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Front Immunol. 2024 Sep 27;15:1408985. doi: 10.3389/fimmu.2024.1408985. eCollection 2024.

ABSTRACT

INTRODUCTION: Inborn errors of immunity (IEI) are characterized by an inherited dysregulation or absence of immune system components that can manifest clinically in complications that predispose an individual to feeding difficulties or impaired swallowing, digestion, and absorption. Treatment side-effects or altered requirements may further impair nutritional status. While adequate nutrition is necessary for optimal growth and immune function, little is known about nutritional intakes in IEI, and best practice nutrition guidelines are limited. This review aimed to synthesize current evidence on the dietary intakes, anthropometry and nutritional biochemistry in individuals with an IEI.

METHODS: A systematic review of literature published from database inception to March 2023 was conducted in accordance with the PRISMA guidelines. Articles eligible for inclusion reported anthropometric, biochemical, or dietary intake-related measures in pediatric or adult patients with a diagnosed IEI. Identified articles were screened for eligibility; data was synthesized descriptively.

RESULTS: A total of 4488 studies were retrieved of which 34 were included. Across studies, 2894 IEI individuals were included (age range 4 weeks to 83y), predominantly focusing on ataxia telangiectasia (AT) and common variable immunodeficiency (CVID). A significant association between inadequate energy intakes and IEI was identified (n=6 studies); however, there was significant variability in adequacy of macro- and micronutrients across studies. Patients with IEI were at risk of malnutrition (range 30% to 70%); although anthropometric assessment measures were not consistent across studies. Biochemical assessments found patients were also at risk of micronutrient deficiencies including vitamin D.

DISCUSSION: This review identified few studies assessing dietary intakes, anthropometry and nutritional biochemistry in patients with IEI, with considerable heterogeneity across studies. Future longitudinal studies using consistent validated dietary assessment tools and anthropometric measures in diverse IEI patient populations are needed. This review reinforces the need for dietetic input in people with an IEI and the development evidence-based clinical practice guidelines for people with an IEI.

SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO, identifier CRD42023412365.

PMID:39399505 | PMC:PMC11466791 | DOI:10.3389/fimmu.2024.1408985

Front Immunol. 2024 Sep 27;15:1472390. doi: 10.3389/fimmu.2024.1472390. eCollection 2024.

ABSTRACT

INTRODUCTION: Cardiovascular pathologies represent the first cause of death in uremic patients and are among the leading causes of mortality in patients with hereditary angioedema due to C1-inhibitor deficiency (HAE-C1INH). Before 2020, the most common treatment for long-term prophylaxis in HAE-C1INH patients in Italy was attenuated androgen, which may increase cardiovascular risk by multiple mechanisms.

CASE DESCRIPTION: We present a case report of a 56-year-old patient with HAE-C1INH type I affected by IgA nephropathy with severe kidney impairment. The patient experienced a first kidney transplant and, after late rejection, underwent a second kidney transplant. Further comorbidities included obesity, hypertensive cardiomyopathy, HCV liver disease, and dyslipidemia. His prophylactic therapy to prevent angioedema attacks had consisted of attenuated androgens for about 40 years. Since 2020, new modern targeted therapy for LTP, particularly lanadelumab, has shown promising results. The majority of patients with attenuated androgens have been successfully switched to lanadelumab, including our patient. Since introducing lanadelumab (300 mg subcutaneously every two weeks; after a six-month attack-free period, the dosing interval of lanadelumab was extended to four weeks), the patient has not experienced any acute HAE attack and did not report any adverse events. Moreover, we observed decreased total cholesterol, C-LDL, and body mass index, reducing the Matsushita et al. score for ten years of cardiovascular risk from 13.2% to 9.3%.

CONCLUSION: lanadelumab is effective and safe in preventing hereditary angioedema attacks, as well as in reducing cardiovascular risk in an immunosuppressed patient with significant comorbidities. The successful outcomes of this case highlight the potential of lanadelumab as a promising prophylactic therapy.

PMID:39399485 | PMC:PMC11466776 | DOI:10.3389/fimmu.2024.1472390

Sci Rep. 2024 Oct 12;14(1):23899. doi: 10.1038/s41598-024-74728-3.

ABSTRACT

Common Variable Immunodeficiency (CVID) is a primary immunodeficiency characterized by reduced levels of specific immunoglobulins, resulting in frequent infections, autoimmune disorders, increased cancer risk, and diminished antibody production despite an adequate B cell count. With its clinical manifestations being highly variable, the classification of CVID, including the widely recognized Freiburg classification, is primarily based on clinical symptoms and genetic variations. Our study aims to refine the classification of CVID by analyzing transcriptomics data to identify distinct disease subtypes. We utilized the GSE51405 dataset, examining transcriptomic profiles from 30 CVID patients without complications. Employing a combination of clustering techniques-KMeans, hierarchical agglomerative clustering, spectral clustering, and Gaussian Mixture models-and differential gene expression analysis with R’s limma package, we integrated molecular findings with demographic data (age and gender) through correlation analysis and identified common genes among clusters. Three distinct clusters of CVID patients were identified using KMeans, Agglomerative Clustering, and Gaussian Mixture Models, highlighting the disease’s heterogeneity. Differential expression analysis unveiled 31 genes with variable expression levels across these clusters. Notably, nine genes (EIF5A, RPL21, ANP32A, DTX3L, NCF2, CDC42EP3, CHP1, FOLR3, and DEFA4) exhibited consistent differential expression across all clusters, independent of demographic factors. The study recommends categorizing patients based on the four genes, NCF2, CHP1, FOLR3, and DEFA4-as they may assist in prognostic prediction. Transcriptomic analysis of common variable immunodeficiency (CVID) patients identified three distinct clusters based on gene expression, independent of age and gender. Nine differentially expressed genes were identified across these clusters, suggesting potential biomarkers for CVID subtype classification. These findings highlight the genetic heterogeneity of CVID and provide novel insights into disease classification and potential personalized treatment approaches.

PMID:39396099 | PMC:PMC11470955 | DOI:10.1038/s41598-024-74728-3

Rev Med Interne. 2024 Oct 9:S0248-8663(24)00767-7. doi: 10.1016/j.revmed.2024.09.005. Online ahead of print.

ABSTRACT

INTRODUCTION: Aspergillosis is an opportunistic infection that can complicate any situation of immunosuppression. The primary manifestations are pulmonary, and more rarely, in cases of severe immunosuppression, the infection can become invasive with extra-pulmonary involvement.

OBSERVATION: We report the case of a 76-year-old female patient, experiencing a relapse of granulomatosis with polyangiitis treated with corticosteroids, rituximab and cyclophosphamide, who presented with diffuse erythematous nodular skin lesions. A biopsy with histological analysis confirmed a diagnosis of invasive cutaneous aspergillosis. Treatment with voriconazole led to a favorable outcome.

CONCLUSION: The appearance of skin lesions in an inflammatory context in a patient receiving immunosuppressive therapy should prompt a comprehensive microbiological assessment for opportunistic pathogens, as well as a skin biopsy to investigate for invasive cutaneous aspergillosis.

PMID:39389853 | DOI:10.1016/j.revmed.2024.09.005

Adv Rheumatol. 2024 Oct 9;64(1):79. doi: 10.1186/s42358-024-00421-8.

ABSTRACT

Systemic vasculitis is a group of rare diseases that share an essential characteristic: inflammation of blood vessel walls. This injury occurs during the disease course, but specific features vary for each entity. In this paper, we will address relevant aspects of the newest monogenic mutation vasculitis, such as deficiency of adenosine deaminase 2 (ADA2) and VEXAS syndrome (UBA1), and other relevant vasculitis, such as Cogan syndrome and Susac syndrome that may share some similarities with them.

PMID:39385260 | DOI:10.1186/s42358-024-00421-8

J Hazard Mater. 2024 Oct 8;480:136096. doi: 10.1016/j.jhazmat.2024.136096. Online ahead of print.

ABSTRACT

Triclocarban (TCC) is a widely applied environmental endocrine-disrupting chemical (EDC). Similar to most of EDCs, TCC potentially damages the immunity of various species. However, whether and how TCC impacts the adaptive immunity in mammals has yet to be determined. Herein, we discovered that TCC disrupts the activation and differentiation of CD8⁺ T cells in primary human peripheral blood samples, purified CD8⁺ T cells, and in mice in vivo. Mechanistically, TCC might block the activation of the vitamin D receptor (VDR) and reduce the synthesis of cholesterol, a precursor of vitamin D, resulting in inhibition of VDR signaling due to the suppression of both its ligand and the receptor itself by TCC. Our findings elucidate the hazard and potential mechanisms of TCC in mammalian adaptive immunity and highlighted VDR as a potential therapeutic target for the immunodeficiency caused by TCC.

PMID:39383692 | DOI:10.1016/j.jhazmat.2024.136096

J Exp Clin Cancer Res. 2024 Oct 9;43(1):280. doi: 10.1186/s13046-024-03203-8.

ABSTRACT

BACKGROUND: Lipid metabolism dysregulation is a key characteristic of hepatocellular carcinoma (HCC) onset and progression. Elevated expression of immunoglobulin (Ig), especially the Igκ free light chain with a unique Vκ4-1/Jκ3 rearrangement in cancer cells, is linked to increased malignancy and has been implicated in colon cancer tumorigenesis. However, the role of Igκ in HCC carcinogenesis remains unclear. The aim of this study was to elucidate the pivotal roles of hepatocyte-derived Igκ in HCC development.

METHODS: The rearrangement sequence and expression level of hepatocyte-derived Igκ in HCC cells were determined via RT-PCR, Sanger sequencing, immunohistochemistry, and western blot analysis. The function of Igκ in HCC tumorigenesis was assessed by silencing Igκ using siRNA or gRNA in various HCC cell lines. To assess the role of Igκ in HCC pathogenesis in vivo, a mouse model with hepatocyte-specific Igκ knockout and diethylnitrosamine (DEN) and carbon tetrachloride (CCL4)-induced HCC was utilized. The molecular mechanism by which Igκ affects HCC tumorigenesis was investigated through multiomics analyses, quantitative real-time PCR, immunoprecipitation, mass spectrometry, immunofluorescence, and metabolite detection.

RESULTS: We confirmed that Igκ, especially Vκ4-1/Jκ3-Igκ, is highly expressed in human HCC cells. Igκ depletion inhibited HCC cell proliferation and migration in vitro, and hepatocyte-specific Igκ deficiency ameliorated HCC progression in mice with DEN and CCL4-induced HCC in vivo. Mechanistically, Vκ4-1/Jκ3-Igκ interacts with electron transfer flavoprotein subunit α (ETFA), delaying its protein degradation. Loss of Igκ led to a decrease in the expression of mitochondrial respiratory chain complexes III and IV, resulting in aberrant fatty acid β-oxidation (FAO) and lipid accumulation, which in turn inhibited HCC cell proliferation and migration.

CONCLUSION: Our findings indicate that the Igκ/ETFA axis deregulates fatty acid β-oxidation, contributing to HCC progression, which suggests that targeting fatty acid metabolism may be an effective HCC treatment strategy. The results of this study suggest that hepatocyte-derived Vκ4-1/Jκ3-Igκ may serve as a promising therapeutic target for HCC.

PMID:39380077 | PMC:PMC11462706 | DOI:10.1186/s13046-024-03203-8

Blood. 2024 Oct 8:blood.2024024123. doi: 10.1182/blood.2024024123. Online ahead of print.

ABSTRACT

Cellular metabolism is highly dynamic during hematopoiesis, yet the regulatory networks that maintain metabolic homeostasis during differentiation are incompletely understood. Here, we have studied the grave immunodeficiency syndrome reticular dysgenesis caused by loss of mitochondrial adenylate kinase 2 (AK2) function. By coupling single-cell transcriptomics in reticular dysgenesis patient samples with a CRISPR model of this disorder in primary human hematopoietic stem cells, we found that the consequences of AK2 deficiency for the hematopoietic system are contingent on the effective engagement of metabolic checkpoints. In hematopoietic stem and progenitor cells, including early granulocyte precursors, AK2 deficiency reduced mechanistic target of rapamycin (mTOR) signaling and anabolic pathway activation. This conserved nutrient homeostasis and maintained cell survival and proliferation. In contrast, during late-stage granulopoiesis, metabolic checkpoints were ineffective, leading to a paradoxical upregulation of mTOR activity and energy-consuming anabolic pathways such as ribonucleoprotein synthesis in AK2-deficient cells. This caused nucleotide imbalance, including highly elevated AMP and IMP levels, the depletion of essential substrates such as NAD+ and aspartate, and ultimately resulted in proliferation arrest and demise of the granulocyte lineage. Our findings suggest that even severe metabolic defects can be tolerated with the help of metabolic checkpoints but that the failure of such checkpoints in differentiated cells results in a catastrophic loss of homeostasis.

PMID:39378586 | DOI:10.1182/blood.2024024123

J Mol Biol. 2024 Oct 5:168813. doi: 10.1016/j.jmb.2024.168813. Online ahead of print.

ABSTRACT

In mammalian cells, DNA ligase 1 (LIG1) functions as the primary DNA ligase in both genomic replication and single-strand break repair. Several reported mutations in human LIG1, including R305Q, R641L, and R771W, cause LIG1 syndrome, a primary immunodeficiency. While the R641L and R771W mutations, respectively located in the nucleotidyl transferase and oligonucleotide binding domains, have been biochemically characterized and shown to reduce catalytic efficiency, the recently reported R305Q mutation within the DNA binding domain (DBD) remains mechanistically unexplored. The R641L and R771W mutations are known to decrease the catalytic activity of LIG1 by affecting both interdomain interactions and DNA binding during catalysis, without significantly impacting overall DNA affinity. To elucidate the molecular basis of the LIG1 syndrome-causing R305Q mutation, we purified this single-residue mutant protein and investigated its secondary structure, protein stability, DNA binding affinity, and catalytic efficiency. Our findings reveal that the R305Q mutation significantly impairs the function of LIG1 by disrupting the DBD-DNA interactions, leading to a 7 to 21-fold lower DNA binding affinity and a 33 to 300-fold reduced catalytic efficiency of LIG1. Additionally, the R305Q mutation slightly decreases LIG1’s protein stability by 2 to 3.6 °C, on par with the effect observed previously with either the R641L or R771W mutant. Collectively, our results uncover a new mechanism whereby the R305Q mutation impairs LIG1-catalyzed nicked DNA ligation, resulting in LIG1 syndrome, and highlight the crucial roles of the DBD-DNA interactions in tight DNA binding and efficient LIG1 catalysis.

PMID:39374888 | DOI:10.1016/j.jmb.2024.168813

J Hosp Infect. 2024 Oct 4:S0195-6701(24)00324-4. doi: 10.1016/j.jhin.2024.09.016. Online ahead of print.

ABSTRACT

BACKGROUND: Previous studies on Clostridioides difficile infection (CDI) in proton pump inhibitor (PPIs) users generally enrolled a heterogeneous population and did not include a control group of histamine H2 receptor antagonists (H2RAs) users or adjust for confounding variables, such as previous antibiotics. It is uncertain whether hospitalized patients using PPIs for stress ulcer prophylaxis (SUP) are at a higher risk of CDI compared to those using H2RAs. This study aimed to compare the association between CDI and the usage of antisecretory drugs (ASDs): PPIs and H2RAs, for stress ulcer prophylaxis (SUP) among hospitalized patients, and the impact of the duration of their use on CDI.

METHODS: In this nationwide population-based cohort study using the Taiwan National Health Insurance Database, hospitalized patients using ASDs for SUP were identified between 2017-2018. A total of 63,266 and 69,269 individuals were included in the PPI and H2RA groups, respectively. The primary endpoint was a 90-day monitoring of CDI occurrence.

RESULTS: The incidences of CDI were 1·6/10,000 and 0·5/10,000 person-days in the PPIs and H2RAs groups, respectively. After adjusting for confounding factors, the risk of infection in the PPIs group remained significantly higher than in the H2RAs group (Hazard ratio [HR], 2·49; 95% Confidence Interval [CI], 1·63-3·81). In the subgroup analysis, during hospitalization, the risk of CDI for patients using high-risk antibiotics or admitted intensive care unit (ICU), as well as patients with immunodeficiency, using PPIs for SUP, was higher than using H2RAs. Furthermore, the risk of CDI was higher in patients using ASDs for durations > 14 days than in those using them for < 7 days (adjusted HR, 3·66; 95% CI, 2·34-5·75).

CONCLUSIONS: The risk of occurrence CDI for hospitalized patients using PPIs for SUP was higher than using H2RAs. It is recommended not to exceed 14 days of any gastric ASDs for SUP during hospitalization, especially for patients who have used high-risk antibiotics, been admitted to the ICU, or have immunodeficiency.

PMID:39369994 | DOI:10.1016/j.jhin.2024.09.016