Manish Butte

Clin Exp Immunol. 2025 May 28:uxaf036. doi: 10.1093/cei/uxaf036. Online ahead of print.

ABSTRACT

Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome characterized by an aberrant immune response against host tissues. It can arise from diverse triggers like infection, inflammation, malignancy, genetic defects, or therapy-related factors. Cytokine storm, capillary leak syndrome, cytokine release syndrome, and macrophage activation syndrome are the different faces of this chimera, and each of them displays significant clinical variability associated with high mortality. The pathogenesis of both primary and secondary HLH generally follows a similar pattern, involving excessive activation of macrophages and uncontrolled destruction of reticuloendothelial tissues. Environmental triggers cause exaggerated activation of innate immune cells in genetically predisposed individuals. This process is further driven by the release of multiple cytokines and soluble mediators that sustain ongoing inflammation and cause subsequent target organ damage. Biomarkers, including cytokines and inflammatory mediators, are crucial for early detection and monitoring treatment response. Persistent immune activation and inadequate resolution mechanisms result in a destructive inflammatory cascade or “immunological massacre”. Animal models of HLH and MAS elucidate the roles of impaired cytotoxicity, IFN-γ, TLR signaling, and inflammatory cytokines in disease pathogenesis. Trigger-specific differences highlight the involvement of CD8+ T cells, NK cells, macrophages, and cytokines. Therapeutic strategies include cytokine neutralization, adoptive T-cell transfer, and mTOR inhibition. Timely diagnosis and prompt initiation of therapy are essential to mitigate the serious consequences of HLH and improve long-term outcomes.

PMID:40435290 | DOI:10.1093/cei/uxaf036

BMC Med Genomics. 2025 May 27;18(1):95. doi: 10.1186/s12920-025-02145-0.

ABSTRACT

BACKGROUND: Chediak-Higashi Syndrome (CHS) is a rare autosomal recessive disorder characterized by oculocutaneous albinism, recurrent infections, bleeding tendencies, and progressive neurological impairment. The syndrome is caused by mutations in the LYST gene, which plays a crucial role in lysosomal trafficking.

OBJECTIVE: This study aims to characterize the molecular basis of CHS in a Tunisian patient by identifying mutations in the LYST gene and analyzing their impact on the protein function, correlating these findings with the patient’s clinical presentation.

METHODS: A comprehensive clinical assessment was conducted on the patient, followed by biochemical, hematological, and microbiological analyses. Additionally, LYST protein levels were quantified in the patient and their parents using an ELISA assay. Genomic DNA was extracted from the patient’s blood, and Whole Exome Sequencing (WES) was performed to identify mutations in the LYST gene. The findings were confirmed through Sanger sequencing, and bioinformatic tools were employed to predict the functional consequences of the detected mutations.

RESULTS: The patient presented with classical symptoms of CHS, including silver hair, hypopigmented skin, recurrent infections, and neurological decline, with an unusually late onset at 18 years. ELISA results demonstrated significantly reduced LYST levels in the patient (1.8 ng/ml) compared to heterozygous parents (7.8 ng/ml and 8.1 ng/ml) and controls (9.2 ng/ml). Genetic analysis revealed a novel homozygous deletion, c.10269_10275del (p.Gly3424SerfsTer15), in the LYST gene, leading to a frameshift mutation and premature termination of the protein. Bioinformatic analysis demonstrated that this mutation leads to the deletion of five out of sven WD40 repeats in the protein’s C-terminal region, which are critical for protein-protein interactions and lysosomal trafficking.

CONCLUSION: The study identifies a novel LYST mutation in a Tunisian patient with CHS, expanding the spectrum of known genetic variants associated with the disease. The findings highlight the importance of genetic screening in populations with high consanguinity and underscore the need for targeted therapies to address the molecular defects in CHS.

PMID:40426172 | DOI:10.1186/s12920-025-02145-0

J Res Pharm Pract. 2025 Apr 24;13(4):111-118. doi: 10.4103/jrpp.jrpp_2_25. eCollection 2024 Oct-Dec.

ABSTRACT

OBJECTIVE: In severe cases, COVID-19 can lead to a hyperinflammatory state, resulting in devastating outcomes. Immune modulation using steroids or other immune modulators can regulate the intensity of the inflammatory response; however, this theory has not been adequately assessed in practice. The current study aims to investigate the use of corticosteroids alone or in combination with tocilizumab to treat patients with severe COVID-19.

METHODS: This cross-sectional study was conducted on 166 Iranian patients with severe COVID-19 infection at Al-Zahra Hospital, who were treated with the standard treatment for severe COVID-19 infection, as per the 11^th version of the Iranian guideline for COVID-19 treatment. Patients were categorized into three treatment groups based on the dose of corticosteroid treatment and tocilizumab therapy: (a) high-dose methylprednisolone (>1 mg/kg) alone, (b) low-dose methylprednisolone (<1 mg/kg) followed by one dose of tocilizumab (8 mg/kg); and (c) high-dose methylprednisolone (>1 mg/kg) followed by one dose of tocilizumab (8 mg/kg). Mortality of patients as our primary outcome, laboratory parameters, length of hospitalization, intensive care unit (ICU) admission requirement, and drug-related adverse events were compared between groups.

FINDINGS: The second group showed significantly better outcomes, including shorter ICU stays, lower C-reactive protein and lactate dehydrogenase levels, and higher oxygen saturation and platelet counts than the other groups. Logistic regression revealed increased risks of mortality, nosocomial infection, and adverse effects, including hepatic and renal dysfunction and gastrointestinal bleeding, in Groups B and C compared with Group A.

CONCLUSION: In all evaluated parameters, a low-dose steroid followed by tocilizumab was superior to a high-dose steroid alone or combined with tocilizumab. Although this combination treatment has been assessed worldwide, few studies have focused on its application in Iranian patients with severe COVID-19.

PMID:40432839 | PMC:PMC12105767 | DOI:10.4103/jrpp.jrpp_2_25

Orphanet J Rare Dis. 2025 May 26;20(1):251. doi: 10.1186/s13023-025-03776-3.

ABSTRACT

BACKGROUND: Hereditary angioedema (HAE) is a rare inherited disease characterized by recurrent, potentially life-threatening angioedema. The vascular endothelium dysfunction is reported to play a role in angioedema episodes. Here, we conducted a case-control study to explore the correlation between vascular endothelium growth factor (VEGF), a representative indicator for endothelium dysfunction, and HAE as well as its attack frequency, disease control and disease severity.

METHODS: Patients with HAE and non-hereditary angioedema in their attack-free period were prospectively recruited. Demographic and disease information were collected through questionnaires. Disease control of HAE was assessed with the angioedema control test (AECT) with a recall period of three months. The current severity of HAE was comprehensively assessed through frequency of angioedema episodes, occurrence of life-threatening angioedema, necessity for hospitalization or emergency department visits. The plasma VEGF level was measured by chemiluminescence microparticle immunoassay. We compared clinical characteristics between HAE and non-hereditary angioedema patients, as well as among HAE patients with different attack frequency, disease control and disease severity. We further performed several generalized linear models (GLMs) to examine the correlation between VEGF levels and the attack frequency, disease control and disease severity of HAE.

RESULTS: We enrolled 74 patients with HAE and 55 patients with non-hereditary angioedema. HAE patients exhibited higher VEGF levels in remission than controls (112 vs. 60 ng/ml, P < 0.001). VEGF levels further increased in HAE patients with more frequent angioedema attacks, poorer disease control and greater disease severity. Results of GLMs confirmed significant correlations between plasma VEGF concentrations and the attack frequency of angioedema, disease control status and disease severity of HAE.

CONCLUSION: Circulating VEGF level elevated in patients with HAE during attack-free periods, particularly among those with greater disease burden, suggesting the involvement of vascular endothelial dysfunction in the pathogenesis of HAE. VEGF may serve as a predictive biomarker for risk stratification and disease monitoring in HAE.

PMID:40420190 | DOI:10.1186/s13023-025-03776-3

Immunology. 2025 May 27. doi: 10.1111/imm.13950. Online ahead of print.

ABSTRACT

Non-catalytic region of tyrosine kinase 1 (Nck1) is an adaptor protein found in many cell types and plays several functions. In T cells, Nck1 is functionally associated with a T cell receptor (TCR)-mediated actin rearrangement, insulin signalling, PI3K/Akt/mTOR pathway, and lipid production. However, the role of Nck1 in regulating glucose metabolism in T cells is still largely unknown. In the present study, the role of Nck1 in glucose metabolism in primary human T cells was investigated. Plasmid encoding Nck1-specific short hairpin RNA (shRNA) was delivered to primary T cells to mediate Nck1 silencing. Plasmids encoding Nck1-specific short hairpin RNA (shRNA) were delivered to primary human T cells to mediate Nck1 silencing. Nck1-knockdown (N1KD) cells were analysed for processes related to glucose metabolism and function. Despite an increased expression of glucose transporter 1 (GLUT1) in N1KD cells, these cells exhibited impaired glucose uptake and ATP production, indicating dysfunction of GLUT1 or altered intracellular glucose metabolism. Nck1 depletion disrupted metabolic signalling characterised by reduced TXNIP and phosphoribosomal protein S6 (pS6) levels, along with an increased phosphorylation of Akt and AMPK. The reduced extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) found in N1KD cells indicated impaired glycolysis and oxidative phosphorylation. Functionally, these metabolic alterations were associated with impaired T cell activation, reduced proliferation, and increased apoptosis. Collectively, Nck1 critically regulated glucose metabolism in T cells, linking metabolic reprogramming to immune function and cell survival.

PMID:40421785 | DOI:10.1111/imm.13950

Nat Chem Biol. 2025 May 26. doi: 10.1038/s41589-025-01919-y. Online ahead of print.

ABSTRACT

Toll-like receptor 9 (TLR9) agonists cause activation of nucleotide-binding domain, leucine-rich repeat protein 3 (NLRP3) inflammasomes but the mechanism is not clear. We found that there is a second signal downstream of TLR9 that induces NLRP3 inflammasome activation. Through screening, adenylate cyclase 7 (ADCY7) was found to be an essential regulator of this process. In cells with Adcy7 deficiency, TLR9 agonists were no longer able to activate the NLRP3 inflammasome. ADCY7 not only catalyzes the generation of cyclic adenosine monophosphate (cAMP) but also catalyzes the synthesis of its dimeric form (c-di-AMP). Moreover, c-di-AMP promotes assembly and maturation of the inflammasome by directly binding to NLRP3. Cells with Adcy7 deletion or mutations impacting enzymatic activity cannot produce c-di-AMP. The survival of Adcy7-deficient mice in acute liver injury was also improved. In summary, we found that ADCY7 is required for NLRP3 inflammasome activation downstream of TLR9 by catalyzing the generation of c-di-AMP, which may serve as a target for controlling inflammatory responses in sterile infections.

PMID:40419769 | DOI:10.1038/s41589-025-01919-y

Sci Rep. 2025 May 26;15(1):18403. doi: 10.1038/s41598-025-00759-z.

ABSTRACT

Kidney renal clear cell carcinoma (KIRC), a cancer characterized by substantial immune infiltration, exhibits limited sensitivity to conventional radiochemotherapy. Although immunotherapy has shown efficacy in some patients, its applicability is not universally effective. Studies have indicated that programmed cell death (PCD) can modulate the activity of immune cells and participate in the regulation of antitumor immune responses. However, systematic research on how various PCD patterns in KIRC affect the responsiveness to immunotherapy is lacking and requires in-depth investigation. We utilized a combination of 101 machine learning algorithms to analyze the TCGA-KIRC cohort and the GSE22541 KIRC patients, screening for cell death patterns closely associated with prognosis from 18 potential modes. Integrating multi-omics analysis, including immune cell infiltration, phenotyping, functional analysis, immune checkpoint exploration, and gene set enrichment analysis (GSEA), we explored the relationship between key cell death patterns and patients’ responses to immunotherapy. Finally, potential drug targets were identified through drug sensitivity screening and molecular docking techniques. Our sophisticated risk assessment model successfully identified two PCD patterns, Anoikis and lysosome-dependent cell death (LDCD), closely associated with the prognosis of KIRC patients, with the high-risk group exhibiting poor outcomes. Immune cell analysis revealed upregulated expression of T follicular helper (Tfh) cells in both PCD patterns. Analysis of immune checkpoints disclosed enhanced expression of human leukocyte antigen E (HLA-E) across both patterns. Frequent mutations in the TTN and MUC16 genes were observed in the Anoikis pattern, whereas in the LDCD pattern, although the high-risk group had a higher mutation rate, there was no significant difference in tumor mutational burden. GSEA analysis indicated significant enrichment of the primary immunodeficiency pathway in the Anoikis high-risk group and significant enrichment of the spliceosomal tri-snrnp complex assembly pathway in the LDCD high-risk group. Drug sensitivity analysis showed notable sensitivity to SB505124 in both PCD patterns. HMOX1 and PIK3CG were identified as common genes in the two key PCD patterns, and molecular docking analysis confirmed stable binding affinity between Carnosol and HMOX1, and between PROTAC and PIK3CG. Our study identifies Anoikis and LDCD as prognostic PCD patterns in KIRC, with key immune cells, genetic mutations, and drug sensitivity profiles. HMOX1 and PIK3CG are common genes with stable binding to Carnosol and PROTAC, respectively, while SB505124 shows significant sensitivity to both PCD modes, suggesting potential therapeutic targets.

PMID:40419510 | DOI:10.1038/s41598-025-00759-z

Disabil Rehabil. 2025 May 26:1-9. doi: 10.1080/09638288.2025.2508940. Online ahead of print.

ABSTRACT

PURPOSE: Primary immunodeficiency (PID) is a clinically, immunologically, and genetically heterogeneous group of diseases resulting from quantitative and/or qualitative deficiencies of immune system. This study aimed to evaluate adults with primary immunodeficiency (PID) within the scope of the International Classification of Functioning, Disability, and Health (ICF).

MATERIALS AND METHODS: We evaluated 20 adults with PID and 20 healthy adults according to the ICF items. For domain b, exercise capacity, hand-grip strength (HGS), sleep functions, fatigue perception, and body composition; for domain s, posture, and muscle mass were evaluated. Health-related quality of life, activities of daily living, and physical activity were evaluated for domain d. For domain e, supports and relationships, societal attitudes, services, and policies of health, employment, and transportation were determined as barriers.

RESULTS: Exercise capacity, HGS, sleep function, and body composition were significantly impaired, fatigue severity from domain b increased in adult patients with PID compared to healthy controls (p < 0.05). Daily life activities and quality of life from domain d were significantly poorer in patients with PID compared to healthy controls (p < 0.05).

CONCLUSIONS: The evaluation and selecting appropriate outcomes based on ICF-framework will assist health professionals in goal-based rehabilitation plans and better improving functional capacity in adult PID.

PMID:40418537 | DOI:10.1080/09638288.2025.2508940

Methods Mol Biol. 2025;2933:31-35. doi: 10.1007/978-1-0716-4574-1_5.

ABSTRACT

DNA damage activates cell cycle checkpoints and repairs damages during cell cycle arrest. Radiation-induced S-phase arrest occurs in normal cells, but cells from ataxia telangiectasia (AT) patients present radioresistant DNA synthesis (RDS). AT-derived cells proceed DNA synthesis with DNA damage. Upon detection of radiation-induced DSBs, ATM becomes activated and initiates a signaling cascade that triggers multiple cellular responses aimed to repair the damaged DNA. One of them is the S-phase checkpoint to stop DNA synthesis. Originally, RDS was detected using pulse chase of two radiolabeled thymidines. This chapter introduces modified nonradiolabeled RDS assay using dual labeling of EdU and BrdU and detection of thymidine analogous by specific antibody and Click reaction.

PMID:40418471 | DOI:10.1007/978-1-0716-4574-1_5

Front Immunol. 2025 May 9;15:1471168. doi: 10.3389/fimmu.2024.1471168. eCollection 2024.

ABSTRACT

INTRODUCTION: Plasma proteomics analyses were performed to identify novel disease state biomarkers of hereditary angioedema due to C1 inhibitor deficiency (HAE-C1INH) and investigate the biological consequences of specific plasma kallikrein inhibition with lanadelumab.

METHODS: Affinity proteomic analyses were performed using plasma from healthy controls (n=30) and patients with HAE-C1INH before (baseline, n=125) and after 6 months of treatment with lanadelumab (300 mg every 2 weeks, n=112) using the SomaScan platform.

RESULTS: Relative plasma levels for several proteins differed significantly between controls and patients with HAE-C1INH, and between matched baseline and post-treatment samples from patients with HAE-C1INH. As expected, C1 inhibitor and complement C4 were significantly lower (P<1.10e-39 false discovery rate [fdr], P<6.6e-25 fdr, respectively) in HAE-C1INH baseline plasma versus controls. Cleaved high-molecular-weight kininogen, a biomarker of excess kallikrein-kinin system (KKS) activation, was higher in HAE-C1INH baseline plasma versus controls (P<6.7e-6 fdr) and was reduced in HAE-C1INH plasma after lanadelumab treatment. Of 1041 identified proteins that differed significantly (P<0.05) from controls and HAE-C1INH baseline plasma, 120 proteins were no longer different between controls and patients with HAE-C1INH after 6 months of lanadelumab treatment. Canonical pathway and local network analyses of HAE-C1INH plasma proteomics suggest dysregulation in KKS, coagulation, cell adhesion, and connective tissue degradation that approach that of healthy controls following treatment with lanadelumab.

CONCLUSION: Proteomic analyses of plasma from patients with HAE-C1INH before and after treatment with lanadelumab compared with healthy controls confirmed known HAE-C1INH biomarkers and identified additional potential biomarkers of plasma kallikrein dysregulation for further investigation.

PMID:40417315 | PMC:PMC12098075 | DOI:10.3389/fimmu.2024.1471168