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Int J Mol Sci. 2025 Aug 6;26(15):7607. doi: 10.3390/ijms26157607.

ABSTRACT

Immunoglobulin light chains are essential components of intact immunoglobulins, traditionally believed to be produced exclusively by B cells. Physiologically, excess light chains not assembled into intact antibodies exist as free light chains (FLCs). Increasingly recognized as important biomarkers for diseases such as multiple myeloma, systemic amyloidosis, and light chain-related renal injuries, FLCs have also been shown in recent decades to originate from non-B cell sources, including epithelial and carcinoma cells. This review primarily focuses on novel non-B cell-derived FLCs, which challenge the conventional paradigms. It systematically compares B cell-derived and non-B cell-derived FLCs, analyzing differences in genetic features, physicochemical properties, and functional roles in both health and disease. By elucidating the distinctions and similarities in their nature as immune regulators and disease mediators, we highlight the significant clinical potential of FLCs, particularly non-B cell-derived FLCs, for novel diagnostic and therapeutic strategies.

PMID:40806736 | DOI:10.3390/ijms26157607

Diagnostics (Basel). 2025 Jul 26;15(15):1879. doi: 10.3390/diagnostics15151879.

ABSTRACT

Background: Regulatory T cells (Tregs) are the main suppressor cells that maintain immune tolerance and prevent autoimmunity. Changes in Treg number or function are implicated in a wide range of autoimmune and inflammatory (AI/I) diseases, with or without underlying inborn errors of immunity (IEI). Understanding the phenotypic profiles of Treg subsets and their associations with immune dysregulation is crucial to identifying potential robust and holistic biomarkers for disease activity. Methods: We examined peripheral blood mononuclear cells from 40 patients diagnosed with various autoimmune/inflammatory diseases, including those with genetically confirmed inborn errors of immunity (IEIs), and compared these samples to those from 38 healthy controls of the same age. Utilizing multiparametric flow cytometry, we measured multiple Treg sub-populations and investigated their correlations with lymphocyte subset profiles and the diversity of autoantibodies. We applied advanced statistical and machine learning techniques, such as t-SNE, k-means clustering, and ROC analysis, to analyze immunophenotypic patterns in the patients. Results: Among all Treg sub-populations, only CD4⁺CD127^lowCD25^highFOXP3⁺ Tregs showed a significant decrease in patients compared to healthy controls (p < 0.05), while other Treg phenotypes did not differ. FOXP3 expression showed reduced intensity in patients and demonstrated diagnostic potential (AUC = 0.754). Notably, this Treg subset negatively correlated with CD19⁺ B cell percentages and positively correlated with the diversity of circulating autoantibodies. Unsupervised clustering revealed three distinct immunophenotypic profiles, highlighting heterogeneity among patients and underlining FOXP3-centered immune dysregulation. Conclusions: Our results presented that patients have an impairment in the CD4⁺CD127^lowCD25^highFOXP3⁺ regulatory T cell subset, which is identified by significantly decreased frequency and decreased expression of FOXP3. Immunological heterogeneity among patients was further uncovered by unsupervised clustering, highlighting the critical role that FOXP3-centered regulatory failure plays in the pathophysiology of illness. The combined evaluation of these three immunological factors, centered around FOXP3, holds promise as an integrative tool for monitoring disease progression across various autoimmune and immunodeficient contexts.

PMID:40804844 | DOI:10.3390/diagnostics15151879

EMBO Mol Med. 2025 Aug 13. doi: 10.1038/s44321-025-00292-6. Online ahead of print.

ABSTRACT

STING gain-of-function (GOF) mutations cause STING-Associated Vasculopathy with onset in Infancy (SAVI), a severe autoinflammatory disease. Mice carrying STING GOF V154M mutation develop profound T cell lymphopenia, partly due to impaired thymic development. To investigate the mechanisms of peripheral T cell dysfunctions, we analyzed transcriptomic and phenotypic profiles of splenic T cells from these mice. We found a terminally exhausted T cell phenotype, established early in life upon entry into the periphery, independent of type I interferons and intrinsic STING activation in T cells or stromal cells. Mechanistically, naive T cells in the lymphopenic periphery experienced heightened stimulation of the IL-7 receptor and TCR, including NFAT pathway, a key factor in T cell exhaustion. Transplantation of STING GOF hematopoietic stem cells with wild-type bone marrow prevented exhaustion in this non-lymphopenic context, placing lymphopenia as a key driver. T cell exhaustion was also observed in lymphopenic mice carrying Rag1 hypomorphic mutations. In conclusion, our results highlight T cell exhaustion induced by lymphopenia and could have important implications for the management of patients with severe immune deficiencies.

PMID:40804163 | DOI:10.1038/s44321-025-00292-6

CEN Case Rep. 2025 Aug 12. doi: 10.1007/s13730-025-01025-x. Online ahead of print.

ABSTRACT

The primary defect in distal renal tubular acidosis (dRTA) is impaired H⁺ ion secretion in the distal nephron, resulting in a normal anion gap metabolic acidosis. The solute carrier family 4-member 1 (SLC4A1) gene encodes the erythroid and renal anion exchanger 1 (AE1) protein for chloride-bicarbonate exchange. Mutations in the gene can result in hereditary dRTA, red blood cell membrane defect, and hemolytic anemia. Chronic granulomatous disease (CGD) is a rare primary immunodeficiency syndrome caused by NADPH oxidase deficiency, leading to impaired neutrophil and phagocyte function, and thus predisposing the patient to multiple bacterial infections. Melioidosis is a rare infection caused by Burkholderia pseudomallei and is often linked to CGD. Here we present an interesting case of an 8-year-old girl with melioidosis secondary to CGD. Also, she had nephrocalcinosis, metabolic acidosis, hypercalciuria, and anemia. The simultaneous presence of distal RTA (Pathogenic homozygous SLC4A1 mutation on whole exome sequencing) and CGD has not been reported previously and reiterates the importance of detailed clinical evaluation combined with investigations for the long-term management of such complex cases.

PMID:40796712 | DOI:10.1007/s13730-025-01025-x

Curr Top Microbiol Immunol. 2025 Aug 13. doi: 10.1007/82_2025_316. Online ahead of print.

ABSTRACT

More than 500 primary immunodeficiencies (PIDs) or inborn errors of immunity (IEIs) have been reported. In general, IEIs are caused by monogenic germinal variants resulting in immunodeficiency and immune dysregulation symptoms. These “in natura” experiments have highlighted selective factors and pathways required for the immune control of a given pathogen, including Epstein-Barr virus (EBV). Several IEIs predominantly predispose to develop severe EBV infections and associated diseases including infectious mononucleosis (IM), hemophagocytic lymphohistiocytosis (HLH) and nonmalignant or malignant B cell lymphoproliferative disorders (B-LPD). Identification of these IEIs revealed critical components/molecules of the immune response to EBV. Notably, these elements differ depending on the type of the EBV viral disease. On one hand, defects in factors involved in the cytotoxic responses of lymphocytes preferentially underlie HLH, whereas, on the other hand, factors implicated in the expansion of EBV-specific T cells are mostly responsible for B-LPD when impaired. IEIs also inform on mechanisms underlying rare EBV viral diseases such as EBV⁺ smooth muscle tumors (EBV⁺SMT) and the “atypical” T/NK cell lymphoproliferative disorders (NK/T-LPD) including chronic active EBV infections (CAEBV). Finally, IEIs not predisposing to EBV provide information on immune components not necessary or redundant for EBV immunity. All these aspects are discussed in this chapter.

PMID:40794140 | DOI:10.1007/82_2025_316

J Clin Immunol. 2025 Aug 11;45(1):122. doi: 10.1007/s10875-025-01899-7.

ABSTRACT

PURPOSE: The Ezrin-Radixin-Moesin (ERM) family member moesin (MSN) plays a crucial role in reversibly linking F-actin to the cell membrane. Patients carrying MSN gene mutations consistently exhibit immunodeficiencies. However, due to the scarce number of reported cases worldwide, the mechanism by which MSN mutation leads to immune function defects remains unclear. This study aims to profile the immunological features in MSN mutant patients elaborately.

METHODS: In this article, we present a case study of a patient with c.511 C > T, p.Arg171Trp (p.R171W) mutation on the MSN gene. We analyzed abnormalities in peripheral immune cell subsets by quantitative analysis, morphological examination, and functional molecule assessment during various infection states. Using total internal reflection fluorescence microscopy (TIRFm), we visualized BCR clusters and F-actin dynamics in B cells, revealing valuable insights into B cell activation and the link between F-actin aggregation and BCR signaling in MSN mutant patients.

RESULTS: The results suggest that the MSN c.511 C > T, p.Arg171Trp (p.R171W) mutation affects the proliferation, differentiation, metabolism, and adhesion functions in peripheral immune cells, as well as the maturation process in bone marrow cells. Additionally, we elucidate the impact of MSN mutation on B cell and T cell metabolism and propose a potential diagnostic indicator for patients with MSN gene mutations.

CONCLUSION: Our findings support the diagnosis of primary immunodeficiency and provide detailed insights into changes occurring in immune cells, especially B cells. Overall, our study adds to the diagnosis and pathogenesis of X-linked moesin-associated immunodeficiency (X-MAID).

PMID:40788322 | DOI:10.1007/s10875-025-01899-7

Jt Dis Relat Surg. 2025 Jun 13;36(3):751-756. doi: 10.52312/jdrs.2025.1988. Epub 2025 Jun 13.

ABSTRACT

Immune dysregulation in children can lead to a variety of health issues, including infections, allergies and autoimmune diseases. However, the coexistence of autoimmune diseases and primary immunodeficiency disorders is extremely rare in clinical practice. A 4-year-old male patient was admitted in July 2017 with joint swelling and pain, alongside a history of recurrent respiratory infections and severe pneumonia. Physical examination revealed tenderness and swelling in multiple joints, and laboratory tests indicated elevated inflammatory markers. Imaging studies showed joint effusion and inflammatory lesions in the lungs. He was diagnosed with rheumatoid factor-negative polyarticular juvenile idiopathic arthritis (PJIA) and treatment was initiated with naproxen, methotrexate and etanercept, leading to significant symptom improvement. In July 2019, following a decline in immunoglobulin (Ig) M (IgM) levels (IgM 0.36 g/L) and recurrent infections, genetic testing was conducted, revealing a frameshift mutation in the CD40LG gene (c.621dup A, p.A208Sfs * 23), which confirmed the diagnosis of X-linked hyper IgM syndrome (XHIGM). The treatment regimen was adjusted to include monthly intravenous Ig infusions and prophylactic antibiotics, significantly reducing the frequency of respiratory infections. By January 2021, PJIA was in clinical remission, allowing for the discontinuation of immunosuppressive therapy, with follow-ups indicating continued recovery without discomfort. In conclusion, this case underscores the rare coexistence of XHIGM and PJIA in the field of pediatrics and identified a new pathogenic variant in CD40LG, enhancing our understanding of the clinical management of individuals with concurrent autoimmune and immunodeficiency disorders.

PMID:40784008 | DOI:10.52312/jdrs.2025.1988

BMC Immunol. 2025 Aug 9;26(1):60. doi: 10.1186/s12865-025-00743-2.

ABSTRACT

BACKGROUND AND AIMS: Common variable immunodeficiency (CVID) represents the most frequently diagnosed symptomatic primary immunodeficiency (PID), marked by a heterogeneous presentation involving infectious and non-infectious symptoms. This study investigated the association between serum copeptin levels and right ventricular functions (RVF) and pulmonary complications in patients diagnosed with CVID.

METHODS: The study analyzed data from 60 individuals with a confirmed diagnosis of CVID and 30 age- and sex-matched healthy volunteers (HVs). Clinical and biochemical parameters were sourced from existing hospital records.CVID patients were categorized into two subgroups: those with and without pulmonary complications. Comparisons of serum copeptin levels were made between these groups and between the overall CVID cohort and healthy controls. RVF was evaluated using tricuspid annular plane systolic excursion (TAPSE) and supplementary echocardiographic indicators.

RESULTS: The CVID group had a median age of 40 years (interquartile range [IQR]: 30-55), with 51.7% being male, while the HVs group had a median age of 37 years (IQR: 28-47.5), with 60% male. No significant differences in age (p = 0.226) or sex distribution (p = 0.45) were observed between the groups. CVID with pulmonary complications (CVID-P) exhibited significantly elevated copeptin levels compared to those without such complications (p < 0.001). According to ROC analysis, a copeptin cut-off value of 11 pmol/L significantly differentiated patients with CVID-P from those without pulmonary complications (p < 0.001). Moreover, overall copeptin levels were significantly higher in the CVID group than in HVs (p < 0.001). A copeptin cut-off value of 21 pmol/L effectively distinguished CVID patients with low TAPSE from those with normal TAPSE values (p < 0.001). Pulmonary complications and low TAPSE were independently associated with increased copeptin levels (p = 0.006 and p = 0.004, respectively).

CONCLUSION: The development of pulmonary complications and RV dysfunction were associated with elevated serum copeptin levels in CVID. Measuring serum copeptin concentration may be a useful biomarker in diagnosing and prognosis pulmonary diseases and RV dysfunction in CVID.

PMID:40783747 | DOI:10.1186/s12865-025-00743-2

Mol Ther. 2025 Aug 7:S1525-0016(25)00636-7. doi: 10.1016/j.ymthe.2025.08.006. Online ahead of print.

ABSTRACT

TFIIB-related factor 2 (BRF2) is a critical component in the recruitment of RNA polymerase III (Pol III) to type III promoters containing a TATA box. These promoters regulate the expression of key elements such as U6 spliceosomal RNA, the tRNA processing enzyme RNase P, and selenocysteine tRNA. Despite its essential role, the genetic disorders associated with BRF2 mutations and their molecular pathogenesis remain poorly defined. In this study, we identified and characterized novel biallelic BRF2 variants with impaired RNA Pol III activity in a familial case presenting with multisystem anomalies, malignancy, and primary immunodeficiency. Whole-exome sequencing revealed compound heterozygous BRF2 variants predicted to disrupt interaction with the TATA box-binding protein. Subsequent gene expression profiling of the patient’s whole blood cells using single-cell RNA sequencing was conducted. Clinically, the patient exhibited recurrent infections and hypogammaglobulinemia in early childhood, which improved over time but was followed by the development of low-grade B-cell lymphoma during adolescence, necessitating chemotherapy. Functional analyses in human cells expressing the BRF2 variants demonstrated defective BRF2-dependent Pol III transcription of redox-regulating genes, specifically GPX1 and GPX4. These findings establish a pathogenic link between BRF2 dysfunction and disrupted redox homeostasis, offering mechanistic insights into the hemato-immunological and developmental abnormalities observed in affected individuals and highlighting potential implications for clinical management.

PMID:40781771 | DOI:10.1016/j.ymthe.2025.08.006

J Allergy Clin Immunol. 2025 Aug 4:S0091-6749(25)00838-3. doi: 10.1016/j.jaci.2025.07.021. Online ahead of print.

ABSTRACT

BACKGROUND: Genetic aberrations in pathways critical for cell development and growth can cause primary immunodeficiency with manifestations including susceptibility to infections, hyper-inflammation, autoimmunity, and lymphoproliferation. Occasionally, these conditions are caused by genetic variants that disrupt the regulation of an immune response by removing essential repressor activities. Roquin-1, encoded by RC3H1, is a post-transcriptional repressor of multiple immune modulatory proteins. It plays a critical role in the control of immune responses through regulation of the post-transcriptional stability of selected mRNA.

OBJECTIVE: To study the mode of inheritance and molecular basis of a novel immunodeficiency disorder in an extended kindred.

METHODS: Whole exome sequencing was performed to identify the genetic change. Molecular and cellular techniques were utilized to assess the variant impact on immune function and RNA regulation.

RESULTS: We studied 3 individuals from an extended kindred presenting with a spectrum of infections, lymphoproliferation, and autoimmune manifestations. Whole exome sequencing performed in patient 1 identified a novel heterozygous missense c.T674C (p.F225S) variant in the highly conserved ROQ domain sequence of RC3H1, encoding the RNA-binding protein Roquin-1. F225S Roquin-1 variant family segregation indicated an autosomal dominant mode of inheritance. Patient’s primary cells as well as F225S Roquin-1-transfected cells demonstrated a marked rise in ICOS1, IL6, and other pro-inflammatory Roquin target RNA, with increased message stability indicating lack of repressor Roquin-1 activity. The resultant aberrations in immunity included a selective antibody deficiency, expansion of CD8 memory and double positive CD4+ CD8+ T cells, skewed TCR repertoire, and enhanced IL-2 secretion and T cell proliferation.

CONCLUSION: The RNA-binding protein Roquin-1 plays a critical role in the regulation of immune responses. We demonstrate here that a single heterozygous variant within the ROQ domain of Roquin-1 manifests as primary immunodeficiency, resulting in variable severity of infections, autoimmune features, and hyper-inflammation.

CLINICAL IMPLICATIONS: A single gene change in RC3H1, encoding the post-transcriptional repressor Roquin-1, can cause immunodeficiency with autoimmune features, hyper-inflammation, lymphoproliferation, and significant infections.

PMID:40769319 | DOI:10.1016/j.jaci.2025.07.021