakpoint was confirmed by Sanger sequencing. Results A new mutation of CD40LG, which deletes A at position 17 followed by a 147‐nucleotide from mitochondrial DNA copies insertion in exon 1, was detected in a 20‐month‐old boy harbouring an X‐HIGM combined with immunodeficiency syndrome. Conclusion This is one of the few cases of a human genetic disease caused by nuclear mitochondrial DNA sequences (NUMTs). The presented data serve to demonstrate that de novo NUMT transfer of nucleic acid is a novel mechanism of X‐HIGM., A new mutation of the CD40 ligand gene (CD40LG) that encodes the CD40 ligand (CD40L) molecule was detected in a 20‐month‐old boy harbouring an X‐linked hyper‐IgM syndrome (X‐HIGM) combined with immunodeficiency syndrome. Inactivation of the CD40LG gene resulted from the insertion of mitochondrial DNA copies into exon 1, which in turn led to a total deficiency of CD40L expression of T lymphocytes.
- Published
- 2021
16. [Genetic analysis of a child with co-commitment progressive multifocal leukoencephalopathy and X-linked hyper IgM syndrome]
- Author
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Dongjun, Li and Qiang, Li
- Subjects
Adult ,Male ,Hyper-IgM Immunodeficiency Syndrome, Type 1 ,CD40 Ligand ,Leukoencephalopathy, Progressive Multifocal ,Mutation, Missense ,Humans ,Female ,Exons ,Child ,Polymerase Chain Reaction - Abstract
To detect variant of the CD40L gene and infection of Jamestown Canyon virus (JCV) in a 7-year-and-9-month-old boy with co-commitment progressive multifocal leukoencephalopathy (PML) and X-linked hyper IgM syndrome (XHIGM).Peripheral blood samples of the child and his parents were collected for the extraction of genomic DNA. The 5 exons and exon/intronic boundaries of the CD40L gene were subjected to PCR amplification and sequencing. Suspected variants were analyzed by using bioinformatic software. The JCV gene was amplified from genomic DNA by nested PCR and sequenced.The child was found to harbor a hemizygous c.506 AC (p.Y169S) missense variant in exon 5 of the CD40L gene. The variant may affect the TNFH domain of the CD40L protein and result in structural instability and loss of hydrophobic interaction between CD40L and CD40. As predicted by PolyPhen2 and SIFT software, the variant was probably damaging (score = 1.00) and deleterious (score= -8.868). His mother was found to be a heterozygous carrier, while the same variant was not found in his father. Gel electrophoresis of the nested PCR product revealed presence of target JCV band, which was confirmed to be 99% identical with the JCV gene by sequencing.The patient was diagnosed with co-commitment XHIGM and PML based on the testing of the CD40L gene and JCV infection.
- Published
- 2021
17. Cryptococcal Meningitis and Post-Infectious Inflammatory Response Syndrome in a Patient With X-Linked Hyper IgM Syndrome: A Case Report and Review of the Literature
- Author
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Caterina Cancrini, Rita Carsetti, Lorenza Romani, Maia De Luca, Gigliola Di Matteo, Silvia Di Cesare, Andrea Finocchi, Lorenzo Figà-Talamanca, Peter R. Williamson, and Paolo Rossi
- Subjects
Male ,0301 basic medicine ,Hyper IgM syndrome ,medicine.medical_specialty ,Opportunistic infection ,Immunology ,Case Report ,Meningitis, Cryptococcal ,primary immunodeficiency ,Gastroenterology ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Cerebrospinal fluid ,Adrenal Cortex Hormones ,Internal medicine ,medicine ,Humans ,Immunology and Allergy ,Diplopia ,Cryptococcus neoformans ,cryptococcal meningoencephalitis ,biology ,Hyper-IgM Immunodeficiency Syndrome, Type 1 ,business.industry ,fungal infection ,X-linked Hyper IgM syndrome ,RC581-607 ,medicine.disease ,biology.organism_classification ,Systemic Inflammatory Response Syndrome ,030104 developmental biology ,Settore MED/02 ,Primary immunodeficiency ,biology.protein ,post-infectious inflammatory response syndrome ,Immunologic diseases. Allergy ,medicine.symptom ,Headaches ,Antibody ,business ,030217 neurology & neurosurgery - Abstract
The hyper IgM syndromes are a rare group of primary immunodeficiency. The X-linked Hyper IgM syndrome (HIGM), due to a gene defect in CD40L, is the commonest variant; it is characterized by an increased susceptibility to a narrow spectrum of opportunistic infection. A few cases of HIGM patients with Cryptococcal meningoencephalitis (CM) have been described in the literature. Herein we report the case of a young male diagnosed in infancy with HIGM who developed CM complicated by a post-infectious inflammatory response syndrome (PIIRS), despite regular immunoglobulin replacement therapy and appropriate antimicrobial prophylaxis. The patient was admitted because of a headache and CM was diagnosed through detection of Cryptococcus neoformans in the cerebrospinal fluid. Despite the antifungal therapy resulting to negative CSF culture, the patient exhibited persistent headaches and developed diplopia. An analysis of inflammatory cytokines on CSF, as well as the brain MRI, suggested a diagnosis of PIIRS. Therefore, a prolonged corticosteroids therapy was started obtaining a complete resolution of symptoms without any relapse.
- Published
- 2021
18. X-Linked Hyper IgM Syndrome Manifesting as Recurrent Pneumocystis jirovecii Pneumonia: A Case Report
- Author
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Xiang Ying Meng, Ying Li, Shui Yan Wu, Sai Hu Huang, and Zhen Jiang Bai
- Subjects
Male ,Opportunistic infection ,Pneumocystis carinii ,03 medical and health sciences ,0302 clinical medicine ,Caspofungin ,Trimethoprim, Sulfamethoxazole Drug Combination ,medicine ,Pneumocystis jirovecii ,Humans ,Exome sequencing ,biology ,business.industry ,Hyper-IgM Immunodeficiency Syndrome, Type 1 ,Pneumonia, Pneumocystis ,High-Throughput Nucleotide Sequencing ,Infant ,biology.organism_classification ,medicine.disease ,Pneumonia ,Infectious Diseases ,Dyspnea ,Treatment Outcome ,Cough ,Immunoglobulin M ,030220 oncology & carcinogenesis ,Pediatrics, Perinatology and Child Health ,Immunology ,biology.protein ,Etiology ,Sputum ,medicine.symptom ,business ,Hyperimmunoglobulin M Syndrome ,030215 immunology - Abstract
We reported a Chinese boy with X-linked hyper IgM (XHIGM) syndrome, manifesting as recurrent and severe pneumonia caused by Pneumocystis jirovecii. His parents were healthy and unrelated. In August 2018, the 5-month-old boy manifested as cough and dyspnea, and then in July 2019, he was admitted because of the same symptoms. Immunological results of the two admissions both showed low IgG, low IgA, normal IgM and high levels of 1,3-β-D-glucan (BDG). Using next-generation sequencing (NGS), great reading counts of P. jirovecii were identified from the deep sputum in both admissions. Caspofungin combined with trimethoprim-sulfamethoxazole were used to anti-infection, and he recovered quickly. Whole-exome sequencing was performed for this family because of immune suppression, the disease-causing gene (exon 10–22 of CD40L) deletion for XHIGM syndrome was identified. NGS is beneficial for etiology diagnosis. Pneumocystis jirovecii pneumonia as an opportunistic infection could be recurrent in patients with XHIGM syndrome.
- Published
- 2020
19. Complex preimplantation genetic tests for Robertsonian translocation, HLA, and X-linked hyper IgM syndrome caused by a novel mutation of CD40LG gene
- Author
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Jie Li, Shuiying Ma, Sexin Huang, Junhao Yan, Xuan Gao, Yuping Niu, Yuan Gao, Ming Gao, and Yan Zhang
- Subjects
0301 basic medicine ,Proband ,Hyper IgM syndrome ,Biopsy ,CD40 Ligand ,Aneuploidy ,Robertsonian translocation ,Human leukocyte antigen ,Fertilization in Vitro ,Biology ,medicine.disease_cause ,DNA sequencing ,Translocation, Genetic ,03 medical and health sciences ,symbols.namesake ,0302 clinical medicine ,HLA Antigens ,Pregnancy ,medicine ,Genetics ,Humans ,Genetic Testing ,Sperm Injections, Intracytoplasmic ,Genetics (clinical) ,Preimplantation Diagnosis ,Sanger sequencing ,030219 obstetrics & reproductive medicine ,Hyper-IgM Immunodeficiency Syndrome, Type 1 ,Haplotype ,Obstetrics and Gynecology ,High-Throughput Nucleotide Sequencing ,General Medicine ,medicine.disease ,Molecular biology ,030104 developmental biology ,Blastocyst ,Reproductive Medicine ,symbols ,Female ,Developmental Biology - Abstract
PURPOSE: To perform complex preimplantation genetic tests (PGT) for aneuploidy screening, Robertsonian translocation, HLA-matching, and X-linked hyper IgM syndrome (XHIGM) caused by a novel mutation c.156 G>T of CD40LG gene. METHODS: Reverse transcription PCR (RT-PCR) and Sanger sequencing were carried out to confirm the causative variant of CD40LG gene in the proband and parents. Day 5 and D6 blastocysts, obtained by in vitro fertilization (IVF) with intracytoplasmic sperm injection, underwent trophectoderm (TE) biopsy and whole genomic amplification (WGA) and next generation sequencing (NGS)-based PGT to detect the presence of a maternal CD40LG mutation, aneuploidy, Robertsonian translocation carrier, and human leukocyte antigen (HLA) haplotype. RESULTS: Sanger sequencing data of the genomic DNA showed that the proband has a hemizygous variant of c. 156 G>T in the CD40LG gene, while his mother has a heterozygous variant at the same position. Complementary DNA (cDNA) of CD40LG amplification and sequencing displayed that no cDNA of CD40LG was found in proband, while only wild-type cDNA of CD40LG was amplified in the mother. PGT results showed that only one of the six tested embryos is free of the variant c.156 G>T and aneuploidy and having the consistent HLA type as the proband. Meanwhile, the embryo is a Robertsonian translocation carrier. The embryo was transplanted into the mother’s uterus. Amniotic fluid testing results are consistent with that of PGT. A healthy baby girl was delivered, and the peripheral blood testing data was also consistent with the testing results of transplanted embryo. CONCLUSIONS: The novel mutation of c. 156 G>T in CD40LG gene probably leads to XHIGM by nonsense-meditated mRNA decay (NMD), and complex PGT of preimplantation genetic testing for monogenic disease (PGT-M), aneuploidy (PGT-A), structural rearrangement (PGT-SR), and HLA-matching (PGT-HLA) can be performed in pedigree with both X-linked hyper IgM syndrome and Robertsonian translocation.
- Published
- 2020
20. Successful Sequential Liver and Hematopoietic Stem Cell Transplantation in a Child With CD40 Ligand Deficiency and Cryptosporidium-Induced Liver Cirrhosis
- Author
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Pier Luigi Calvo, Mauro Salizzoni, Michele Pinon, Renato Romagnoli, Francesco Tandoi, Paola Quarello, Dominic Dell Olio, Ezio David, E. Vassallo, Franca Fagioli, and Francesca Carraro
- Subjects
Liver Cirrhosis ,Male ,medicine.medical_specialty ,Cirrhosis ,Opportunistic infection ,medicine.medical_treatment ,CD40 Ligand ,Cryptosporidiosis ,Hematopoietic stem cell transplantation ,Opportunistic Infections ,030230 surgery ,Liver transplantation ,Gastroenterology ,Host-Parasite Interactions ,Time-to-Treatment ,Immunocompromised Host ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Young adult ,Child ,Immunodeficiency ,Cryptosporidium parvum ,Transplantation ,Hyper-IgM Immunodeficiency Syndrome, Type 1 ,business.industry ,Immunosuppression ,medicine.disease ,Liver Transplantation ,Treatment Outcome ,surgical procedures, operative ,hematopoietic stem cell transplantation ,Portal hypertension ,business ,030215 immunology - Abstract
BACKGROUND Hematopoietic stem cell transplantation (HSCT) is curative in patients with primary immunodeficiencies. However, pre-HSCT conditioning entails unacceptably high risks if the liver is compromised. The presence of a recurrent opportunistic infection affecting the biliary tree and determining liver cirrhosis with portal hypertension posed particular decisional difficulties in a 7-year-old child with X-linked CD40-ligand deficiency. We aim at adding to the scanty experience available on such rare cases, as successful management with sequential liver transplantation (LT) and HSCT has been reported in detail only in 1 young adult to date. METHODS A closely sequential strategy, with a surgical complication-free LT, followed by reduced-intensity conditioning, allowed HSCT to be performed only one month after LT, preventing Cryptosporidium parvum recolonization of the liver graft. RESULTS Combined sequential LT and HSCT resolved the cirrhotic evolution and corrected the immunodeficiency so that the infection responsible for the progressive sclerosing cholangitis did not recur. CONCLUSIONS Hopefully, this report of the successful resolution of a potentially fatal combination of immunodeficiency and chronic opportunistic infection with end-stage organ damage in a child will encourage others to adapt a sequential transplant approach to this highly complex pathology. However, caution is to be exercised to carefully balance the risks intrinsic to transplant surgery and immunosuppression in primary immunodeficiencies.
- Published
- 2018
21. X-linked hyper-IgM syndrome associated with pulmonary manifestations: A very rare case of functional mutation in CD40L gene in Iran
- Author
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Mohammad Shahrooei, Mohammad Nabavi, Mehdi Torabizadeh, and Masoud Zadkarami
- Subjects
Lung Diseases ,Male ,0301 basic medicine ,Hyper IgM syndrome ,CD40 Ligand ,Iran ,medicine.disease_cause ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,symbols.namesake ,0302 clinical medicine ,Exome Sequencing ,medicine ,Humans ,Respiratory system ,Respiratory Tract Infections ,Gene ,Exome sequencing ,Sanger sequencing ,Mutation ,Hyper-IgM Immunodeficiency Syndrome, Type 1 ,business.industry ,General Medicine ,medicine.disease ,030104 developmental biology ,Child, Preschool ,030220 oncology & carcinogenesis ,Immunology ,Primary immunodeficiency ,symbols ,Radiography, Thoracic ,Chills ,medicine.symptom ,business - Abstract
Hyper IgM (HIGM) syndromes are a complex of primary immunodeficiency disorders. A 4-years-old boy with recurrent fever and chills, dyspnea, sort throat for a month was admitted to emergency department. In the current case, whole exome sequencing followed by Sanger sequencing were employed in order to screen probable functional mutations. Molecular analysis revealed a functional mutation across the CD40L gene ( NM_000074 : exon5: c.T464C) resulted in amino acid change p.L155P attributed to X-linked hyper IgM syndrome. The findings of the current study signify the critical role of microbial infection as well as XHIGM screening, particularly in those children cases with respiratory symptoms.
- Published
- 2019
22. X-linked Hyper-IgM Syndrome: A Phenotype of Crohn's Disease with Hemophagocytic Lymphohistiocytosis
- Author
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Dun-Hua Zhou, Jian-Pei Fang, Xiong-yu Liao, Ke Huang, Ruohao Wu, and Kunyin Qiu
- Subjects
Male ,0301 basic medicine ,CD40 Ligand ,Disease ,Lymphohistiocytosis, Hemophagocytic ,03 medical and health sciences ,0302 clinical medicine ,Crohn Disease ,medicine ,Humans ,Point Mutation ,Gene ,Crohn's disease ,Hemophagocytic lymphohistiocytosis ,CD40 ,X-Linked Hyper IgM Syndrome ,biology ,Hyper-IgM Immunodeficiency Syndrome, Type 1 ,business.industry ,Hematology ,medicine.disease ,Phenotype ,030104 developmental biology ,Oncology ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Mutation (genetic algorithm) ,Immunology ,biology.protein ,030211 gastroenterology & hepatology ,business - Abstract
X-linked hyper-immunoglobulin M (IgM) syndrome is characterized by recurrent infections, low or undetectable levels of IgG and IgA, and normal to increased serum IgM, and is also rare. It is associated with mutation in the gene encoding CD40 ligand. This study aimed to describe the first international report of hemizygous CD40LG c.542G>A mutation in a 5-year-old boy with a phenotype of Crohn's disease and hemophagocytic lymphohistiocytosis. Also, the clinical implications of this mutation and associated atypical phenotype are discussed.
- Published
- 2017
23. Diagnostic approach of hypogammaglobulinemia in infancy
- Author
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Alessandro Plebani, Vassilios Lougaris, Laura Dotta, and Laura Palumbo
- Subjects
medicine.drug_class ,CD40 Ligand ,Immunology ,Antibiotics ,Infections ,Lymphocyte Activation ,B cell ,immunodeficiency ,immunoglobulin ,infancy ,Hypogammaglobulinemia ,Agammaglobulinemia ,Recurrence ,medicine ,Humans ,Immunology and Allergy ,IgA deficiency ,Transient hypogammaglobulinemia of infancy ,Immunodeficiency ,Antibody deficiency ,B-Lymphocytes ,biology ,Hyper-IgM Immunodeficiency Syndrome, Type 1 ,business.industry ,IgA Deficiency ,Infant, Newborn ,Infant ,medicine.disease ,Immunoglobulin A ,medicine.anatomical_structure ,Pediatrics, Perinatology and Child Health ,biology.protein ,Antibody ,business - Abstract
Primary B-cell immunodeficiency is the most frequent immune defect in infancy. Selective absence of serum and secretory immunoglobulin IgA is the most common, with rates ranging from 1/333 persons to 1/16 000, among different races. By contrast, it has been estimated that hypo/agammaglobulinemia occurs with a frequency of 1/50 000 persons. Patients with antibody deficiency are usually recognized because they have recurrent infections with encapsulated bacteria or a history of failure to respond adequately to antibiotic treatment. However, some individuals, mainly those affected by IgA deficiency (SIgAD) or transient hypogammaglobulinemia of infancy , may have few or no infections.
- Published
- 2020
24. A Novel
- Author
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Liangshan, Li, Jing, Ji, Mengmeng, Han, Yinglei, Xu, Xiao, Zhang, Wenmiao, Liu, and Shiguo, Liu
- Subjects
Hemizygote ,Male ,Asian People ,Hyper-IgM Immunodeficiency Syndrome, Type 1 ,CD40 Ligand ,Mutation ,Hematopoietic Stem Cell Transplantation ,Humans ,Immunoglobulins ,Infant ,Serum Albumin, Human ,Pedigree - Published
- 2019
25. CD40 Ligand Deficiency
- Author
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Tainá Mosca, Tiago Arruda Maximo, Wilma Carvalho Neves Forte, and Luiz Fernando Bacarini Leite
- Subjects
Pulmonary and Respiratory Medicine ,Male ,T cell ,Hyper-IgM Immunodeficiency Syndrome ,medicine.medical_treatment ,Immunology ,CD40 Ligand ,Hematopoietic stem cell transplantation ,03 medical and health sciences ,0302 clinical medicine ,Immunity ,medicine ,Immunology and Allergy ,Humans ,Immunodeficiency ,biology ,business.industry ,Hyper-IgM Immunodeficiency Syndrome, Type 1 ,General Medicine ,CD40 Ligand Deficiency ,medicine.disease ,medicine.anatomical_structure ,030228 respiratory system ,Humoral immunity ,biology.protein ,Antibody ,business ,030215 immunology - Abstract
CD40 ligand deficiency (CD40L), currently classified as an inborn error of immunity affecting cellular and humoral immunity, prevalently emerges in boys within the first two years of life. It manifests itself as a decrease in serum IgG, IgA and IgE, with normal or high IgM, defects in T cell proliferation, and decrease in soluble CD40L. These accompany sinopulmonary and/or gastrointestinal infections, and there may be infections caused by pyogenic bacteria, opportunistic infections, autoimmune diseases, and neoplasms. Mild and moderate cases of this deficiency may respond well to prophylactic antibiotic therapy or to human immunoglobulin replacement therapy, in addition to the early treatment of infections. Severe cases can be treated with hematopoietic stem cell transplantation, which allows the healing of such patients, rather than sequelae and a poor progression. Thus, its differential diagnosis with other inborn errors of immunity is essential, especially CD40 deficiency and variable common immunodeficiency; the reason why we have proposed the present literature review.
- Published
- 2019
26. Pneumocystis jirovecii pneumonia as an initial manifestation of hyper-IgM syndrome in an infant
- Author
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Nack-Gyun Chung, Dae Chul Jeong, Danbi Kim, Seung Beom Han, and Ju Ae Shin
- Subjects
hyper-IgM syndrome ,Male ,Pediatrics ,medicine.medical_specialty ,Hyper IgM syndrome ,Hyper-IgM Immunodeficiency Syndrome ,medicine.medical_treatment ,Hematopoietic stem cell transplantation ,Pneumocystis pneumonia ,03 medical and health sciences ,0302 clinical medicine ,Trimethoprim, Sulfamethoxazole Drug Combination ,medicine ,Pneumocystis jirovecii ,Humans ,030212 general & internal medicine ,Clinical Case Report ,biology ,business.industry ,Hyper-IgM Immunodeficiency Syndrome, Type 1 ,Pneumonia, Pneumocystis ,Hematopoietic Stem Cell Transplantation ,Infant ,General Medicine ,medicine.disease ,biology.organism_classification ,Trimethoprim ,respiratory tract diseases ,Anti-Bacterial Agents ,Transplantation ,Pneumonia ,030220 oncology & carcinogenesis ,business ,medicine.drug ,Research Article - Abstract
Rationale: Pneumocystis jirovecii causes severe pneumonia in immunocompromised hosts. Human immunodeficiency virus infection, malignancy, solid organ or hematopoietic cell transplantation, and primary immune deficiency compose the risk factors for Pneumocystis pneumonia (PCP) in children, and PCP can be an initial clinical manifestation of primary immune deficiency. Patient concerns: A 5-month-old infant presented with cyanosis and tachypnea. He had no previous medical or birth history suggesting primary immune deficiency. He was diagnosed with interstitial pneumonia on admission. Diagnoses: He was diagnosed with PCP, and further evaluations revealed underlying X-linked hyper-IgM syndrome. Interventions: He was treated with trimethoprim/sulfamethoxazole for PCP, and eventually received allogeneic hematopoietic cell transplantation for hyper-IgM syndrome. Outcomes: Twenty months have passed after transplantation without severe complications. Lessons: PCP should be considered in infants presenting with severe interstitial pneumonia even in the absence of evidence of immune deficiency. Primary immune deficiency should also be suspected in infants diagnosed with PCP.
- Published
- 2019
27. CD40 ligand deficiency: treatment strategies and novel therapeutic perspectives
- Author
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Hans D. Ochs, Lucila Akune Barreiros, Tabata Takahashi França, Antonio Condino-Neto, Otavio Cabral-Marques, and Basel K. al-Ramadi
- Subjects
T cell ,Immunology ,CD40 Ligand ,Context (language use) ,Bioinformatics ,Disease-Free Survival ,Granulocyte Colony-Stimulating Factor ,medicine ,Immunology and Allergy ,Animals ,Humans ,CD40 Antigens ,Innate immune system ,biology ,business.industry ,Hyper-IgM Immunodeficiency Syndrome, Type 1 ,Mortality rate ,Hematopoietic Stem Cell Transplantation ,hemic and immune systems ,CD40 Ligand Deficiency ,Genetic Therapy ,medicine.disease ,Allografts ,Immunity, Innate ,Transplantation ,Survival Rate ,medicine.anatomical_structure ,Mutation ,Primary immunodeficiency ,biology.protein ,Antibody ,business - Abstract
CD40 ligand (CD40L) deficiency or X-linked Hyper-IgM syndrome is a severe primary immunodeficiency caused by mutations in the CD40L gene. Despite currently available treatments, CD40L-deficient patients remain susceptible to life-threatening infections and have poor long term survival. Areas covered: Here, we discuss clinical and immunological characteristics of CD40L deficiency as well as current therapeutic strategies used for patient management. This review highlights that beyond B cell defects, patients' susceptibility to opportunistic pathogens might be due to impaired T cell and innate immune responses. In this context, we discuss how better knowledge of CD40L function and regulation may result in the development of new treatments. Expert opinion: Despite the introduction of hematopoietic stem-cell transplantation, immunoglobulin replacement, granulocyte colony-stimulating factor (G-CSF) administration, and prophylactic antibiotic therapies, life-threatening infections still cause high morbidity and mortality among CD40L-deficient patients. The reasons for this inadequate response to current therapies remains poorly understood, but recent reports suggest the involvement of CD40L-CD40 interaction in early stages of the innate immune system ontogeny. The development of novel gene therapeutic approaches and the use of redirected immunotherapies represent alternative treatment methods that could offer reduced morbidity and mortality rates for patients with CD40L deficiency.
- Published
- 2019
28. Integrin Binding to the Trimeric Interface of CD40L Plays a Critical Role in CD40/CD40L Signaling
- Author
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Yoko K. Takada, Michiko Shimoda, Jessica Yu, and Yoshikazu Takada
- Subjects
Immunology ,Integrin ,Mutant ,CD40 Ligand ,chemical and pharmacologic phenomena ,CHO Cells ,Cell Line ,03 medical and health sciences ,0302 clinical medicine ,Cricetulus ,stomatognathic system ,immune system diseases ,Cell Line, Tumor ,Immunology and Allergy ,Animals ,Humans ,Binding site ,CD40 Antigens ,Receptor ,Ternary complex ,Integrin binding ,CD40 ,Binding Sites ,biology ,Chemistry ,Hyper-IgM Immunodeficiency Syndrome, Type 1 ,hemic and immune systems ,Integrin alphaVbeta3 ,Cell biology ,stomatognathic diseases ,HEK293 Cells ,Docking (molecular) ,Mutation ,biology.protein ,K562 Cells ,030215 immunology ,Integrin alpha5beta1 ,Protein Binding ,Signal Transduction - Abstract
CD40L plays a major role in immune response and is a major therapeutic target for inflammation. Integrin α5β1 and CD40 simultaneously bind to CD40L. It is unclear if α5β1 and CD40 work together in CD40/CD40L signaling or how α5β1 binds to CD40L. In this article, we describe that the integrin-binding site of human CD40L is predicted to be located in the trimeric interface by docking simulation. Mutations in the predicted integrin-binding site markedly reduced the binding of α5β1 to CD40L. Several CD40L mutants defective in integrin binding were defective in NF-κB activation and B cell activation and suppressed CD40L signaling induced by wild-type CD40L; however, they still bound to CD40. These findings suggest that integrin α5β1 binds to monomeric CD40L through the binding site in the trimeric interface of CD40L, and this plays a critical role in CD40/CD40L signaling. Integrin αvβ3, a widely distributed vascular integrin, bound to CD40L in a KGD-independent manner, suggesting that αvβ3 is a new CD40L receptor. Several missense mutations in CD40L that induce immunodeficiency with hyper-IgM syndrome type 1 (HIGM1) are clustered in the integrin-binding site of the trimeric interface. These HIGM1 CD40L mutants were defective in binding to α5β1 and αvβ3 (but not to CD40), suggesting that the defect in integrin binding may be a causal factor of HIGM1. These findings suggest that α5β1 and αvβ3 bind to the overlapping binding site in the trimeric interface of monomeric CD40L and generate integrin-CD40L-CD40 ternary complex. CD40L mutants defective in integrins have potential as antagonists of CD40/CD40L signaling.
- Published
- 2018
29. FATAL cryptococcal meningitis in a child with hyper-immunoglobulin M syndrome, with an emphasis on the agent
- Author
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Patrícia de Souza Bonfim-Mendonça, Vânia Aparecida Vicente, Erika Seki Kioshima, Terezinha Inez Estivalet Svidzinski, F. Morelli, S.M.L. Suzuki, Melyssa Negri, Tânia Pereira Salci, and Morgana Ferreira Voidaleski
- Subjects
Male ,Hyper IgM syndrome ,Antifungal Agents ,Spleen ,Microbial Sensitivity Tests ,Meningitis, Cryptococcal ,Microbiology ,03 medical and health sciences ,Mice ,Fatal Outcome ,Amphotericin B ,Medicine ,Animals ,Humans ,Cryptococcus neoformans ,Voriconazole ,0303 health sciences ,Mice, Inbred BALB C ,biology ,030306 microbiology ,business.industry ,Hyper-IgM Immunodeficiency Syndrome, Type 1 ,medicine.disease ,biology.organism_classification ,Disease Models, Animal ,Infectious Diseases ,medicine.anatomical_structure ,Immunoglobulin M ,Child, Preschool ,biology.protein ,business ,Tomography, X-Ray Computed ,Meningitis ,Fluconazole ,medicine.drug - Abstract
Following a fatal case of Cryptococcus neoformans meningitis in a child with X-linked hyper-immunoglobulin M syndrome (XHIGM), we evaluated the fungal isolate in an experimental infection in a mouse model with respect to microbiology, epidemiology, virulence and response to therapy. The minimum inhibitory concentrations for antifungals in the susceptibility test were 0.5 mg/L for amphotericin B, 4.0 mg/L for fluconazole and 0.12 mg/L for voriconazole. Evaluation of pathogenicity by means of an experimental infection in BALB/c mice showed that fungus isolated from the blood and cerebrospinal fluid of the child was able to disseminate, reaching the spleen, lungs and brain, where it caused significant macroscopic alterations in the size and texture of each organ. Treatment of infected mice with amphotericin B reduced the fungal load in the spleen and lungs, but not in the brain.
- Published
- 2018
30. Clinical features and hematopoietic stem cell transplantations for CD40 ligand deficiency in Japan
- Author
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Kohsuke Imai, Hiroki Sato, Tomohiro Morio, Masayuki Nagasawa, Daisuke Tomizawa, Kanako Mitsui-Sekinaka, Michiko Kajiwara, and Shigeaki Nonoyama
- Subjects
Adult ,Male ,Hyper IgM syndrome ,Pediatrics ,medicine.medical_specialty ,Adolescent ,medicine.medical_treatment ,CD40 Ligand ,Immunology ,Hematopoietic stem cell transplantation ,Young Adult ,Japan ,medicine ,Humans ,Immunology and Allergy ,Pneumocystis jirovecii ,Child ,Survival rate ,Retrospective Studies ,biology ,Hyper-IgM Immunodeficiency Syndrome, Type 1 ,Hematopoietic Stem Cell Transplantation ,Infant ,medicine.disease ,biology.organism_classification ,Immunoglobulin Class Switching ,Survival Analysis ,Granulocyte colony-stimulating factor ,Transplantation ,Treatment Outcome ,surgical procedures, operative ,Graft-versus-host disease ,Child, Preschool ,Mutation ,Primary immunodeficiency ,Female - Abstract
Background The long-term outcome of X-linked hyper-IgM syndrome (XHIM) caused by mutations in CD40LG is poor, and the only curative treatment is hematopoietic stem cell transplantation (HSCT). Objective We sought to determine the clinical features and factors affecting outcomes in patients with XHIM. Methods We enrolled and retrospectively analyzed data from 56 Japanese patients with XHIM, including 29 patients who received HSCT. Results The long-term survival rate was poor in those not undergoing HSCT (overall survival rate at 40 years of age, 28.2%). The overall survival rate of patients undergoing HSCT (n = 29) was significantly higher than that of those not undergoing HSCT (n = 27, P = .0231). Moreover, event-free and disease-free survival rates were significantly greater in patients 5 years old or younger at the time of transplantation (n = 14) than in older patients (n = 15). Conclusion On the basis of these results, we concluded that HSCT improved the outcomes of patients with XHIM and that an age of 5 years or younger was optimal for the timing of HSCT because persistent infections and severe organ damage were frequently observed in patients older than 6 years.
- Published
- 2015
31. Interstitial pneumonia as the initial presentation in an infant with a novel mutation of CD40 ligand-associated X-linked hyper-IgM syndrome
- Author
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Jian Li, Yongjun Fang, Hongjun Miao, and Lihui Wu
- Subjects
Male ,Ganciclovir ,medicine.medical_specialty ,Hyper IgM syndrome ,Hyper-IgM Immunodeficiency Syndrome ,medicine.medical_treatment ,CD40 Ligand ,Congenital cytomegalovirus infection ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Internal medicine ,medicine ,Humans ,Clinical Case Report ,CD40 ligand deficiency ,030212 general & internal medicine ,Continuous positive airway pressure ,cytomegalovirus ,Pneumocystis jirovecii ,Voriconazole ,biology ,Hyper-IgM Immunodeficiency Syndrome, Type 1 ,business.industry ,Infant ,General Medicine ,medicine.disease ,030220 oncology & carcinogenesis ,biology.protein ,Antibody ,Hyper-IgM syndrome ,Lung Diseases, Interstitial ,Tomography, X-Ray Computed ,business ,Research Article ,medicine.drug - 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.
- Published
- 2020
32. 50 Years Ago in The Journal of Pediatrics: Familial Granulocytopenia and Associated Immunoglobulin Abnormality: Report of 3 Cases in Young Brothers
- Author
-
Emily, Heikamp, Titilope, Fasipe, and Lisa, Forbes
- Subjects
Male ,Hyper-IgM Immunodeficiency Syndrome, Type 1 ,Siblings ,Humans ,Female ,History, 20th Century ,Agranulocytosis - Published
- 2018
33. Clinical and molecular features of X-linked hyper IgM syndrome – An experience from North India
- Author
-
Shubham Goel, Deepti Suri, Surjit Singh, Madhubala Sharma, Ranjana W. Minz, Silvia Giliani, Babu Mathew, Vignesh Pandiarajan, Koon-Wing Chan, Adil Karim, Osamu Ohara, Yu-Lung Lau, Anju Gupta, Shigeaki Nonoyama, Amit Rawat, Ankur Kumar Jindal, Kohsuke Imai, Luigi D. Notarangelo, and Biman Saikia
- Subjects
Diarrhea ,Male ,0301 basic medicine ,medicine.medical_specialty ,Hyper IgM syndrome ,Neutropenia ,CD40 ligand ,Immunoglobulin class switching ,Mycobacterium sp ,Pulmonary alveolar proteinosis ,X-linked hyper-IgM syndrome ,Immunology and Allergy ,Immunology ,India ,Necrotising fasciitis ,medicine.disease_cause ,Gastroenterology ,Article ,Mycobacterium ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Missense mutation ,Child ,Respiratory Tract Infections ,Cells, Cultured ,Mycobacterium Infections ,Mutation ,Hyper-IgM Immunodeficiency Syndrome, Type 1 ,business.industry ,Infant ,Flow Cytometry ,medicine.disease ,Phenotype ,030104 developmental biology ,Child, Preschool ,medicine.symptom ,business ,030215 immunology - Abstract
X-linked hyper IgM Syndrome (XLHIGM), the most frequent form of the Hyper IgM syndromes is a primary immune deficiency resulting from a mutation in the CD40 ligand gene (CD40LG). We analyzed the clinical and laboratory features of ten patients with XLHIGM, who were diagnosed at a tertiary care hospital in North India. Most common infections were sinopulmonary infections (80%) and diarrhea (50%). Sclerosing cholangitis and necrotising fasciitis were noted in one patient each. Three novel mutations in CD40LG (c.429_429 delA, p. G144DfsX5; c.500 G > A, p.G167E and c.156 G > C, p.K52 N) were detected. In addition, we found one missense mutation, two splice site mutations and two large deletions, which have been previously reported. Four (4) patients had expired at the time of analysis. We report the first series of XLHIGM from North India where we have documented unique features such as pulmonary alveolar proteinosis and infections with Mycobacterium sp.
- Published
- 2018
34. A delayed diagnosis of X-linked hyper IgM syndrome complicated with toxoplasmic encephalitis in a child
- Author
-
Liu, Xiaoliang, Zhou, Kaiyu, Yu, Dan, Cai, Xiaotang, Hua, Yimin, Zhou, Hui, and Wang, Chuan
- Subjects
Male ,child ,Hyper-IgM Immunodeficiency Syndrome, Type 1 ,X-linked hyper-IgM syndrome ,Child, Preschool ,Toxoplasmosis, Cerebral ,Humans ,Clinical Case Report ,CD40 ligand ,delayed diagnosis ,Research Article ,cerebral toxoplasmosis - Abstract
Introduction: The X-linked hyper-immunoglobulin M syndrome (XHIGM) is an uncommon primary combined immunodeficiency disease caused by CD40L gene mutations. A delayed or missed diagnosis of XHIGM is common and concerning, owing to atypical immunoglobulin profile and phenotype of some patients, low recognition, and limited knowledge of clinicians on XHIGM in some underdeveloped areas. Opportunistic infections are a prominent clinical feature of XHIGM. However, toxoplasma encephalitis occurs sporadically and is extremely rare in patients with XHIGM. Diagnostic and therapeutic procedure: A 2 years and 10 months’ old male suffered from 3 times of serious infection since 1 year and 4 months of age. Although with history of recurrent respiratory infections, protracted diarrhea, persistent or intermittent neutropenia companioned with oral ulcer, and a typical immunoglobulin profile during his second disease attack, the consideration of XHIGM was still completely ignored because of our low recognition and limited knowledge of this disorder. The diagnosis of XHIGM was ultimately confirmed by detection of elevated serum IgM concentration, decreased serum IgG and IgE concentration, and identification of a mutation c.654C>A (p.C218X) in CD40L gene. Given clinical manifestation of lethargy, uncontrollable somnolence and ataxia, a cat/dog exposure history, positive serum Toxoplasma gondii (T gondii) IgM, positive cerebrospinal fluid T gondii PCR results, and typical characteristics of brain magnetic resonance imaging as multiple rings liked nodules lesions in bilateral cerebral hemisphere cortex, bilateral basal ganglia, and dorsal thalamus, the diagnosis of toxoplasmic encephalitis was considered during his third disease attack. Thereafter, oral administration of sulfadiazine and azithromycin, intravenous immunoglobulin, and subcutaneous injection of G-CSF were initiated. Regrettably, the patient abandoned the treatment because of economic factor and died 3 months after discharge. Conclusions: A more thorough clinical history and some features like recurrent respiratory infections, protracted diarrhea, and persistent or intermittent neutropenia companioned with oral ulcer could increase clinical suspicion of XHIGM. Cerebral toxoplasmosis is rare in patients with XHIGM, but still should be considered. The present study firstly reported a delayed diagnosed case of XHIGM with CD40L gene c.654C>A (p.C218X) mutant complicated with toxoplasma encephalitis in Chinese population, which highlighted the importance of CD40-CD40L interaction in cell-mediated immunity against T gondii.
- Published
- 2017
35. A novel CD40LG deletion causes the hyper-IgM syndrome with normal CD40L expression in a 6-month-old child
- Author
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Francisco J. Espinosa-Rosales, Leopoldo Santos-Argumedo, Laura Berrón-Ruiz, Emmanuel Ramirez-Sánchez, José L. Maravillas-Montero, Gabriela López-Herrera, Marco Antonio Yamazaki-Nakashimada, and Alexander Vargas-Hernández
- Subjects
Hyper IgM syndrome ,Hyper-IgM Immunodeficiency Syndrome ,CD40 Ligand ,Immunology ,CHO Cells ,Transfection ,medicine.disease_cause ,Frameshift mutation ,Exon ,Cricetulus ,medicine ,Extracellular ,Animals ,Humans ,Frameshift Mutation ,Sequence Deletion ,Mutation ,CD40 ,Base Sequence ,biology ,Hyper-IgM Immunodeficiency Syndrome, Type 1 ,Infant ,medicine.disease ,Molecular biology ,Transmembrane protein ,Leukocytes, Mononuclear ,biology.protein - Abstract
The X-linked hyper-IgM syndrome (XHIGM) is the most common form of HIGM. Patients are clinically diagnosed on the basis of recurrent sinopulmonary infections, accompanied with low levels of IgG and IgA, normal to elevated levels of IgM, and the presence of peripheral B cells. Here, we have reported a novel deletion of four nucleotides in CD40LG exon 3, c.375_378delCAAA, which led to a frameshift mutation with a premature stop codon, p.Asn101*126. The deletion resulted in a truncated protein, in which majority of the extracellular domain was lost. However, detection of surface CD40L was still possible as the intracellular, transmembrane, and part of the extracellular domains were not affected. This indicated that this mutation did not affect protein stability and that immunodetection of CD40L expression is not enough for the diagnosis of XHIGM. Our study strongly suggests that genetic diagnosis for XHIGM should always be performed when clinical data support this diagnosis and CD40L protein is present.
- Published
- 2015
36. Knock-in editing: it functionally corrects!
- Author
-
Matthew H. Porteus
- Subjects
Male ,0301 basic medicine ,T-Lymphocytes ,CD40 Ligand ,Immunology ,Mice, SCID ,medicine.disease_cause ,Biochemistry ,Mice ,03 medical and health sciences ,Genome editing ,Inside BLOOD Commentary ,Mice, Inbred NOD ,Gene knockin ,Complementary DNA ,medicine ,Animals ,Humans ,3' Untranslated Regions ,Gene ,Gene Editing ,Genetics ,B-Lymphocytes ,Nuclease ,Mutation ,biology ,Hyper-IgM Immunodeficiency Syndrome, Type 1 ,Double-Stranded DNA Breaks ,Cell Biology ,Hematology ,Immunoglobulin Class Switching ,Enhancer Elements, Genetic ,030104 developmental biology ,Gene Expression Regulation ,RNA editing ,biology.protein ,Female ,RNA Editing ,Somatic Hypermutation, Immunoglobulin ,CRISPR-Cas Systems ,Targeted Gene Repair - Abstract
Loss of CD40 ligand (CD40L) expression or function results in X-linked hyper-immunoglobulin (Ig)M syndrome (X-HIGM), characterized by recurrent infections due to impaired immunoglobulin class-switching and somatic hypermutation. Previous attempts using retroviral gene transfer to correct murine CD40L expression restored immune function; however, treated mice developed lymphoproliferative disease, likely due to viral-promoter-dependent constitutive CD40L expression. These observations highlight the importance of preserving endogenous gene regulation in order to safely correct this disorder. Here, we report efficient, on-target, homology-directed repair (HDR) editing of the CD40LG locus in primary human T cells using a combination of a transcription activator-like effector nuclease-induced double-strand break and a donor template delivered by recombinant adeno-associated virus. HDR-mediated insertion of a coding sequence (green fluorescent protein or CD40L) upstream of the translation start site within exon 1 allowed transgene expression to be regulated by endogenous CD40LG promoter/enhancer elements. Additionally, inclusion of the CD40LG 3'-untranslated region in the transgene preserved posttranscriptional regulation. Expression kinetics of the transgene paralleled that of endogenous CD40L in unedited T cells, both at rest and in response to T-cell stimulation. The use of this method to edit X-HIGM patient T cells restored normal expression of CD40L and CD40-murine IgG Fc fusion protein (CD40-muIg) binding, and rescued IgG class switching of naive B cells in vitro. These results demonstrate the feasibility of engineered nuclease-directed gene repair to restore endogenously regulated CD40L, and the potential for its use in T-cell therapy for X-HIGM syndrome.
- Published
- 2016
37. A Novel Mutation in CD40LG Gene Causing X-Linked Hyper IgM Syndrome
- Author
-
Tae Min Um, Hyung Young Kim, and Hee Ju Park
- Subjects
0301 basic medicine ,030201 allergy ,X-Linked Hyper IgM Syndrome ,biology ,business.industry ,Hyper-IgM Immunodeficiency Syndrome, Type 1 ,Hyper-IgM Immunodeficiency Syndrome ,CD40LG gene ,Virology ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Immunoglobulin M ,Pediatrics, Perinatology and Child Health ,Mutation (genetic algorithm) ,Mutation ,biology.protein ,Medicine ,Humans ,CD40 Antigens ,business ,Novel mutation - Published
- 2017
38. Clinical Features and Genetic Analysis of 20 Chinese Patients with X-Linked Hyper-IgM Syndrome
- Author
-
Xiao-Fang Wang, Lin-Lin Wang, Wei Zhao, Zhi-Qing Tian, Wei Zhou, Wei-Fan Wang, and Tong-Xin Chen
- Subjects
Adult ,lcsh:Immunologic diseases. Allergy ,China ,medicine.medical_specialty ,Adolescent ,Article Subject ,Anemia ,medicine.medical_treatment ,CD40 Ligand ,Immunology ,Hematopoietic stem cell transplantation ,Neutropenia ,medicine.disease_cause ,Young Adult ,Asian People ,Internal medicine ,medicine ,Humans ,Transplantation, Homologous ,Immunology and Allergy ,Genetic Testing ,Age of Onset ,Young adult ,Child ,Aged ,Genetic testing ,Aged, 80 and over ,Mycobacterium Infections ,Mutation ,medicine.diagnostic_test ,Hyper-IgM Immunodeficiency Syndrome, Type 1 ,business.industry ,Hematopoietic Stem Cell Transplantation ,Infant ,General Medicine ,Middle Aged ,Prognosis ,medicine.disease ,Child, Preschool ,BCG Vaccine ,Primary immunodeficiency ,Age of onset ,lcsh:RC581-607 ,business ,Research Article - Abstract
X-linked hyper-IgM syndrome (XHIGM) is one type of primary immunodeficiency diseases, resulting from defects in the CD40 ligand/CD40 signaling pathways. We retrospectively analyzed the clinical and molecular features of 20 Chinese patients diagnosed and followed up in hospitals affiliated to Shanghai Jiao Tong University School of Medicine from 1999 to 2013. The median onset age of these patients was 8.5 months (range: 20 days–21 months). Half of them had positive family histories, with a shorter diagnosis lag. The most common symptoms were recurrent sinopulmonary infections (18 patients, 90%), neutropenia (14 patients, 70%), oral ulcer (13 patients, 65%), and protracted diarrhea (13 patients, 65%). Six patients had BCGitis. Six patients received hematopoietic stem cell transplantations and four of them had immune reconstructions and clinical remissions. Eighteen unique mutations inCD40Lgene were identified in these 20 patients from 19 unrelated families, with 12 novel mutations. We compared with reported mutation results and used bioinformatics software to predict the effects of mutations on the target protein. These mutations reflected the heterogeneity ofCD40Lgene and expanded our understanding of XHIGM.
- Published
- 2014
39. Liver disease predicts mortality in patients with X-linked immunodeficiency with hyper-IgM but can be prevented by early hematopoietic stem cell transplantation
- Author
-
Vian Azzu, Dinakantha S. Kumararatne, J. David M. Edgar, William J.H. Griffiths, Mary Slatter, Beatriz Morillo-Gutierrez, and Lucinda Kennard
- Subjects
0301 basic medicine ,Diagnostic Imaging ,Hyper-IgM Immunodeficiency Syndrome ,medicine.medical_treatment ,Biopsy ,Immunology ,Time to treatment ,Hematopoietic stem cell transplantation ,Kaplan-Meier Estimate ,Immunodeficiency With Hyper-IgM ,Time-to-Treatment ,03 medical and health sciences ,Liver disease ,0302 clinical medicine ,Text mining ,Immunology and Allergy ,Medicine ,Humans ,In patient ,medicine.diagnostic_test ,business.industry ,Hyper-IgM Immunodeficiency Syndrome, Type 1 ,Liver Diseases ,Hematopoietic Stem Cell Transplantation ,medicine.disease ,030104 developmental biology ,business ,Biomarkers ,030215 immunology - Published
- 2016
40. Immunoglobulin class switch recombination deficiency type 1 or CD40 ligand deficiency: from bedside to bench and back again
- Author
-
Nima Rezaei, Armin Hirbod-Mobarakeh, and Asghar Aghamohammadi
- Subjects
Hyper-IgM Immunodeficiency Syndrome ,CD40 Ligand ,Immunology ,Opportunistic Infections ,medicine.disease_cause ,Immunoglobulin Class Switch Recombination ,Autoimmune Diseases ,Autoimmunity ,Neoplasms ,medicine ,Animals ,Humans ,Immunology and Allergy ,Immunodeficiency ,biology ,Hyper-IgM Immunodeficiency Syndrome, Type 1 ,business.industry ,CD40 Ligand Deficiency ,medicine.disease ,Immunoglobulin Class Switching ,Phenotype ,Immunoglobulin class switching ,biology.protein ,Antibody ,business - Abstract
The immunoglobulin class switch recombination deficiency or hyper-IgM syndrome is characterized by normal or elevated serum IgM and low serum levels of other immunoglobulins. Since the first reported patient with hyper-IgM, more than 200 patients with this phenotype resulted from CD40 ligand deficiency have been reported. However, in addition to this common finding, they presented with different manifestations like opportunistic infections, autoimmunity and malignancies each of them are worth a detailed look. In this review, we will focus on different underlying mechanisms of these presentations to review what we have learned from our patients. In the end, we will discuss different treatment options available for these patients using this knowledge.
- Published
- 2013
41. CD40 ligand deficiency causes functional defects of peripheral neutrophils that are improved by exogenous IFN-γ
- Author
-
Regina Sumiko Watanabe Di Gesu, Gabriela Riemekasten, Claudia Feriotti, Taj Ali Khan, Tania Alves da Costa, Troy R. Torgerson, Cristina Worm Weber, Tabata Takahashi França, Basel K. al-Ramadi, Otavio Cabral-Marques, Hans D. Ochs, José Alexandre Marzagão Barbuto, Gustavo P. Amarante-Mendes, Maria J. Fernandez-Cabezudo, Luigi D. Notarangelo, Lena F. Schimke, Cláudia França Cavalcante Valente, Janaíra Fernandes Ferreira, Ashraf Al-Sbiei, Vera Lúcia Garcia Calich, Asif Iqbal, Osvaldo Reis Junior, Beatriz Tavares Costa-Carvalho, Antonio Condino-Neto, Paulo Vitor Soeiro Pereira, and Fabiola Scancetti Tavares
- Subjects
0301 basic medicine ,Staphylococcus aureus ,Phagocyte ,Neutrophils ,medicine.medical_treatment ,CD40 Ligand ,Immunology ,HL-60 Cells ,chemical and pharmacologic phenomena ,CD16 ,Article ,Transcriptome ,Interferon-gamma ,03 medical and health sciences ,immune system diseases ,medicine ,Animals ,Humans ,Immunology and Allergy ,Respiratory Burst ,Mice, Knockout ,Hyper-IgM Immunodeficiency Syndrome, Type 1 ,business.industry ,Paracoccidioides ,hemic and immune systems ,CD40 Ligand Deficiency ,Neutrophil extracellular traps ,Recombinant Proteins ,PROLIFERAÇÃO CELULAR ,Respiratory burst ,Mice, Inbred C57BL ,N-Formylmethionine Leucyl-Phenylalanine ,030104 developmental biology ,medicine.anatomical_structure ,Cytokine ,Knockout mouse ,Tetradecanoylphorbol Acetate ,Female ,Reactive Oxygen Species ,business - Abstract
Background Patients with X-linked hyper-IgM syndrome caused by CD40 ligand (CD40L) deficiency often present with episodic, cyclic, or chronic neutropenia, suggesting abnormal neutrophil development in the absence of CD40L-CD40 interaction. However, even when not neutropenic and despite immunoglobulin replacement therapy, CD40L-deficient patients are susceptible to life-threatening infections caused by opportunistic pathogens, suggesting impaired phagocyte function and the need for novel therapeutic approaches. Objectives We sought to analyze whether peripheral neutrophils from CD40L-deficient patients display functional defects and to explore the in vitro effects of recombinant human IFN-γ (rhIFN-γ) on neutrophil function. Methods We investigated the microbicidal activity, respiratory burst, and transcriptome profile of neutrophils from CD40L-deficient patients. In addition, we evaluated whether the lack of CD40L in mice also affects neutrophil function. Results Neutrophils from CD40L-deficient patients exhibited defective respiratory burst and microbicidal activity, which were improved in vitro by rhIFN-γ but not soluble CD40L. Moreover, neutrophils from patients showed reduced CD16 protein expression and a dysregulated transcriptome suggestive of impaired differentiation. Similar to CD40L-deficient patients, CD40L knockout mice were found to have impaired neutrophil responses. In parallel, we demonstrated that soluble CD40L induces the promyelocytic cell line HL-60 to proliferate and mature by regulating the expression of genes of the same Gene Ontology categories (eg, cell differentiation) when compared with those dysregulated in peripheral blood neutrophils from CD40L-deficient patients. Conclusion Our data suggest a nonredundant role of CD40L-CD40 interaction in neutrophil development and function that could be improved in vitro by rhIFN-γ, indicating a potential novel therapeutic application for this cytokine.
- Published
- 2018
42. Modeling, optimization, and comparable efficacy of T cell and hematopoietic stem cell gene editing for treating hyper-IgM syndrome.
- Author
-
Vavassori V, Mercuri E, Marcovecchio GE, Castiello MC, Schiroli G, Albano L, Margulies C, Buquicchio F, Fontana E, Beretta S, Merelli I, Cappelleri A, Rancoita PM, Lougaris V, Plebani A, Kanariou M, Lankester A, Ferrua F, Scanziani E, Cotta-Ramusino C, Villa A, Naldini L, and Genovese P
- Subjects
- Animals, Gene Editing, Hematopoietic Stem Cells, Humans, Mice, T-Lymphocytes, Hyper-IgM Immunodeficiency Syndrome, Hyper-IgM Immunodeficiency Syndrome, Type 1
- Abstract
Precise correction of the CD40LG gene in T cells and hematopoietic stem/progenitor cells (HSPC) holds promise for treating X-linked hyper-IgM Syndrome (HIGM1), but its actual therapeutic potential remains elusive. Here, we developed a one-size-fits-all editing strategy for effective T-cell correction, selection, and depletion and investigated the therapeutic potential of T-cell and HSPC therapies in the HIGM1 mouse model. Edited patients' derived CD4 T cells restored physiologically regulated CD40L expression and contact-dependent B-cell helper function. Adoptive transfer of wild-type T cells into conditioned HIGM1 mice rescued antigen-specific IgG responses and protected mice from a disease-relevant pathogen. We then obtained ~ 25% CD40LG editing in long-term repopulating human HSPC. Transplanting such proportion of wild-type HSPC in HIGM1 mice rescued immune functions similarly to T-cell therapy. Overall, our findings suggest that autologous edited T cells can provide immediate and substantial benefits to HIGM1 patients and position T-cell ahead of HSPC gene therapy because of easier translation, lower safety concerns and potentially comparable clinical benefits., (© 2021 The Authors. Published under the terms of the CC BY 4.0 license.)
- Published
- 2021
- Full Text
- View/download PDF
43. Pediatric allergy and immunology in Brazil
- Author
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Renata Rodrigues Cocco, Emanuel Sarinho, Luisa Karla de Paula Arruda, Jacob Cm, Herberto José Chong-Neto, Ana Paula Beltran Moschione Castro, Inês Cristina Camelo-Nunes, Antonio Condino-Neto, Nelson Augusto Rosario-Filho, Antonio Carlos Pastorino, Beatriz Tavares Costa-Carvalho, Ariana Campos Yang, Dirceu Solé, and Gustavo F. Wandalsen
- Subjects
medicine.medical_specialty ,Pediatrics ,Allergy ,Adolescent ,Immunology ,Granulomatous Disease, Chronic ,Infections ,medicine.disease_cause ,Subspecialty ,Food allergy ,Allergy and Immunology ,Epidemiology ,Prevalence ,medicine ,Humans ,Immunology and Allergy ,Child ,Hyper-IgM Immunodeficiency Syndrome, Type 1 ,business.industry ,Incidence ,Mortality rate ,Incidence (epidemiology) ,Infant ,Aeroallergen ,Allergens ,medicine.disease ,Asthma ,Education, Medical, Graduate ,Air Pollution, Indoor ,Pediatrics, Perinatology and Child Health ,business ,Brazil ,Food Hypersensitivity ,Anaphylaxis - Abstract
The subspecialty of pediatric allergy and immunology in Brazil is in its early years and progressing steadily. This review highlights the research developed in the past years aiming to show the characteristics of allergic and immunologic diseases in this vast country. Epidemiologic studies demonstrated the high prevalence of asthma in infants, children, and adolescents. Mortality rates and average annual variation of asthma hospitalization have reduced in all pediatric age groups. Indoor aeroallergen exposure is excessively high and contributes to the high rates of allergy sensitization. Prevalence of food allergy has increased to epidemic levels. Foods (35%), insect stings (30%), and drugs (23%) are the main etiological agents of anaphylaxis in children and adolescents. Molecular diagnosis of primary immunodeficiencies (PID) showed a high incidence of fungal infections including paracoccidioidomycosis in X-linked hyper-IgM syndrome, and the occurrence of BCG adverse reactions or other mycobacterial infections in patients with chronic granulomatous disease. Education in pediatric allergy and immunology is deficient for medical students, but residency programs are effective in training internists and pediatricians for the practice of allergy. The field of PID requires further training. Last, this review is a tribute to Prof. Dr. Charles Naspitz, one of the pioneers of our specialty in Brazil.
- Published
- 2013
44. X-linked Hyper IgM Syndrome Presenting as Pulmonary Alveolar Proteinosis
- Author
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Sara Szabo, Mina Salib, Hans D. Ochs, Mary Hintermeyer, Jesus M. Lopez-Guisa, James W. Verbsky, John M. Routes, Juan Adams, Troy R. Torgerson, and Joel L. Gallagher
- Subjects
0301 basic medicine ,Male ,Hyper IgM syndrome ,Pathology ,medicine.medical_specialty ,Immunology ,CD40 Ligand ,Somatic hypermutation ,Pulmonary Alveolar Proteinosis ,Lymphocyte Activation ,Diagnosis, Differential ,03 medical and health sciences ,0302 clinical medicine ,Exome Sequencing ,Immunology and Allergy ,Medicine ,Missense mutation ,Humans ,Lymphocyte Count ,Immunodeficiency ,CD40 ,medicine.diagnostic_test ,biology ,business.industry ,Hyper-IgM Immunodeficiency Syndrome, Type 1 ,Infant ,hemic and immune systems ,medicine.disease ,Lymphocyte Subsets ,030104 developmental biology ,Bronchoalveolar lavage ,Phenotype ,Immunoglobulin class switching ,Mutation ,biology.protein ,Radiography, Thoracic ,business ,Pulmonary alveolar proteinosis ,Tomography, X-Ray Computed ,Biomarkers ,030215 immunology - Abstract
X-linked hyper IgM syndrome (XHIGM) is a combined immunodeficiency caused by mutations in the CD40 ligand (CD40L) gene that typically results in decreased or absent CD40L expression on activated T cells, leading to defective class switching and somatic hypermutation. We describe an infant who presented with respiratory failure due to pulmonary alveolar proteinosis (PAP) with a novel damaging missense mutation in the CD40L gene. Whole exome sequencing (WES) was used to identify a mutation in the CD40L gene. CD40L expression and function were determined by flow cytometry. A 5-month-old previously-healthy male presented with respiratory failure and diffuse pulmonary ground glass opacities on CT scan of the chest. Laboratory evaluation revealed an undetectable IgG, normal IgA, and elevated IgM. A bronchoalveolar lavage demonstrated pulmonary alveolar proteinosis. WES demonstrated a c.608G > C mutation in the CD40L gene resulting in p.R203T. Flow cytometry demonstrated normal CD40L expression on activated T cells but absent binding of CD40-Ig to CD40L on activated patient T cells. The clinical manifestations of XHIGM in our patient had several unique features, including the presentation with PAP, normal serum IgA, and expression of non-functional CD40L on activated T cells. To our knowledge, this is the first published case of PAP in a patient with XHIGM.
- Published
- 2016
45. Expanding the Clinical and Genetic Spectrum of Human CD40L Deficiency: The Occurrence of Paracoccidioidomycosis and Other Unusual Infections in Brazilian Patients
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Paolo Ruggero Errante, Angela Falcai, Janaíra Fernandes Ferreira, Mary J. Hackett, Troy R. Torgerson, Hans D. Ochs, Paulo Vitor Soeiro Pereira, Gisele Kuntze, Lena F. Schimke, Nelson Augusto Rosario-Filho, Otavio Cabral-Marques, Joao Bosco Oliveira, Antonio Condino-Neto, Beatriz Tavares Costa Carvalho, and Cristina Worm Weber
- Subjects
Adult ,Male ,Adolescent ,Hyper-IgM Immunodeficiency Syndrome ,CD40 Ligand ,Molecular Sequence Data ,Immunology ,Cohort Studies ,Young Adult ,medicine ,Humans ,Immunology and Allergy ,Missense mutation ,Amino Acid Sequence ,Lymphocyte Count ,Age of Onset ,Child ,Candida albicans ,IMUNOLOGIA ,Paracoccidioides brasiliensis ,Base Sequence ,biology ,Hyper-IgM Immunodeficiency Syndrome, Type 1 ,Paracoccidioidomycosis ,Incidence ,Infant ,CD40 Ligand Deficiency ,biology.organism_classification ,medicine.disease ,Virology ,Lymphocyte Subsets ,Corpus albicans ,Pedigree ,Immunoglobulin Isotypes ,Child, Preschool ,Mutation ,Primary immunodeficiency ,Sequence Alignment ,Brazil - Abstract
CD40 ligand (CD40L) deficiency or X-linked hyper-IgM syndrome (X-HIGM) is a well-described primary immunodeficiency in which Pneumocystis jiroveci pneumonia is a common clinical feature. We have identified an unusual high incidence of fungal infections and other not yet described infections in a cohort of 11 X-HIGM patients from nine unrelated Brazilian families. Among these, we describe the first case of paracoccidioidomycosis (PCM) in X-HIGM. The molecular genetic analysis of CD40L was performed by gene sequencing and evaluation of CD40L protein expression. Nine of these 11 patients (82%) had fungal infections. These included fungal species common to CD40L deficiency (P. jiroveci and Candida albicans) as well as Paracoccidioides brasiliensis. One patient presented with PCM at age 11 years and is now doing well at 18 years of age. Additionally, one patient presented with a simultaneous infection with Klebsiella and Acinetobacter, and one with condyloma caused by human papilloma virus. Molecular analysis revealed four previously described CD40L mutations, two novel missense mutations (c.433 T G and c.476 G C) resulting in the absence of CD40L protein expression by activated CD4(+) cells and one novel insertion (c.484_485insAA) within the TNFH domain leading to a frame shift and premature stop codon. These observations demonstrated that the susceptibility to fungal infections in X-HIGM extends beyond those typically associated with X-HIGM (P. jiroveci and C. albicans) and that these patients need to be monitored for those pathogens.
- Published
- 2011
46. The Role of CD40/CD40 Ligand Interactions in Bone Marrow Granulopoiesis
- Author
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Irene Mavroudi and Helen A. Papadaki
- Subjects
Neutropenia ,Stromal cell ,CD40 Ligand ,lcsh:Medicine ,Review Article ,G-CSF ,Granulocyte ,lcsh:Technology ,Granulopoiesis ,General Biochemistry, Genetics and Molecular Biology ,tumor necrosis factor family ,Bone Marrow ,CD40 ,medicine ,CD40L ,Humans ,CD40 Antigens ,Progenitor cell ,Flt3-L ,lcsh:Science ,and granulocytic progenitor cells ,General Environmental Science ,granulopoiesis ,biology ,Hyper-IgM Immunodeficiency Syndrome, Type 1 ,lcsh:T ,Chemistry ,lcsh:R ,apoptosis ,GM-CSF ,hemic and immune systems ,General Medicine ,Acquired immune system ,Hematopoiesis ,Haematopoiesis ,medicine.anatomical_structure ,Immunology ,biology.protein ,lcsh:Q ,Bone marrow ,Granulocytes - Abstract
The CD40 ligand (CD40L) and CD40 are two molecules belonging to the TNF/TNF receptor superfamily, and their role in adaptive immune system has widely been explored. However, the wide range of expression of these molecules on hematopoietic as well as nonhematopoietic cells has revealed multiple functions of the CD40/CD40L interactions on different cell types and processes such as granulopoiesis. CD40 triggering on stromal cells has been documented to enhance the expression of granulopoiesis growth factors such as granulocyte-colony-stimulating factor (G-CSF) and granulocyte/monocyte-colony-stimulating factor (GM-CSF), and upon disruption of the CD40/CD40L-signaling pathway, as in the case of X-linked hyperimmunoglobulin M (IgM) syndrome (XHIGM), it can lead to neutropenia. In chronic idiopathic neutropenia (CIN) of adults, however, under the influence of an inflammatory microenvironment, CD40L plays a role in granulocytic progenitor cell depletion, providing thus a pathogenetic cause of CIN.
- Published
- 2011
47. A tissue-specific, activation-inducible, lentiviral vector regulated by human CD40L proximal promoter sequences
- Author
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Z Romero, Ignacio J. Molina, Francisco Martin, Marién Cobo, J D Unciti, Pilar Muñoz, and S Torres
- Subjects
T-Lymphocytes ,Genetic enhancement ,Transgene ,CD40 Ligand ,Genetic Vectors ,chemical and pharmacologic phenomena ,Lymphocyte Activation ,Cell Line ,Viral vector ,Transduction (genetics) ,Transduction, Genetic ,Genetics ,Humans ,CD154 ,Promoter Regions, Genetic ,Molecular Biology ,Gene ,Reporter gene ,CD40 ,biology ,Hyper-IgM Immunodeficiency Syndrome, Type 1 ,Lentivirus ,hemic and immune systems ,Genetic Therapy ,Virology ,Cell biology ,Organ Specificity ,biology.protein ,Molecular Medicine - Abstract
The application of new protocols for gene therapy against monogenic diseases requires the development of safer therapeutic vectors, particularly in the case of diseases in which expression of the mutated gene is subject to fine regulation, as it is with CD40L (CD154). CD40L, the gene mutated in the X-linked hyper-immunoglobulin M syndrome (HIGM1), is tightly regulated to allow surface expression of its product only on T cells stimulated by antigen encounter. Previous studies in an HIGM1 animal model showed that transduction of progenitor cells corrected the syndrome but caused a thymic lymphoproliferative disease because of the unregulated expression of the transgene by constitutive vectors. To develop a tissue-specific, activation-inducible, lentiviral vector (LV) for gene therapy to counter HIGM1, we have constructed two self-inactivating LVs, pCD40L-eGFP and pCD40L-CD40L, regulated by a 1.3 kb fragment of the human CD40L proximal promoter. The expression of pCD40L-eGFP LV is restricted to cells in which mRNA transcripts of the endogenous CD40L gene can be detected. Moreover, the expression of the reporter gene in primary T lymphocytes depends on the activation state of the cells. Remarkably, primary HIGM1 lymphocytes transduced with pCD40L-CD40L LV expressed CD40L only after T-cell stimulation. Therefore, the CD40L-promoter-driven vectors are able to achieve a near-physiological expression pattern that follows very closely that of the endogenous CD40L gene.
- Published
- 2010
48. Mutation analysis in primary immunodeficiency diseases: case studies
- Author
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Amy P. Hsu, Julie E. Niemela, and Thomas A. Fleisher
- Subjects
Male ,Candidate gene ,Hyper-IgM Immunodeficiency Syndrome ,CD40 Ligand ,DNA Mutational Analysis ,Immunology ,Computational biology ,Gene mutation ,Article ,DNA sequencing ,medicine ,Humans ,Immunology and Allergy ,Diagnostic Errors ,Child ,Lymphatic Diseases ,Immunodeficiency ,Genetics ,Purpura, Thrombocytopenic, Idiopathic ,Ectodermal Dysplasia 1, Anhidrotic ,Hyper-IgM Immunodeficiency Syndrome, Type 1 ,business.industry ,Autoimmune Lymphoproliferative Syndrome ,Infant ,Bacterial Infections ,medicine.disease ,I-kappa B Kinase ,Interleukin-1 Receptor-Associated Kinases ,Mutation ,Mutation (genetic algorithm) ,Primary immunodeficiency ,Female ,Severe Combined Immunodeficiency ,Identification (biology) ,business ,Interleukin Receptor Common gamma Subunit - Abstract
Purpose of review—The application of mutation analysis is becoming an integral part of the complete evaluation of patients with primary immunodeficiencies, and as such, clinicians caring for these patients must develop a better understanding of the utility and challenges of this important laboratory technology. Recent findings—Genomic DNA sequencing is currently the standard approach used to characterize a possible gene mutation causing a specific primary immunodeficiency. There are clinical situations in which this approach is revealing of a genetic defect and other circumstances in which this generates a false-positive or false-negative result. One case study is presented that reviews a straightforward analysis that clarifies the genetic basis of a primary immunodeficiency, and four cases are presented that required additional studies to clarify the underlying basis of the immunodeficiency. In the latter circumstances, the rationale for additional studies is outlined and the outcome of these is presented. Summary—The identification of a gene mutation as the underlying basis of a primary immunodeficiency begins with the evaluation of the clinical presentation focusing on the infection history so as to develop a differential diagnosis including potential genetic causes. The next step is to obtain specific laboratory studies, including immunologic function evaluation, and, based on these findings, to proceed with DNA sequencing of one or several selected candidate genes. Genomic DNA sequencing has certain limitations, and alternative follow-up approaches may be necessary to establish the molecular basis of the primary immunodeficiency in a given patient.
- Published
- 2009
49. Analysis of somatic hypermutation in X-linked hyper-IgM syndrome shows specific deficiencies in mutational targeting
- Author
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Peter E. Lipsky, Dereje D. Jima, Wen Zhang, Amrie C. Grammer, Peter H.L. Krijger, Daniel E. Russ, Nancy S. Longo, Sandeep S. Dave, Patricia L. Lugar, and Sule Yavuz
- Subjects
Adult ,Male ,Adolescent ,CD40 Ligand ,DNA Mutational Analysis ,Immunology ,Somatic hypermutation ,Biology ,medicine.disease_cause ,Biochemistry ,Gene Expression Regulation, Enzymologic ,DNA Glycosylases ,Germline mutation ,Cytidine Deaminase ,medicine ,Activation-induced (cytidine) deaminase ,Humans ,Immunologic Capping ,CD40 Antigens ,Child ,X chromosome ,Immunobiology ,Genetics ,B-Lymphocytes ,Mutation ,Hyper-IgM Immunodeficiency Syndrome, Type 1 ,Germinal center ,Cell Biology ,Hematology ,Cytidine deaminase ,Germinal Center ,Molecular biology ,Up-Regulation ,biology.protein ,Immunoglobulin heavy chain ,Somatic Hypermutation, Immunoglobulin ,Immunoglobulin Heavy Chains ,Immunologic Memory - Abstract
Subjects with X-linked hyper-IgM syndrome (X-HIgM) have a markedly reduced frequency of CD27+ memory B cells, and their Ig genes have a low level of somatic hypermutation (SHM). To analyze the nature of SHM in X-HIgM, we sequenced 209 nonproductive and 926 productive Ig heavy chain genes. In nonproductive rearrangements that were not subjected to selection, as well as productive rearrangements, most of the mutations were within targeted RGYW, WRCY, WA, or TW motifs (R = purine, Y = pyrimidine, and W = A or T). However, there was significantly decreased targeting of the hypermutable G in RGYW motifs. Moreover, the ratio of transitions to transversions was markedly increased compared with normal. Microarray analysis documented that specific genes involved in SHM, including activation-induced cytidine deaminase (AICDA) and uracil-DNA glycosylase (UNG2), were up-regulated in normal germinal center (GC) B cells, but not induced by CD40 ligation. Similar results were obtained from light chain rearrangements. These results indicate that in the absence of CD40-CD154 interactions, there is a marked reduction in SHM and, specifically, mutations of AICDA-targeted G residues in RGYW motifs along with a decrease in transversions normally related to UNG2 activity.
- Published
- 2009
50. Stem cell transplantation in primary immunodeficiency disease patients
- Author
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Makoto Kaneda, Tomonobu Sato, Nariaki Toita, Ryoji Kobayashi, Nobuaki Kawamura, Akihiro Iguchi, Norikazu Hatano, and Tadashi Ariga
- Subjects
Male ,Pediatrics ,medicine.medical_specialty ,Transplantation Conditioning ,Hyper-IgM Immunodeficiency Syndrome ,Graft vs Host Disease ,Cord Blood Stem Cell Transplantation ,Disease ,medicine ,Humans ,Bone Marrow Transplantation ,Severe combined immunodeficiency ,Hyper-IgM Immunodeficiency Syndrome, Type 1 ,business.industry ,Graft Survival ,Immunologic Deficiency Syndromes ,Infant ,medicine.disease ,Wiskott-Aldrich Syndrome ,Surgery ,Transplantation ,surgical procedures, operative ,Child, Preschool ,Cytomegalovirus Infections ,Pediatrics, Perinatology and Child Health ,Primary immunodeficiency ,Female ,Severe Combined Immunodeficiency ,business ,Complication ,Follow-Up Studies ,Stem Cell Transplantation - Abstract
Background: Primary immunodeficiency diseases (PID) are rare but have a high associated risk of death from overwhelming infection in early childhood. Stem cell transplantation (SCT) can be curative for PID, but standardized protocols for each disease have not yet been established. Methods: Between May 1995 and May 2005, nine patients diagnosed with a PID received SCT at the Department of Pediatrics, Hokkaido University Hospital. The median age of the patients (eight boys and one girl) was 1.0 year (range: 6 months–4 years). Five patients had Wiskott–Aldrich syndrome (WAS), three had severe combined immunodeficiency (SCID), and one had X-linked hyper-IgM syndrome (X-HIGM). Four patients received bone marrow transplantation (BMT), and five received cord blood stem cell transplantation (CBSCT). All patients, including those with SCID, received a conditioning regimen: six (WAS and X-HIGM) received a myeloablative conditioning regimen, and three (SCID) received a reduced-intensity conditioning regimen. Results: All the patients are alive and have stable, complete chimerism, based on a median follow-up period of 4 years. Moreover, all patients have good immune reconstitution, and none required immunoglobulin replacement therapy. Two patients had significant acute graft-versus-host disease (GVHD), and three patients had chronic GVHD. Four of the nine patients developed cytomegalovirus (CMV) infection after SCT. Conclusion: The transplantation procedures appear to have provided a permanent cure in nine PID patients. Early diagnosis and prompt performance of SCT with an optimal donor and conditioning regimen contributed to the favorable outcomes.
- Published
- 2007
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