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BMC Pediatr. 2022 Nov 22;22(1):675. doi: 10.1186/s12887-022-03726-z.

ABSTRACT

BACKGROUND: X-linked hyper-immunoglobulin M (XHIGM), a primary immunodeficiency syndrome caused by mutations in the CD40 ligand gene(CD40LG), presents with recurrent respiratory infections in pediatric patients. We aimed to evaluate the spectrum of clinical features and respiratory pathogens in pediatric patients with XHIGM in China.

METHODS: We retrospectively reviewed seven pediatric patients who were diagnosed with XHIGM and received follow-up treatment at the Guangzhou Women and Children’s Medical Center between January 2010 and January 2021. We determined their clinical characteristics, causative pathogens, and prognosis by performing peripheral immunological and genetic tests.

RESULTS: There were seven boys with age ranging from 4-20 months (median age, 13 months). Four of the seven respiratory infections were caused by Talaromyces marneffei(T. marneffei). Two patients had viral infections caused by cytomegalovirus (CMV) and human adenovirus respectively. One patient had a mixed infection caused by Pneumocystis carinii and CMV. Except for one child who died of respiratory failure, one patient received hematopoietic stem cell transplantation (HSCT) and recovered well, the other five patients survived with regular infusions of intravenous immunoglobulin (IVIg) during the follow-up period. Six patients had reduced antibody levels, especially IgG, IgA, and IgE levels. Increased serum IgM levels were detected in four cases, and three cases presented normal IgM levels at onset. All children were diagnosed with XHIGM with CD40LG variation. Three novel mutations were identified in the present study.

CONCLUSIONS: Our study suggests that respiratory infections usually begin within 2 years old, fungi and viruses are important pathogens causing respiratory infections in children with XHIGM. In endemic areas, T. marneffei is the common pathogen of respiratory tract infection in children with the disease.

PMID:36419145 | DOI:10.1186/s12887-022-03726-z

RNA Biol. 2022 Jan;19(1):1244-1255. doi: 10.1080/15476286.2022.2146919.

ABSTRACT

Intracellular and intercellular signalling networks play an essential role in optimizing cellular homoeostasis and are thought to be partly reflected in nuclear mRNA dynamics. However, the regulation of nuclear mRNA dynamics by intracellular and intercellular signals remains largely unexplored, and research tools are lacking. Through an original screening based on the mRNA metabolic mechanism, we discovered that eight well-known inhibitors cause significant nuclear poly(A)⁺ RNA accumulation. Among these inhibitors, we discovered a new mRNA metabolic response in which the addition of antimycin A, an inhibitor of mitochondrial respiratory-chain complex III (complex III), resulted in a marked accumulation of poly(A)⁺ RNA near the nuclear speckles. Furthermore, dihydroorotate dehydrogenase (DHODH) inhibitors, a rate-limiting enzyme in the intracellular de novo pyrimidine synthesis reaction that specifically exchanges electrons with complex III, also caused a remarkable accumulation of nuclear poly(A)⁺ RNA adjacent to the nuclear speckles, which was abolished by extracellular uridine supply, indicating that the depletion of intracellular pyrimidine affects poly(A)⁺ RNA metabolism. Further analysis revealed that ataxia telangiectasia mutated (ATM), a serine and threonine kinase and a master regulator of DNA double-strand break (DSB) and nucleolar stress, is required for this poly(A)⁺ RNA nuclear accumulation phenomenon. This study reports new insights into novel aspects of nuclear poly(A)⁺ RNA metabolism, especially the relationship between mitochondrial respiratory-chain functions, pyrimidine metabolism, and nuclear RNA metabolism.

PMID:36412986 | DOI:10.1080/15476286.2022.2146919

Niger J Clin Pract. 2022 Nov;25(11):1838-1845. doi: 10.4103/njcp.njcp_272_22.

ABSTRACT

BACKGROUND: School Health Instruction (SHI) comprises of series of formal, well-planned, and organized learning whereby information concerning knowledge, habits, attitudes, practices, and conducts are given pertaining to the health of an individual or members of the school community. A well-structured and implemented SHI forms the basis for a healthy health promotion.

AIM: The study aimed at assessing the implementation of SHI among primary schools in a Local Government Area, Southwest, Nigeria.

SUBJECTS AND METHODS: A cross-sectional descriptive study was carried out among 67 private and public schools in a Local Government Area of Ekiti State using a standardized checklist and direct observation. Data were analyzed using SPSS version 25.

RESULTS: The ratio of teachers to pupils was 1:16 in public schools and 1:10 in private schools. More public-school teachers (93.8%) compared to private school teachers (28.9) had education-related qualifications (P < 0.0001). All public schools adhered to the recommended three periods per week on health education while the frequency of adherence varied in private schools. About half of the private school teachers and 60.4% of the public school teachers have had in-service training on general health and health promotion. Direct teaching by a subject teacher was carried out by 11.9% of the schools while 49.3% had supplemental teaching aids. The scope of health education was uniform among all the schools. Only 46.3% of the schools attained the recommended minimum acceptable score on SHI.

CONCLUSION: School health instruction was poorly implemented in the study location. There is a need to scale up SHI and monitor its implementation in the study location. These efforts should be supported by all stakeholders and backed with adequate oversight function by regulatory authorities, provision of in-service training, and teaching aids for teachers.

PMID:36412291 | DOI:10.4103/njcp.njcp_272_22

Immunol Allergy Clin North Am. 2023 Feb;43(1):145-157. doi: 10.1016/j.iac.2022.05.011. Epub 2022 Oct 28.

ABSTRACT

In recent years, hereditary angioedema (HAE) management has substantially advanced but also become more complex with additional therapeutic options. Pregnancy significantly influences the clinical symptoms of HAE in many women because of estrogen effects or other physiologic factors, and also introduces important safety concerns related to HAE medications. Management of HAE during pregnancy requires clinicians to be familiar with the potential clinical course, triggers, and recommended treatment strategies to provide guidance and optimal medical management to women and families affected by the condition. This review provides an overview of data, considerations, and recommendations related to HAE and pregnancy.

PMID:36411000 | DOI:10.1016/j.iac.2022.05.011

Immunol Allergy Clin North Am. 2023 Feb;43(1):133-144. doi: 10.1016/j.iac.2022.07.009. Epub 2022 Oct 28.

ABSTRACT

An overview of primary antibody immunodeficiency in pregnancy is presented. Indications for immunoglobulin replacement therapy (IGRT), dosing, and safety considerations are highlighted. Uses of immunizations and antimicrobial therapy are also discussed. In general, IGRT, both intravenous and subcutaneous, is considered safe in pregnancy.

PMID:36410999 | DOI:10.1016/j.iac.2022.07.009

J Med Cases. 2022 Oct;13(10):521-524. doi: 10.14740/jmc3798. Epub 2022 Oct 31.

ABSTRACT

Primary colorectal lymphoma is incredibly rare and cases of iatrogenic immunodeficiency associated lymphoproliferative disorder (IILPD) isolated to colorectal area are even more uncommon. Immunodeficiency associated lymphoproliferative disorders can occur in association with primary immune disorders such as inflammatory bowel diseases (IBDs) which are often treated with various immunomodulatory drugs. Of the immunomodulatory drugs, thiopurines, in particular, are known to have a significantly increased relative risk for development of IILPDs. Here we present the case of a 43-year-old Caucasian man with a 22-year history of IBD treated with longstanding immunomodulatory therapy who presented with severe rectal pain and drainage. He underwent an examination under anesthesia with rigid proctoscopy and biopsies were taken of a hard exophytic appearing tissue along the posterior wall of the rectosigmoid junction. Pathological investigation of the samples revealed IILPD. He underwent treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) and achieved complete remission. Literature demonstrates that the use of immunomodulators such as azathioprine has been shown to significantly improve the quality of life in patients with IBD. However, while the absolute risk of lymphoma for any given patient remains quite low, the relative risk of lymphoma in patients who are actively treated with thiopurines is moderate. Therefore, the decision to proceed with thiopurine treatment, especially in the setting of long-term therapy, requires extensive discussion and patient education of the risks/benefits along with closer monitoring of new or uncharacteristic symptoms.

PMID:36407867 | PMC:PMC9635768 | DOI:10.14740/jmc3798

Front Immunol. 2022 Nov 2;13:1011646. doi: 10.3389/fimmu.2022.1011646. eCollection 2022.

ABSTRACT

PURPOSE: Heterozygous mutations in CTLA4 lead to an inborn error of immunity characterized by immune dysregulation and immunodeficiency, known as CTLA-4 insufficiency. Cohort studies on CTLA4 mutation carriers showed a reduced penetrance (around 70%) and variable disease expressivity, suggesting the presence of modifying factors. It is well studied that infections can trigger autoimmunity in humans, especially in combination with a genetic predisposition.

METHODS: To investigate whether specific infections or the presence of specific persisting pathogens are associated with disease onset or severity in CTLA-4 insufficiency, we have examined the humoral immune response in 13 CTLA4 mutation carriers, seven without clinical manifestation and six with autoimmune manifestations, but without immunoglobulin replacement therapy against cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus 1/2 (HSV 1/2), parvovirus B19 and Toxoplasma gondii. Additionally, we have measured FcγRIII/CD16A activation by EBV-specific IgG antibodies to examine the functional capabilities of immunoglobulins produced by CTLA4 mutation carriers.

RESULTS: The seroprevalence between affected and unaffected CTLA4 mutation carriers did not differ significantly for the examined pathogens. Additionally, we show here that CTLA4 mutation carriers produce EBV-specific IgG, which are unimpaired in activating FcγRIII/CD16A.

CONCLUSIONS: Our results show that the investigated pathogens are very unlikely to trigger the disease onset in CTLA-4-insufficient individuals, and their prevalence is not correlated with disease severity or expressivity.

PMID:36405723 | PMC:PMC9667032 | DOI:10.3389/fimmu.2022.1011646

J Autoimmun. 2022 Nov 16:102946. doi: 10.1016/j.jaut.2022.102946. Online ahead of print.

ABSTRACT

BACKGROUND: Genetic aberrations in the NFκB pathway lead to primary immunodeficiencies with various degrees of severity. We previously demonstrated that complete ablation of the RelB transcription factor, a key component of the alternative pathway, results in an early manifested combined immunodeficiency requiring stem cell transplantation.

OBJECTIVE: To study the molecular basis of a progressive severe autoimmunity and immunodeficiency in three patients.

METHODS: Whole exome sequencing was performed to identify the genetic defect. Molecular and cellular techniques were utilized to assess the variant impact on NFκB signaling, canonical and alternative pathway crosstalk, as well as the resultant effects on immune function.

RESULTS: Patients presented with multiple autoimmune progressive severe manifestations encompassing the liver, gut, lung, and skin, becoming debilitating in the second decade of life. This was accompanied by a deterioration of the immune system, demonstrating an age-related decline in naïve T cells and responses to mitogens, accompanied by a gradual loss of all circulating CD19⁺ cells. Whole exome sequencing identified a novel homozygous c. C1091T (P364L) transition in RELB. The P364L RelB protein was unstable, with extremely low expression, but retained some function and could be transiently and partially upregulated following Toll-like receptor stimulation. Stimulation of P364L patient fibroblasts resulted in a marked rise in a cluster of pro-inflammatory hyper-expressed transcripts consistent with the removal of RelB inhibitory effect on RelA function. This is likely the main driver of autoimmune manifestations in these patients.

CONCLUSION: Incomplete loss of RelB provided a unique opportunity to gain insights into NFκB’s pathway interactions as well as the pathogenesis of autoimmunity. The P364L RelB mutation leads to gradual decline in immune function with progression of severe debilitating autoimmunity.

PMID:36402602 | DOI:10.1016/j.jaut.2022.102946

Sci Immunol. 2022 Nov 25;7(77):eabq4531. doi: 10.1126/sciimmunol.abq4531. Epub 2022 Nov 18.

ABSTRACT

Herpes simplex virus 1 (HSV-1) infects several billion people worldwide and can cause life-threatening herpes simplex encephalitis (HSE) in some patients. Monogenic defects in components of the type I interferon system have been identified in patients with HSE, emphasizing the role of inborn errors of immunity underlying HSE pathogenesis. Here, we identify compound heterozygous loss-of-function mutations in the gene GTF3A encoding for transcription factor IIIA (TFIIIA), a component of the RNA polymerase III complex, in a patient with common variable immunodeficiency and HSE. Patient fibroblasts and GTF3A gene-edited cells displayed impaired HSV-1-induced innate immune responses and enhanced HSV-1 replication. Chromatin immunoprecipitation sequencing analysis identified the 5S ribosomal RNA pseudogene 141 (RNA5SP141), an endogenous ligand of the RNA sensor RIG-I, as a transcriptional target of TFIIIA. GTF3A mutant cells exhibited diminished RNA5SP141 expression and abrogated RIG-I activation upon HSV-1 infection. Our work unveils a crucial role for TFIIIA in transcriptional regulation of a cellular RIG-I agonist and shows that GTF3A genetic defects lead to impaired cell-intrinsic anti-HSV-1 responses and can predispose to HSE.

PMID:36399538 | DOI:10.1126/sciimmunol.abq4531

Acta Clin Croat. 2022 Mar;61(1):107-114. doi: 10.20471/acc.2022.61.01.13.

ABSTRACT

Coronavirus disease 2019 (COVID-19) is an emerging infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The usual presentation of the disease is a common cold-like illness but it can present with more severe and sometimes fatal manifestations. Immunocompromised patients such as those with common variable immunodeficiency (CVID) also are among the infected population. A limited number of reports have been published concerning CVID patients with COVID-19. The main reported symptoms were fever, cough, dyspnea and fatigue while the median duration of illness was 19 (interquartile range 14-26.5) days. Total recovery rate was 88.4%. It is still unknown whether primary immunodeficiency interacts as a predisposing or protective factor against the severe forms of COVID-19. Substitute immunoglobulin (IG) therapy is the only treatment option for CVID. Some reports suggest that early administration of intravenous IGs or convalescent plasma infusion may positively influence the outcome of COVID-19 in these patients.

PMID:36398083 | PMC:PMC9616023 | DOI:10.20471/acc.2022.61.01.13