Manish Butte

Front Genet. 2024 Jun 24;15:1413641. doi: 10.3389/fgene.2024.1413641. eCollection 2024.

ABSTRACT

BACKGROUND: Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is a rare autosomal dominant disorder with a low incidence in Asia. The most frequent clinical manifestations include fever, rash, myalgia, joint pain and abdominal pain. Misdiagnosis rates are high because of the clinical and genetic variability of the disease. The pathogenesis of TRAPS is complex and yet to be fully defined. Early genetic diagnosis is the key to precise treatment.

METHODS: In this study, a Chinese family with suspected TRAPS were analyzed by genome-wide SNP genotyping, linkage analysis and targeted sequencing for identification of mutations in causative genes. To study the pathogenicity of the identified gene mutation, we performed a conservation analysis of the mutation site and protein structure analysis. Flow cytometry was used to detect TNFRSF1A shedding and quantitative real-time PCR were used to assess the activation of unfolded protein response (UPR) in the mutation carriers and healthy individuals.

RESULTS: A typical TRAPS family history, with a pattern of autosomal dominant inheritance, led to the identification of a rare mutation in the TNFRSF1A gene (c.G374A [p.Cys125Tyr]) with unknown significance. The patient responded well to corticosteroids, and long-term therapy with colchicine effectively reduced the inflammatory attacks. No amyloid complications occurred during the 6-year follow-up. In silico protein analysis showed that the mutation site is highly conversed and the mutation prevents the formation of intrachain disulfide bonds in the protein. Despite a normal shedding of the TNFRSF1A protein from stimulated monocytes in the TRAPS patients with p.C125Y mutation, the expression of CHOP and the splicing of XBP1 was significantly higher than healthy controls, suggesting the presence of an activation UPR.

CONCLUSION: This is the first report of a Chinese family with the rare p.C125Y mutation in TNFRSF1A. The p.C125Y mutation does not result in aberrant receptor shedding, but instead is associated with an activated UPR in these TRAPS patients, which may provide new insights into the pathogenesis of this rare mutation in TRAPS.

PMID:38978873 | PMC:PMC11228257 | DOI:10.3389/fgene.2024.1413641

Pediatr Transplant. 2024 Aug;28(5):e14820. doi: 10.1111/petr.14820.

ABSTRACT

BACKGROUND: There is a lack of studies analyzing the association between oral mucositis (OM) and nutritional imbalance in children during hematopoietic stem cell transplantation (HSCT). The aim of this study was to compare the risk factors for OM and nutritional imbalance during HSCT in pediatric patients with nonmalignant diseases (NMD) and malignant diseases (MD).

METHODS: Data on age, sex, primary disease, transplantation type, conditioning regimen, GVHD prophylaxis, gastrointestinal toxicity, OM, percent body weight loss or gain, nutritional repositioning, and overall survival (OS) were retrospectively collected from the 132 medical records. The data were then compared between patients with NMD (n = 70) and MD (n = 62).

RESULTS: OM had a similar severity between the groups. The primary risk factor for OM in the NMD group was the conditioning regimen with busulfan, while in the MD group it was GVHD prophylaxis with cyclosporin and methotrexate. OM did not have an impact on body weight loss or gain in any of the groups. In the NMD, body weight gain due to fluid overload was more pronounced and associated with a lower age range. OS was similar between the groups and was not affected by OM.

CONCLUSIONS: OM pattern was similar in pediatric patients with or without MD, but the factors that determined these oral lesions were different. There were disparities in body weight changes between the two groups, and these changes were not associated to OM.

PMID:38977381 | DOI:10.1111/petr.14820

Scand J Immunol. 2024 Jul 7:e13396. doi: 10.1111/sji.13396. Online ahead of print.

ABSTRACT

While it is known that immunoglobulin replacement therapy (IgRT) used in the treatment of primary immunodeficiency disorders (PIDs) can lead to the passive transfer of autoantibodies, there is no data indicating that these antibodies can cause clinical symptoms in patients. This study aimed to investigate the presence of autoantibodies and their clinical correlation in patients diagnosed with PIDs receiving IgRT. Paediatric patients who were diagnosed with PIDs, and administered IgRT at our immunology clinic between 1 January 2012 and 31 December 2021, were included in the study. The medical records of these patients were retrospectively analysed, and autoantibodies were screened. Autoantibody screening was conducted at least once in 48 cases. Among these cases, 29 cases (60.4%) demonstrated positivity for at least one of the autoantibodies screened in the study. Among these cases, 23 tested positive for anti-TPO, 9 for anti-TG and 2 for both anti-TPO and anti-TG. Only two of these patients were confirmed to have Hashimoto’s thyroiditis. In 30 cases, autoantibodies related to Celiac disease (CD) were screened, with at least one being positive in five different cases; CD was not confirmed. The results of our study suggest that passive transfer of autoantibodies to patients with IgRT does not cause any significant clinical findings. In addition, in cases of PID, autoantibodies detected in the blood passed to patients with IgRT can lead to misdiagnosis. Screening for autoantibodies in patients with PID undergoing IgRT may not yield accurate results in terms of detecting autoimmune diseases.

PMID:38973103 | DOI:10.1111/sji.13396

J Pediatr. 2024 Jul 4:114180. doi: 10.1016/j.jpeds.2024.114180. Online ahead of print.

ABSTRACT

To evaluate a novel candidate disease gene, we engaged international collaborators and identified rare, biallelic, specifically homozygous, loss of function variants in SENP7 in four children from three unrelated families presenting with neurodevelopmental abnormalities, dysmorphism, and immunodeficiency. Their clinical presentations were characterized by hypogammaglobulinemia, intermittent neutropenia, and ultimately death in infancy for all four patients. SENP7 is a sentrin-specific protease involved in posttranslational modification of proteins essential for cell regulation, via a process referred to as deSUMOylation. We propose that deficiency of deSUMOylation may represent a novel mechanism of primary immunodeficiency.

PMID:38972567 | DOI:10.1016/j.jpeds.2024.114180

Reumatol Clin (Engl Ed). 2024 Jul 5:S2173-5743(24)00085-6. doi: 10.1016/j.reumae.2024.06.001. Online ahead of print.

ABSTRACT

OBJECTIVE: To assess the prevalence of systemic and organ-specific autoimmunity among individuals with human inborn errors of immunity (IEI).

METHODS: Retrospective study. We recorded demographic variables, type of immunodeficiency, and systemic and organ specific autoimmunity.

RESULTS: We included 48 patients (54.1% men) with mean age of 32.1 years. The most common IEIs included combined immunodeficiency with syndromic features (31.2%) and predominantly antibody deficiency (20.1%). We observed autoimmunity in 15 patients (31.2%): 12 organ-specific autoimmunity and 5 systemic autoimmunity, not mutually exclusive groups. Organ-specific autoimmunity preceded the onset of IEI in 5 patients, was concurrent in one patient, and developed after the diagnosis of IEI in 6 cases. From the systemic autoimmunity group, we observed polyarteritis nodosa (n = 2), antiphospholipid syndrome (APS) (n = 2), and overlap of limited systemic sclerosis/APS/Sjögren’s syndrome (n = 1), and in all cases, this occurred after the IEI diagnosis.

CONCLUSION: Our findings confirm the coexistence of autoimmunity and IEI. This overlap may be attributed to B and T cell disorders, as well as potential alterations in the microbiota in these patients.

PMID:38971706 | DOI:10.1016/j.reumae.2024.06.001

Nat Cell Biol. 2024 Jul 5. doi: 10.1038/s41556-024-01457-0. Online ahead of print.

ABSTRACT

Eukaryotic cells contain several membrane-separated organelles to compartmentalize distinct metabolic reactions. However, it has remained unclear how these organelle systems are coordinated when cells adapt metabolic pathways to support their development, survival or effector functions. Here we present OrgaPlexing, a multi-spectral organelle imaging approach for the comprehensive mapping of six key metabolic organelles and their interactions. We use this analysis on macrophages, immune cells that undergo rapid metabolic switches upon sensing bacterial and inflammatory stimuli. Our results identify lipid droplets (LDs) as primary inflammatory responder organelle, which forms three- and four-way interactions with other organelles. While clusters with endoplasmic reticulum (ER) and mitochondria (mitochondria-ER-LD unit) help supply fatty acids for LD growth, the additional recruitment of peroxisomes (mitochondria-ER-peroxisome-LD unit) supports fatty acid efflux from LDs. Interference with individual components of these units has direct functional consequences for inflammatory lipid mediator synthesis. Together, we show that macrophages form functional multi-organellar units to support metabolic adaptation and provide an experimental strategy to identify organelle-metabolic signalling hubs.

PMID:38969763 | DOI:10.1038/s41556-024-01457-0

Blood. 2024 Jul 4;144(1):1-2. doi: 10.1182/blood.2024024942.

NO ABSTRACT

PMID:38963672 | DOI:10.1182/blood.2024024942

Nat Immunol. 2024 Jul 3. doi: 10.1038/s41590-024-01890-1. Online ahead of print.

ABSTRACT

The differentiation of naive and memory B cells into antibody-secreting cells (ASCs) is a key feature of adaptive immunity. The requirement for phosphoinositide 3-kinase-delta (PI3Kδ) to support B cell biology has been investigated intensively; however, specific functions of the related phosphoinositide 3-kinase-gamma (PI3Kγ) complex in B lineage cells have not. In the present study, we report that PI3Kγ promotes robust antibody responses induced by T cell-dependent antigens. The inborn error of immunity caused by human deficiency in PI3Kγ results in broad humoral defects, prompting our investigation of roles for this kinase in antibody responses. Using mouse immunization models, we found that PI3Kγ functions cell intrinsically within activated B cells in a kinase activity-dependent manner to transduce signals required for the transcriptional program supporting differentiation of ASCs. Furthermore, ASC fate choice coincides with upregulation of PIK3CG expression and is impaired in the context of PI3Kγ disruption in naive B cells on in vitro CD40-/cytokine-driven activation, in memory B cells on toll-like receptor activation, or in human tonsillar organoids. Taken together, our study uncovers a fundamental role for PI3Kγ in supporting humoral immunity by integrating signals instructing commitment to the ASC fate.

PMID:38961274 | DOI:10.1038/s41590-024-01890-1

N Engl J Med. 2024 Jul 4;391(1):56-59. doi: 10.1056/NEJMoa2400403.

ABSTRACT

Hereditary angioedema is a potentially life-threatening autosomal dominant condition, causing attacks of angioedema due to failure to regulate bradykinin. Nearly all cases of hereditary angioedema are caused by mutations in the gene encoding C1 inhibitor, SERPING1. C1 inhibitor is a multifunctional protein produced in the liver that regulates the kallikrein-kinin system at multiple points. An infant with genetically confirmed hereditary angioedema and low C1 inhibitor levels (but without previous episodes of angioedema) underwent liver transplantation for biliary atresia, an unrelated condition. Liver transplantation led to normalization of the C1 inhibitor level and function. To our knowledge, this represents the first patient to be potentially cured of hereditary angioedema.

PMID:38959481 | DOI:10.1056/NEJMoa2400403

Cureus. 2024 Jun 2;16(6):e61531. doi: 10.7759/cureus.61531. eCollection 2024 Jun.

ABSTRACT

Acute mesenteric ischemia is a critical condition marked by a sudden loss of blood supply to the intestines, often leading to rapid tissue necrosis and severe clinical outcomes if untreated. In the context of hypogammaglobulinemia, an immunodeficiency characterized by decreased levels of immunoglobulins, this vascular emergency becomes even more daunting. Hypogammaglobulinemia can impair the immune system’s response to both infection and ischemic injury, intensifying the severity of intestinal damage. This report describes the case of a 52-year-old female with hypogammaglobulinemia who presented with severe abdominal pain. Surgical exploration revealed 100 cm of necrotic small bowel extending from 150 cm distal to the ligament of Treitz to within 10 cm of the ileocecal valve. The necrotic section was surgically removed, and primary anastomosis was performed. This instance highlights the significant impact of immunodeficiency on the progression and management of acute mesenteric ischemia, demonstrating the critical need for early intervention and tailored management strategies, especially in immunocompromised patients, to prevent severe outcomes. The case illuminates the importance of recognizing immunodeficiency as a complicating factor in acute gastrointestinal emergencies, stressing the necessity for prompt and effective medical and surgical interventions to improve prognosis and patient outcomes in complex clinical scenarios.

PMID:38957256 | PMC:PMC11218428 | DOI:10.7759/cureus.61531