Research

J Pediatr Gastroenterol Nutr. 2024 Feb 14. doi: 10.1002/jpn3.12147. Online ahead of print.

NO ABSTRACT

PMID:38356297 | DOI:10.1002/jpn3.12147

Front Pediatr. 2024 Jan 31;11:1258301. doi: 10.3389/fped.2023.1258301. eCollection 2023.

ABSTRACT

Systemic autoinflammatory diseases (SAIDs) are disorders of innate immunity, which are characterized by unprovoked recurrent flares of systemic inflammation often characterized by fever associated with clinical manifestations mainly involving the musculoskeletal, mucocutaneous, gastrointestinal, and nervous systems. Several conditions also present with varied, sometimes prominent, involvement of the vascular system, with features of vasculitis characterized by variable target vessel involvement and organ damage. Here, we report a systematic review of vasculitis and vasculopathy associated with inborn errors of immunity.

PMID:38357265 | PMC:PMC10866297 | DOI:10.3389/fped.2023.1258301

Pediatr Allergy Immunol. 2024 Feb;35(2):e14073. doi: 10.1111/pai.14073.

ABSTRACT

PURPOSE: We aimed to describe the clinical, immunological, and genetic features of patients with DOCK8 deficiency (DOCK8-Def) in a tertiary care center for children.

METHODS: Retrospective chart review of patients’ clinical, immunological, and genetic characteristics with DOCK8-Def. Genetic analysis was performed with targeted- or whole-exome sequencing; we also assessed DOCK8 protein expression and a lymphoproliferation assay and analyzed survival by the Kaplan-Meier method.

RESULTS: We described 11 patients from 8 unrelated kindreds. The median age at symptoms’ onset was 10 months (range 1-54 months). The median follow-up time was 53.4 months (4.8-118.8). All patients presented eczema and recurrent sinopulmonary and cutaneous infections. Besides those symptoms, the most frequent manifestations were bronchiectases (8/11), food allergies (6/11), and severe infections (6/11). Infrequent characteristics were detection of CMV in bronchial lavage, C. parvum-driven sclerosing cholangitis, Takayasu vasculitis, neurological syndromes, pulmonary tuberculosis, and lymphomatoid granulomatosis.

CONCLUSION: DOCK8-Def has a broad spectrum of manifestations, including allergy, autoimmunity, inflammation, infection, and cancer. The hallmark of this inborn error of immunity is IEI-associated eczema with eosinophilia and increased IgE. Here, we report six new mutations causing human DOCK8 deficiency and symptoms previously unrecognized to occur in DOCK8-Def. Therefore, an early diagnosis of DOCK8-Def is essential to facilitate an adequate treatment such as HSCT.

PMID:38351896 | DOI:10.1111/pai.14073

bioRxiv. 2024 Jan 29:2024.01.25.577009. doi: 10.1101/2024.01.25.577009. Preprint.

ABSTRACT

BACKGROUND: Primary immunodeficiencies are heritable defects in immune system function. Antibody deficiency is the most common form of primary immunodeficiency in humans, can be caused by abnormalities in both the development and activation of B cells, and may result from B-cell-intrinsic defects or defective responses by other cells relevant to humoral immunity. Inflammatory gastrointestinal complications are commonly observed in antibody-deficient patients, but the underlying immune mechanisms driving this are largely undefined.

METHODS: In this study, several mouse strains reflecting a spectrum of primary antibody deficiency (IgA ^-/- , Aicda ^-/- , CD19 ^-/- and J _H ^-/- ) were used to generate a functional small-bowel-specific cellular atlas using a novel high-parameter flow cytometry approach that allows for the enumeration of 59 unique cell subsets. Using this cellular atlas, we generated a direct and quantifiable estimate of immune dysregulation. This estimate was then used to identify specific immune factors most predictive of the severity of inflammatory disease of the small bowel (small bowel enteropathy).

RESULTS: Results from our experiments indicate that the severity of primary antibody deficiency positively correlates with the degree of immune dysregulation that can be expected to develop in an individual. In the SI of mice, immune dysregulation is primarily explained by defective homeostatic responses in T cell and invariant natural killer-like T (iNKT) cell subsets. These defects are strongly correlated with abnormalities in the balance between protein (MHCII-mediated) versus lipid (CD1d-mediated) antigen presentation by intestinal epithelial cells (IECs) and intestinal stem cells (ISCs), respectively.

CONCLUSIONS: Multivariate statistical approaches can be used to obtain quantifiable estimates of immune dysregulation based on high-parameter flow cytometry readouts of immune function. Using one such estimate, we reveal a previously unrecognized tradeoff between iNKT cell activation and type 1 immunity that underlies disease in the small bowel. The balance between protein/lipid antigen presentation by ISCs may play a crucial role in regulating this balance and thereby suppressing inflammatory disease in the small bowel.

PMID:38352330 | PMC:PMC10862736 | DOI:10.1101/2024.01.25.577009

Mol Biol Rep. 2024 Feb 14;51(1):302. doi: 10.1007/s11033-024-09222-0.

ABSTRACT

BACKGROUND: Severe Combined Immunodeficiency (SCID) is an autosomal recessive inborn error of immunity (IEI) characterized by recurrent chest and gastrointestinal (GI) infections and in some cases associated with life-threatening disorders.

METHODOLOGY AND RESULTS: This current study aims to unwind the molecular etiology of SCID and also extended the patients’ phenotype associated with identified particular variants. Herein, we present 06 disease-causing variants identified in 07 SCID-patients in three different SCID related genes. Whole Exome Sequencing (WES) followed by Sanger Sequencing was employed to explore genetic variations. The results included identification of two previously reported heterozygous variants in homozygous form for the first time in RAG1gene [(p.Arg410Gln);(p.Arg737His)], followed by a recurrent variant (p.Trp959*) in RAG1, a novel variant in IL2RG (p.Asp48Lfs*24), a recurrent variant in IL2RG (p.Gly271Glu) and a recurrent variant in DCLRE1C (p.Arg191*) gene.

CONCLUSION: To conclude, the immune-profiling and WES revealed two novel, two as homozygous state for the first time, and two recurrent disease causing variants contributing valuably to our existing knowledge of SCID.

PMID:38355773 | DOI:10.1007/s11033-024-09222-0

Drug Dev Res. 2024 Feb;85(1):e22151. doi: 10.1002/ddr.22151.

ABSTRACT

Drug repurposing is used to propose new therapeutic perspectives. Here, we introduce “Drug Upgrade”, that is, characterizing the mode of action of an old drug to generate new chemical entities and new therapeutics. We proposed a novel methodology covering target identification to pharmacology validation. As an old drug, we chose hydroxychloroquine (HCQ) for its well-documented clinical efficacy in lupus and its side effect, retinal toxicity. Using the Nematic Protein Organization Technique (NPOT®) followed by liquid chromatography-tandem mass spectrometry analyses, we identified myeloperoxidase (MPO) and alpha-crystallin β chain (CRYAB) as primary and secondary targets to HCQ from lupus patients’ peripheral blood mononuclear cells (PBMCs) and isolated human retinas. Surface plasmon resonance (SPR) and enzymatic assays confirmed the interaction of HCQ with MPO and CRYAB. We synthesized INS-072 a novel analog of HCQ that increased affinity for MPO and decreased binding to CRYAB compared to HCQ. INS-072 delayed cutaneous eruption significantly compared to HCQ in the murine MRL/lpr model of spontaneous lupus and prevents immune complex vasculitis in mice. In addition, long-term HCQ treatment caused retinal toxicity in mice, unlike INS-072. Our study illustrates a method of drug development, where new applications or improvements can be explored by fully characterizing the drug’s mode of action.

PMID:38349254 | DOI:10.1002/ddr.22151

BMC Pediatr. 2024 Feb 13;24(1):116. doi: 10.1186/s12887-024-04597-2.

ABSTRACT

BACKGROUND: Severe combined immunodeficiencies (SCIDs) are hereditary disorders characterized by impaired T and B cell function, resulting in significant immune system dysfunction. Recombination-activating gene (RAG) mutations account for a substantial proportion of SCID cases. Here, we present two sibling cases of SCID caused by a novel RAG2 gene mutation.

CASE PRESENTATION: The index case was an 8-year-old boy who had a history of recurring infections. After a comprehensive immunological workup, the initial diagnosis of agammaglobulinemia was revised to combined immunodeficiency (CID). The patient underwent hematopoietic stem cell transplantation (HSCT) but succumbed to cytomegalovirus (CMV) infection. His brother, a 4-month-old boy, presented with CMV chorioretinitis. Leaky SCID was diagnosed based on genetic tests and immunological findings. The patient received appropriate treatment and was considered for HSCT. Both siblings had a homozygous RAG2 gene variant, with the first case classified as a variant of uncertain significance (VUS). The presence of the same mutation in the second brother, and the clinical phenotype, supports considering the mutation as likely pathogenic.

CONCLUSIONS: This case report highlights a novel RAG2 gene mutation associated with CID. The classification of a VUS may evolve with accumulating evidence, and additional studies are warranted to establish its pathogenicity. Proper communication between genetic counselors and immunologists, accurate documentation of patient information, increased public awareness, and precise utilization of genetic techniques are essential for optimal patient management.

PMID:38350907 | DOI:10.1186/s12887-024-04597-2

J Allergy Clin Immunol. 2024 Feb 8:S0091-6749(24)00124-6. doi: 10.1016/j.jaci.2024.01.021. Online ahead of print.

ABSTRACT

BACKGROUND: Mendelian susceptibility to mycobacterial diseases (MSMD) is a rare clinical syndrome characterized by vulnerability to weakly virulent mycobacterial species, including Bacillus Calmette-Guérin (BCG) vaccines and environmental mycobacteria.

OBJECTIVE: We performed a systematic review of the genetic, immunological, and clinical findings for reported MSMD patients.

METHODS: We searched PubMed, Web of Science, and Scopus databases for publications in English relating to MSMD. All full texts were evaluated for eligibility for inclusion. Two reviewers independently selected the publications, with a third reviewer consulted in cases of disagreement.

RESULTS: A primary systematic search and searches of other resources identified 16,155 articles. In total, 158 articles from 63 countries were included in qualitative and quantitative analyses. In total, 830 patients – 436 males (52.5%), 369 females (44.5%), and 25 patients of unknown sex (3.0%) – from 581 families were evaluated. A positive family history was reported in 347 patients (45.5%). The patients had a mean age of 10.41 ± 0.42 (standard error of the mean) years. The frequency of MSMD was highest in Iran, Turkey, and Saudi Arabia. Lymphadenopathy was the most common clinical manifestation of MSMD, reported in 378 (45.5%) cases and multifocal in 35.1%. Fever, organomegaly, and sepsis were the next most frequent findings, reported in 251 (30.2%), 206 (24.8%), and 171 (20.8%) cases, respectively. In total, 299 unique mutations in 21 genes known to be involved in MSMD were reported: 100 missense (34%), 80 indel-frameshift (insertion or deletion, 27%), 53 nonsense (18%), 35 splice site (12%), 10 indel-in frame (2.7%), 6 indel (2%) and 15 large deletion/duplication mutations. Finally, 61% of the reported MSMD patients had mutations of IL12RB1 (41%) or IFNGR1 (20%). At the time of the report, 177 of the patients (21.3%) were dead, and 597 (71.9%) were still alive.

CONCLUSION: MSMD is associated with a high mortality rate, mostly due to impaired control of infection. Pre-exposure strategies, such as changes in vaccination policy in endemic areas, the establishment of a worldwide registry of MSMD patients, and precise follow-up over generations in affected families, appear to be vital, to decrease MSMD-related mortality.

PMID:38341181 | DOI:10.1016/j.jaci.2024.01.021

Acta Dermatovenerol Alp Pannonica Adriat. 2024 Feb 13;33(1):actaapa.2024.3.

ABSTRACT

INTRODUCTION: Hereditary angioedema (HAE) is a potentially life-threatening genetic disorder characterized by recurrent episodes of angioedema. From the onset of symptoms until diagnosis, patients often have several contacts with the healthcare system. It was hypothesized that a “digital fingerprint” of undiagnosed HAE patients could be identified in Danish registries.

METHODS: This study compared patients with a control group of patients with a diagnosis of Quincke’s edema (QE) or bee/wasp allergy because they could have phenotypic similarities.

RESULTS: QE was the most common diagnosis code in the hospital sector among HAE patients before a specific diagnosis of HAE was established. HAE patients had been seen at the hospital on average once every other year before the diagnosis was established, and on average once during the year before the diagnosis was established. Many patients contacted a practicing dermatologist during the year before the diagnosis was established.

CONCLUSIONS: HAE patients had several hospital contacts due to swelling attacks during the years before their diagnosis was established, and half of them consulted a dermatologist. It was not possible to identify a specific “digital fingerprint” in Danish registries regarding specific procedures or diagnoses distinguishing them from the control group. It is recommended that hospitalized patients with angioedema of unknown cause be screened for HAE.

PMID:38347716

Nutrients. 2024 Jan 26;16(3):373. doi: 10.3390/nu16030373.

ABSTRACT

Despite substantial heterogeneity of studies, there is evidence that antibiotics commonly used in primary care influence the composition of the gastrointestinal microbiota in terms of changing their composition and/or diversity. Benzyl isothiocyanate (BITC) from the food and medicinal plant nasturtium (Tropaeolum majus) is known for its antimicrobial activity and is used for the treatment of infections of the draining urinary tract and upper respiratory tract. Against this background, we raised the question of whether a 14 d nasturtium intervention (3 g daily, N = 30 healthy females) could also impact the normal gut microbiota composition. Spot urinary BITC excretion highly correlated with a weak but significant antibacterial effect against Escherichia coli. A significant increase in human beta defensin 1 as a parameter for host defense was seen in urine and exhaled breath condensate (EBC) upon verum intervention. Pre-to-post analysis revealed that mean gut microbiome composition did not significantly differ between groups, nor did the circulating serum metabolome. On an individual level, some large changes were observed between sampling points, however. Explorative Spearman rank correlation analysis in subgroups revealed associations between gut microbiota and the circulating metabolome, as well as between changes in blood markers and bacterial gut species.

PMID:38337658 | PMC:PMC10857499 | DOI:10.3390/nu16030373