Journal of Clinical Immunology最新文献

Behçet's disease (BD) is a chronic inflammatory disorder characterized by recurrent oral aphthous ulcers, genital ulcers, skin lesions, and uveitis. Recent genetic studies have identified monogenic diseases with phenotypes resembling BD, including RELA-associated inflammatory disease (RAID), Haploinsufficiency of A20 (HA20), and otulipenia. The RelA gene encodes the RELA protein, which is involved in the nuclear factor kappa B (NF-κB) signaling pathway that regulates the transcription of genes associated with cell survival, apoptosis, and immune responses. In RAID, dysfunction of the NF-κB pathway leads to reduced cell survival and symptoms of BD, such as recurrent fever, chronic mucocutaneous ulceration, arthralgia, and colitis. Herein, we report a pediatric patient who presented with recurrent, severe oral and genital ulcers from the age of five years and was diagnosed with RAID following a documented RelA gene mutation. The patient responded to a combination of corticosteroids, colchicine and methotrexate. RAID should be considered in the differential diagnosis of patients with early onset recurrent fever and mucosal ulcerations.

We describe a 3-year-old patient with xeroderma pigmentosum (XP) and genetically confirmed XPA deficiency who presented with recurrent infections in early childhood. Immunological assessment revealed mild hypogammaglobulinemia with IgG2 and IgG3 subclass deficiencies, as well as impaired humoral immunity demonstrated by a reduced antibody response to repeated vaccinations against bacterial antigens. Flow cytometric analysis further showed an altered distribution of peripheral T helper (TH) cell subsets. In addition, we report a second case: a 33-year-old XP patient with ERCC4 deficiency who also exhibited IgG3 subclass deficiency and reduced response to booster vaccination. Functional studies revealed defective nucleotide excision repair (NER) following UV-C exposure, along with reduced B-cell activation capacity. These findings suggest a potential link between XP and immunoglobulin subclass deficiencies, indicating a susceptibility to infections in affected individuals. We therefore recommend that patients diagnosed with XP undergo comprehensive immunological evaluation to allow early detection of immunodeficiency and timely intervention, including booster vaccinations or prophylactic measures such as low-dose antibiotics or immunoglobulin replacement therapy when indicated.

The tumor necrosis factor (TNF) receptor superfamily member, transmembrane activator and CAML interactor (TACI) encoded by TNFRSF13B, are extensively involved in immune responses. In our previous work, TNFRSF13B exon 2 variants were recurrently identified in chronic active Epstein-Barr virus disease (CAEBV). Here we aim to reveal the roles of TNFRSF13B variants in CAEBV, and investigate the feasibility of targeting TNFRSF13B/TACI as a new approach to control EBV infection. The lymphoblastoid cell lines (LCL) models carrying homozygous TNFRSF13B exon 2 frameshift mutations were constructed using CRISPR/Cas9. Immunological assays, transcriptomic analysis, and gene silencing experiments were performed on LCL models to measure the effect of TNFRSF13B exon 2 variants and explore the underlying mechanisms. TACI ligands and a TLR9 agonist were applied to modulate TACI signaling and EBV activities. Frameshift mutations in exon 2 of TNFRSF13B significantly up-regulated the short isoforms of TACI (TACI-S) at the expense of its long isoforms (TACI-L) in LCLs. The up-regulated TACI-S induced more intense activation of NF-κB, MAPK, and Rho signaling pathways, leading to the switch of EBV activities to lytic reactivation. The subsequent increased viral load and viral IL-10 provide a rational for the susceptibility of variant carriers to CAEBV. The BAFF trimer, an indirect TACI-signaling inhibitor, also significantly suppressed the EBV lytic program. Gene silencing experiments indicated that XBP-1 might be involved in the TACI-mediated regulation of EBV lytic activities in EBV-immortalized B cells. This study underscores the impact of TNFRSF13B variants on EBV infection and host immune responses, offering insights into CAEBV pathogenesis and potential therapeutic strategies.

Objective: The presence of unique monocyte subsets and sub-populations plays a significant role in the onset and progression of rheumatic diseases. This study aimed to characterize variations in monocyte subsets and sub-populations and functional roles in patients with primary Sjögren's syndrome (pSS) using single-cell RNA sequencing (scRNA-seq).

Method: Monocyte samples from patients with pSS and healthy controls (HCs) were analyzed using single-cell RNA sequencing (scRNA-seq). This approach identified divergent gene expression patterns, transcription factors, and immune cells interactions within monocyte subset and sub-populations, highlighting pathways potentially involved in the pathogenesis of pSS.

Results: The scRNA-seq analysis delineated three major monocyte subsets: classical monocytes (CD14⁺⁺CD16^-), non-classical monocytes (CD14^-CD16⁺), and cDC2, with further identification of sub-populations within the classical and non-classical monocyte subsets. A notable increase in the proportions of classical monocyte sub-population 2 and non-classical monocyte sub-population 2 was observed in pSS patients. Compared to the HCs, pSS patients exhibited enhanced immune cell interactions within monocyte subsets. Furthermore, in pSS patients, the dominant increased pathways within monocytes were those related to viral responses, interferon activity, and oxidative phosphorylation. Additionally, significantly elevated expression levels of IFI44, IFI44L, HBA2, LY6E, XAF1, EPSTI1, APOBEC3A, and IFIT3 were identified in pSS monocytes.

Conclusion: This research revealed irregular alterations in monocyte subsets and sub-populations, transcription factors, and gene expression patterns within pSS patients, pinpointing prospective biomarkers in pSS as viable targets for therapeutic intervention.

Type II interferon (IFN) immunity is crucial for controlling intramacrophagic infections, driven by the interaction between innate immunity (macrophage-derived IL-12) and adaptive immunity (Th-derived IFN-γ). This study examines the maturation of type II IFN immunity in 55 healthy children (ages 1-18) to enable proper identification of deficiencies as part of the diagnostic evaluation of Mendelian Susceptibility to Mycobacterial Diseases (MSMD). The IL-12/IFN-γ axis was assessed through: (1) cytokine production after mycobacterial stimulation (Luminex and ELISA for IFN-γ, IL-12p70, TNF, CXCL10, IL-1RA, IL-10, IL-1β and IL-6), (2) IFN-γR1/R2 expression on monocytes, and (3) STAT1 phosphorylation/dephosphorylation. T cell maturation (primary IFN-γ source) was evaluated via immunophenotyping (naïve/memory/activated, Th1; Th2; Th17; Th1/17; Tfh) and proliferation assays. Main findings: (1) stable expression/production of key components of the IL-12/IFN-γ axis (IFN-γ, IL-12, TNF, IFN-γR1/2, and STAT1 activity) across ages confirming the stability of innate immune function throughout childhood; (2) increasing responses to IFN-γ with age reflected by increased CXCL10 production, and increase in the IFN-γ counter-acting anti-inflammatory cytokines (IL-10, IL-1RA); and (3) progressive T cell maturation, including Th1, Th17 and Th1/17 subsets, with significant milestones between 6 and 8.6 years, while T cell proliferative capacity remained stable. These observations highlight the stability of IL-12/IFN-γ axis innate components with age, accompanied by enhanced downstream IFN-γ signaling, aligning with the maturation of Th cell compartment. These underscore the limited benefit of age-specific controls in the evaluation of IL-12/IFN-γ axis in MSMD diagnosis, while emphasizing the importance of T cell maturation in the overall type II IFN immunity.

Trained immunity, a de-facto innate immune memory, has been extensively studied in response to live-attenuated vaccines, but its presence following the new COVID-19 vaccines has not yet been fully elucidated. In this study, we investigate markers of trained immunity in individuals vaccinated with mRNA-1273 or BNT162b2. As part of the vaccine roll-out in Denmark and recruited for a comparative study. Our primary objective was to determine whether these vaccines elicit lasting changes in innate immune responses, particularly in monocyte populations and cytokine production following stimulation with a panel of agonists. The study was conducted at four time points: Day-0 (pre-vaccination), Day-28, Day-90, and Day-180 post-vaccination. We observed no significant differences in monocyte subpopulations between vaccine groups; however, cytokine and chemokine analysis revealed distinct immune signatures. While IL-6 and TNFα production remained unchanged after ex-vivo restimulation in the BNT162b2 group, individuals vaccinated with mRNA-1273 exhibited a sustained increase in the production of these cytokines, persisting for up to 180 days post-vaccination. Additionally, CCL2, a key chemokine involved in monocyte recruitment, was upregulated following mRNA-1273 vaccination but decreased in the BNT162b2 group, further supporting the finding of differential innate immune responses between the two vaccines. In conclusion, our study provides evidence that mRNA-1273, but not BNT162b2, induces immune responses consistent with the concept of trained immunity. These results highlight the potential for mRNA vaccine platforms to shape innate immunity, with implications for future vaccine design aimed at enhancing non-specific and specific protection against infectious diseases.