Research

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

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

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

Eur J Immunol. 2025 May;55(5):e202451382. doi: 10.1002/eji.202451382.

ABSTRACT

The innate immune system relies on nucleic acid (NA) sensors to detect viral infections and trigger type I interferon (IFN-I) responses, which are crucial for antiviral defense. NA pattern recognition receptors detect viral RNA or DNA within various cellular compartments, initiating antiviral signaling pathways. However, inherited deficiencies in these NA sensing mechanisms can result in increased susceptibility to severe viral infections. This review explores key genetic mutations affecting NA sensing and IFN-I pathways that predispose individuals to life-threatening viral diseases, including herpesviruses, respiratory viruses, enteroviruses, arboviruses, and vaccine-strain disseminated viral diseases. The identification of these monogenic defects in individuals afflicted by severe viral infections, along with the observed incomplete penetrance of these mutations, highlight the intricate interplay of the host’s intrinsic, innate, and adaptive immune response with invading viral pathogens. These insights into the molecular basis of antiviral immunity not only underscore the clinical challenges associated with viral susceptibility but also offers the opportunity for personalized treatment strategies, including genetic screening, tailored vaccination protocols, and targeted antiviral therapies.

PMID:40415206 | DOI:10.1002/eji.202451382

Front Immunol. 2025 May 9;16:1596963. doi: 10.3389/fimmu.2025.1596963. eCollection 2025.

ABSTRACT

INTRODUCTION: The Bacillus Calmette-Guérin (BCG) vaccine is widely used to prevent tuberculosis but is associated with significant complications in patients with severe combined immunodeficiency (SCID). Considering the high incidence of SCID in Saudi Arabia, the Ministry of Health revised its national vaccination schedule in 2019, postponing BCG administration from birth to 6 months of age, aiming to enable time for the diagnosis of primary immunodeficiency diseases before vaccination. This study evaluated the consequences of this policy change on the incidence of BCG-related complications in SCID patients.

METHODS: This retrospective study included 178 SCID patients diagnosed at King Faisal Specialist Hospital and Research Center, Riyadh, between 2015 and 2023. Patients were divided into two cohorts: Era 1 (2015-2019), when BCG vaccination was administered at birth, and Era 2 (2019-2023), when BCG vaccination was administered at 6 months of age. Data on demographics, clinical presentations, BCG-related complications, genetic testing, treatment, and outcomes were analyzed.

RESULTS: A total of 49 SCID patients developed BCGitis, of which 65.3% experienced disseminated disease. The incidence of BCG-related complications dropped significantly after the policy change, from 46.1% in Era 1 to 2.6% in Era 2. Patients required stem cell transplantation and a median of 17.6 months of anti-mycobacterial therapy. The crude mortality rate was high (36.7%; 18/49), with 66.7% (12/18) of these fatalities linked to disseminated BCGitis.

CONCLUSIONS: Postponing BCG vaccination to 6 months of age significantly decreases the incidence of BCG-related complications in SCID patients and highlights the importance of tailoring vaccination schedules for high-risk populations. Early newborn screening and timely diagnosis of immunodeficiencies are essential to further minimize complications. The revised vaccination policy of Saudi Arabia provides a model for optimizing immunization strategies in regions with a high prevalence of inborn errors of immunity.

PMID:40416983 | PMC:PMC12098544 | DOI:10.3389/fimmu.2025.1596963

Malays J Med Sci. 2025 Feb;32(1):141-153. doi: 10.21315/mjms-08-2024-608. Epub 2025 Feb 28.

ABSTRACT

BACKGROUND: This study aimed to determine the knowledge and attitude of the Malaysian public towards blood donation during the COVID-19 pandemic.

METHOD: This cross-sectional study utilised an online questionnaire to survey 409 Malaysians between 18 to 60 years old who were non-healthcare workers recruited via convenient snowball sampling. Data were analysed descriptively and via multiple logistic regression.

RESULTS: About half (49.2%) of the participants have good knowledge of blood donation while 71.2% of them reported a positive attitude. Gender and blood donation experience were significantly associated with knowledge of blood donation. However, only gender was associated with attitude concerning blood donation. Gender, age, income and donation experience were significantly related to the perception of blood need. No factor was identified as significantly associated with the perception of blood donation risk. The majority of the participants quoted the main reason for blood donation as to save lives.

CONCLUSION: Most of the participants in this study showed a good knowledge and positive attitude towards blood donation. Gender, age, income and donation experience were the main associated factors. Based on these findings, future recruitment approaches for blood donors should target these identified groups, whereas promotional campaigns should be held among populations with poorer knowledge and attitudes towards blood donation, i.e., males, non-donors, younger populations and those with lower income.

PMID:40417200 | PMC:PMC12097151 | DOI:10.21315/mjms-08-2024-608