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J Clin Immunol. 2024 Nov 28;45(1):50. doi: 10.1007/s10875-024-01842-2.

ABSTRACT

Griscelli syndrome type 2 (GS2) is a rare, life-threatening immunodysregulatory disorder characterised by impaired cytotoxic activity leading to susceptibility to haemophagocytic lymphohistiocytosis (HLH) and hypopigmentation. We completed a literature review and analysis of clinical data of 149 patients with GS2 including 8 new patients.We identified three founder mutations which show diverse phenotypic profiles (RAB27A c.244 C > T, p.R82C, c.514_518delCAAGC, p.Q172NfsX2, c.550 C > T, p.R184X). The most common presentation was HLH (119/149, 80%), with high proportion of central nervous system involvement (68/149, 46%). Features of partial albinism were present in 105 of 149 cases (70%). Hypopigmentation can be absent in GS2 and should not exclude the diagnosis. Patients with biallelic protein truncating variants (PTV) were more likely to have systemic HLH (44/56, 79%) and partial albinism (45/56, 80%), in comparison to hypomorphic variants (9/41, 22%; 20/41, 49%). Patients with hypomorphic variants presented later (5.4 years cf. 0.4 years, p = < 0.0001) and were more likely to have isolated CNS HLH (2% cf. 42%, p = 0.001).Mortality was high in the cohort (50/149, 34%). Survival of cases post-HLH who underwent transplantation is superior to un-transplanted patients, suggesting adequate HLH control followed by early HSCT is highly beneficial. Mortality was reduced in HSCT recipients versus the un-transplanted group where follow-up data was available (14% compared to 58%).Asymptomatic cases identified through family history/genetic screening may benefit from pre-emptive HSCT, but access and development of robust functional testing are required. High mortality related to HLH remains concerning and emphasises the need for improved molecular characterisation and clinical prognostic factors to guide management decisions.

PMID:39607447 | DOI:10.1007/s10875-024-01842-2

Elife. 2024 Nov 28;12:RP90875. doi: 10.7554/eLife.90875.

ABSTRACT

Deficient Anterior pituitary with common Variable Immune Deficiency (DAVID) syndrome results from NFKB2 heterozygous mutations, causing adrenocorticotropic hormone deficiency (ACTHD) and primary hypogammaglobulinemia. While NFKB signaling plays a crucial role in the immune system, its connection to endocrine symptoms is unclear. We established a human disease model to investigate the role of NFKB2 in pituitary development by creating pituitary organoids from CRISPR/Cas9-edited human induced pluripotent stem cells (hiPSCs). Introducing homozygous TBX19^K146R/K146R missense pathogenic variant in hiPSC, an allele found in congenital isolated ACTHD, led to a strong reduction of corticotrophs number in pituitary organoids. Then, we characterized the development of organoids harboring NFKB2^D865G/D865G mutations found in DAVID patients. NFKB2^D865G/D865G mutation acted at different levels of development with mutant organoids displaying changes in the expression of genes involved on pituitary progenitor generation (HESX1, PITX1, LHX3), hypothalamic secreted factors (BMP4, FGF8, FGF10), epithelial-to-mesenchymal transition, lineage precursors development (TBX19, POU1F1) and corticotrophs terminal differentiation (PCSK1, POMC), and showed drastic reduction in the number of corticotrophs. Our results provide strong evidence for the direct role of NFKB2 mutations in the endocrine phenotype observed in patients leading to a new classification of a NFKB2 variant of previously unknown clinical significance as pathogenic in pituitary development.

PMID:39607428 | DOI:10.7554/eLife.90875

Pathogens. 2024 Nov 6;13(11):969. doi: 10.3390/pathogens13110969.

ABSTRACT

As the world is approaching the eradication of wild poliovirus serotype 1, the last of the three wild types, the question of how to maintain a polio-free world becomes imminent. To mitigate the risk of sporadic vaccine-associated paralytic polio (VAPP) caused by oral polio vaccines (OPVs) that are routinely used in global immunization programs, the Polio Antivirals Initiative (PAI) was established in 2006. The primary goal of the PAI is to facilitate the discovery and development of antiviral drugs to stop the excretion of immunodeficiency-associated vaccine-derived poliovirus (iVDPV) in B cell-deficient individuals. This review summarizes the major progress that has been made in the development of safe and effective poliovirus antivirals and highlights the candidates that have shown promising results in vitro, in vivo, and in clinical trials.

PMID:39599522 | DOI:10.3390/pathogens13110969

Genes (Basel). 2024 Nov 13;15(11):1467. doi: 10.3390/genes15111467.

ABSTRACT

BACKGROUND/OBJECTIVES: Genetic newborn screening (NBS) has already entered the phase of common practice in many countries. In Germany, spinal muscular atrophy (SMA), severe combined immunodeficiency (SCID) and sickle cell disease (SCD) are currently a mandatory part of NBS. Here, we describe the experience of six years of genetic NBS including the prevalence of those three diseases in Germany.

METHODS: Samples and nucleic acids were extracted from dried blood spot cards, commonly used for NBS. A qPCR assay was used to detect disease-causing variants for SMA and SCD, and the detection of T-cell receptor excision circles (TRECs) was performed for SCID screening.

RESULTS: The results of the NBS of over 1 million newborns for SMA, approximately 770,000 for SCID and over 410,000 for SCD are discussed in detail. In these newborns, we have identified 121 cases of SMA, 15 cases of SCID and syndrome-based immunodeficiencies and 77 cases of SCD or β-thalassemia.

CONCLUSIONS: The flexibility of multiplex qPCR is assessed as an effective tool for incorporating different molecular genetic markers for screening. The processing of dried blood spot (DBS) filter cards for molecular genetic assays and the assays are described in detail; turn-around times and cost estimations are included to give an insight into the processes and discuss further options for optimization. The identified cases are in the range expected for the total number of screened newborns, but present a more exact view on the actual prevalences for Germany.

PMID:39596667 | DOI:10.3390/genes15111467

Otolaryngol Head Neck Surg. 2024 Nov 26. doi: 10.1002/ohn.1068. Online ahead of print.

ABSTRACT

OBJECTIVE: The objective of this study was to evaluate the role of diet quality in children with tympanostomy tube placement (TTP) complicated by tympanostomy tube otorrhea (TTO).

STUDY DESIGN: Three-day 24-hour diet recall.

SETTING: Tertiary care medical center.

METHODS: Children between the ages of 2 to 6 years old with TTP performed 6 months to 2 years prior to enrollment were included. Children with a history of Down syndrome, cleft palate, craniofacial syndromes, known immunodeficiency, g-tube dependent, or a non-English speaking family were excluded. The primary outcome variable was TTO. The primary predictor was total caloric intake measured by percent estimated energy rate (%EER).

RESULTS: A total of 120 families completed the 3-day diet recall. The median age was 27 months (interquartile range: 7.9-68.5), with 57% male sex. Most children reported dietary intake within the recommended range percent intake for carbohydrates and fat and less than recommended range for percent vitamin D. Within this cohort 63 (52.5%) participants had >1 TTO episode and 57 (47.5%) $\le$ 1 TTO episode. Children with an EER% that was average or high were at higher odds of >1 TTO episodes compared to participants with a low EER% with ORs of 4.6 (95% confidence interval [CI]: 1.4, 15.6) and 5.7 (95% CI: 1.5, 22.1) respectively.

CONCLUSION: Children with a typical or high total daily caloric intake are approximately 5 to 6 times more likely to have multiple TTO episodes compared to those with low intake.

PMID:39588668 | DOI:10.1002/ohn.1068

Front Immunol. 2024 Nov 11;15:1468823. doi: 10.3389/fimmu.2024.1468823. eCollection 2024.

ABSTRACT

BACKGROUND: WHIM (Warts, Hypogammaglobulinemia, Infections, and Myelokathexis) syndrome is an ultra-rare, combined primary immunodeficiency and chronic neutropenic disorder characterized by a range of clinical presentations, including peripheral neutropenia, lymphopenia, and recurrent infections. WHIM syndrome is most often caused by gain-of-function mutations in the gene encoding C-X-C chemokine receptor 4 (CXCR4). As such, inhibition of CXCR4 with XOLREMDI^® (mavorixafor), an orally bioavailable CXCR4 antagonist, demonstrated clinically meaningful increases in absolute neutrophil and lymphocyte counts and concomitant reduction in infections in patients with WHIM syndrome, resulting in its recent U.S. Food and Drug Administration approval. The impact of CXCR4 antagonism on other aspects of the pathobiology in WHIM syndrome, such as lymphopoiesis and leukocyte trafficking between primary and secondary lymphoid organs, is less understood.

METHODS: In the current study, the effects of CXCR4 antagonism on leukocyte trafficking and distribution in primary and secondary lymphoid organs were investigated in a mouse model of WHIM syndrome carrying the heterozygous Cxcr4¹⁰¹³ mutation. Cxcr4^+/1013 and Cxcr4 wild-type mice received the orally bioavailable CXCR4 antagonist X4-185. Blood, spleen and bone marrow samples were collected for numeration, flow cytometry, and functional studies.

RESULTS: Cxcr4^+/1013 mice exhibited profound peripheral blood leukopenia as seen in patients with WHIM syndrome. CXCR4 antagonism corrected circulating leukopenia and mobilized functional neutrophils without disrupting granulopoiesis in the bone marrow of Cxcr4^+/1013 mice. Furthermore, Cxcr4^+/1013 displayed aberrant splenic T and B-cell counts and frequency. Treatment with X4-185 normalized splenic T-cell abnormalities, correcting the reduced CD8⁺ T-cell numbers, restoring the CD4/CD8 T-cell ratio, and ameliorating peripheral blood T-cell lymphopenia. In addition, CXCR4 antagonism was able to correct the abnormal frequencies and numbers of splenic marginal zone and follicular B cells in Cxcr4^+/1013 mice, and ultimately normalize B-cell lymphopenia in the peripheral circulation.

CONCLUSIONS: Our study provides comprehensive evidence that oral dosing with a CXCR4 antagonist can effectively correct WHIM-associated neutrophil and lymphocyte abnormalities in a mouse model of WHIM syndrome. These findings extend our understanding of how targeting the dysregulated CXCR4 signaling pathway can ameliorate the pathogenesis of WHIM syndrome.

PMID:39588369 | PMC:PMC11586337 | DOI:10.3389/fimmu.2024.1468823

Iran J Allergy Asthma Immunol. 2024 Oct 6;23(5):594-599. doi: 10.18502/ijaai.v23i5.16754.

ABSTRACT

Nephrotic syndrome is characterized by the leakage of protein from the blood into the urine along with the triad of proteinuria, albuminuria, and peripheral edema. Loss of protein leads to the loss of immunoglobulin and complements. X-linked agammaglobulinemia (XLA), or Bruton disease, is a primary immunodeficiency disease caused by a defect in the development of B cells in the bone marrow and a low serum level of immunoglobulins. The present case involves a 12-year-old boy with nephrotic syndrome, osteomyelitis, and recurrent infections. We discovered that he had XLA. This report underscores the importance of considering inborn errors of immunity in cases of protein loss, such as nephrotic syndrome.

PMID:39586752 | DOI:10.18502/ijaai.v23i5.16754

Nurs Rep. 2024 Nov 1;14(4):3280-3290. doi: 10.3390/nursrep14040238.

ABSTRACT

BACKGROUND/OBJECTIVES: Inborn errors of immunity (IEI) encompass various congenital disorders, resulting in immunity defects and recurrent infections. Home-based subcutaneous immunoglobulin replacement therapy (scIgRT) is the best treatment option for those with primary antibody deficiency (PAD). However, the lack of standardized procedures in patient training remains a challenge. Our study investigates nurses’ practice and perspectives, aiming to identify areas for improvement in at-home scIgRT practice.

METHODS: We prepared a structured survey regarding scIgRT, including needle choice experience and perception of adverse events, and distributed it among qualified nurses involved in patient training and scIgRT supervising.

RESULTS: We included 56 nurses with a median age of 50 years. Among them, 67.9% represented adult care providers, while 32.1% supervised IgRT in children. Most respondents (83.9%) used the classic or assisted with hyaluronidase scIgRT preparations. Single-channel needles were administered most commonly (85.7%). The needle length was mostly chosen solely by a nurse (57.1%) or in cooperation with the patient (23.2%). Next, 9 mm and 12 mm needles were used most often (92.9% and 78.6%, respectively). As expected, the 6 mm needle was more frequently applied for children compared to adults (n = 16, 88.9% vs. n = 11, 28.9%, p < 0.001), while 12 mm was primarily used in adults (n = 35, 92.1% vs. n = 9, 50.0%, p < 0.001). Visual skin fold assessment was the basis for the needle selection (58.9%), followed by the injection site rule (26.8%) or a choice between two available needle types for thinner or thicker patients (25.0%). Results of this survey indicate that, according to nurses’ opinions presented in this survey, the needle length could be associated with local scIgRT adverse events, such as side needle leakage or local burning. Yet, it was likely unrelated to general adverse signs, such as headaches or dizziness. Most respondents (66.1%) indicated that, even if local adverse events occur, patients are reluctant to change scIgRT preparation or needle length. Most participants (69.6%) reported that the optimal administration technique needs to be discussed with the patient before and during scIgRT.

CONCLUSIONS: This study sheds light on scIgRT practice in Poland, emphasizing deficiency in needle selection technique. Future research should focus on standardized training and advanced needle selection procedures on patient outcomes, investigating the correlation between needle strategies and adverse events, as well as the effectiveness of scIgRT.

PMID:39585129 | DOI:10.3390/nursrep14040238

J Clin Immunol. 2024 Nov 25;45(1):49. doi: 10.1007/s10875-024-01840-4.

ABSTRACT

Multisystem inflammatory syndrome in children (MIS-C) has been reported in patients with inborn errors of immunity (IEI), providing insights into disease pathogenesis. Here, we present the first case of MIS-C in a child affected by Wiskott-Aldrich syndrome (WAS) gene mutation, elucidating underlying predisposing factors and the involved inflammatory pathways. Genetic analysis revealed a frameshift truncating variant in the WAS gene, resulting in WAS protein expression between mild and severe forms, despite a clinical phenotype resembling X-linked thrombocytopenia (XLT). IL-1β secretion by LPS-stimulated peripheral blood mononuclear cells from patient during MIS-C was lower compared to healthy subjects but increased during follow-up. Conversely, the percentage of ASC (apoptosis-associated speck-like protein containing a CARD) specks in the patient’s circulating monocytes during the acute phase was higher than in healthy subjects. The type I interferon (IFN) signature during MIS-C was normal, in contrast to the raised IFN signature measured far from the acute event. This case supports the association of IEI with MIS-C, potentially linked to delayed immune responses to SARS-CoV-2. The XLT phenotype underlies a subclinical immunodysregulation involving the NLRP3 inflammasome and the type-I IFN response.

PMID:39581942 | DOI:10.1007/s10875-024-01840-4

Clin Immunol. 2024 Nov 22:110403. doi: 10.1016/j.clim.2024.110403. Online ahead of print.

ABSTRACT

Low immunoglobulin E (IgE) levels are defined as values below 2.5 IU/mL. Selective IgE deficiency (sIgED) refers to reduced serum IgE levels in patients with normal IgA/G/M levels. We evaluated 677 patients with low IgE levels. Recurrent infections (78.8 %), a history of allergy (27.3 %), and autoimmune/inflammatory diseases (18.3 %) are common. The primary immunodeficiency disease (PID) (n = 483, 71.3 %) diagnoses include 313 (46.2 %) patients with antibody deficiency and 119 (17.6 %) with combined immunodeficiency. Genetic pathogenic variants were present in 154 out of 207 PID patients. Within sIgED group, 23 (19.8 %) had primary immunodeficiencies. We observed a high prevalence of autoimmune/inflammatory diseases, allergies, malignancies, and PID among patients with low IgE levels. Therefore, clinicians should be vigilant when evaluating patients with low IgE levels, as this finding may indicate an underlying systemic disease or PID.

PMID:39581560 | DOI:10.1016/j.clim.2024.110403