Immunology letters最新文献

Antiphospholipid syndrome (APS) is an acquired thrombophilia characterized by thrombotic and non-thrombotic (or non-criteria) manifestations, in the context of persistent presence of autoantibodies targeting phospholipids and associated proteins. The complement system, which shares common actors with coagulation cascade, is nowadays well established to be implicated in APS pathophysiology in different ways. Animal models using knock out strains or complement blocking therapies have helped to decipher the different complement components implicated in the processes of thrombosis and fetal morbidity. In APS patients, complement activation may be assessed through the detection of activation fragments (C4d, C3a, C5a, sC5b9) in plasma and on blood cells surface (C4d, C3d and C5b9) or on APS-affected tissues such as cardiac valves, vessels walls, kidneys and placentae. APS patients are currently treated to avoid thrombosis recurrence by long-term treatment by vitamin K antagonists but various complement targeting molecules are tested in trials or now available and may be of major interest to treat APS patients. Several cases report described the use of eculizumab, an anti-C5 monoclonal antibody, to treat severe forms of APS (recurrent thrombosis, Catastrophic APS) but these studies are not sufficient and need to be more standardized. C4d measurement may be useful to assess classical and lectin pathways activation, C5a may allow evaluating the C5a/C5aR axis activity whereas, associated with sC5b9, it may also assess the terminal pathway activation but also the therapeutic efficacy of complement blocking molecules. Thus, assessment of good complement biomarkers and their kinetics needs to be done to determine personalized therapeutic options.

Purpose: Rheumatoid arthritis (RA) is a common autoimmune disease causing significant bone lesions. This study aims to explore RA through efferocytosis, identify hub genes, and construct a risk prediction model for clinical management and targeted therapy.

Method: RA data was obtained from the GEO database. Differential gene expression analysis was performed using R packages. Hub genes were identified via LASSO regression and validated with ROC curves. Functional analysis included constructing PPI, mRNA-miRNA, and transcription factor (TF) networks. Gene modules were analyzed by WGCNA, and immune cell infiltration was assessed using CIBERSORT. CD300A expression was knocked down in macrophages and assessed by immunofluorescence and flow cytometry. In vivo, CD300A was silenced in a CIA mouse model using AAV lentivirus, followed by joint pathology and TUNEL staining.

Result: Six hub genes were identified: IL1R1, WASL, AIM2, NLRP3, CD24, and CD300A, with coefficients of -1.968, -0.445, 1.367, 0.077, 0.248, and 0.523, respectively. B cells, macrophages, and T cells were significantly correlated with the risk score. Additionally, 30 TFs and 56 candidate miRNAs were identified. Knockdown of CD300A in macrophages enhanced efferocytosis in vitro, while silencing CD300A in vivo reduced joint scores, improved joint pathology, and decreased apoptosis in CIA mice.

Conclusion: Efferocytosis plays a key role in RA pathogenesis. IL1R1, WASL, AIM2, NLRP3, CD24, and CD300A are significant hub genes for RA prediction, with CD300A being a promising therapeutic target.

Innate immunity has long been viewed as a defense system that evolved to detect and eliminate invading microbes. However, its functions extend beyond pathogen control to the continuous surveillance of cellular integrity. Cellular homeostasis relies on repair mechanisms that preserve genome stability, proteostasis, lipid balance, and organelle quality. When these systems fail, endogenous molecules such as nucleic acids, lipids, protein aggregates, and metabolites become mislocalized or modified and act as damage-associated molecular patterns (DAMPs). These signals mark sites of failed repair and activate innate sensors, sustaining inflammation even in the absence of infection. In this minireview, we outline the major classes of DAMPs and show how their accumulation reflects defects in specific repair pathways. We propose that innate immunity and cellular repair are fundamentally interconnected. When repair is intact, inflammation is transient and resolves. When repair fails, inflammation becomes chronic and drives disease.

Fc receptor-like (FCRL) proteins constitute a receptor family that displays overlapping yet distinct features compared to classical Fc receptors. In a healthy immune system, FCRL proteins play a role in promoting and regulating the immune response through their immunoreceptor tyrosine-based motifs. FCRL proteins are expressed mainly by B cells, suggesting a primary role in B-cell responses. For several autoimmune diseases, studies have shown that particularly FCRL4, which binds to dimeric IgA, and FCRL5, which binds to IgG, may have a role in disease pathology and prognosis. These proteins and their transcripts are often enriched in blood and/or affected tissue of patients with a systemic or organ-specific autoimmune disease like rheumatoid arthritis, Sjögren's disease, systemic lupus erythematous, Graves' disease or myasthenia gravis. The expression of FCRL4 and FCRL5 appears to be disease- and context-specific, and influenced by the tissue microenvironment. Yet, the functions of FCRL proteins are still incompletely understood, and more mechanistic studies are necessary to unravel the contribution of FCRL4 and FCRL5 to pathogenic B-cell responses occurring in autoimmune diseases.

Th2 cells were originally described as a homogeneous population capable of simultaneously producing interleukin (IL)-4, IL-5, and IL-13, thereby playing a central role in allergic asthma and related conditions. Subsequent studies have revealed substantial heterogeneity within the Th2 lineage, with distinct subpopulations defined by unique surface markers and cytokine profiles. Of particular interest are pathogenic Th2 subsets, referred to as peTh2, Tpath2, or Th2A, that exhibit specialised effector functions and actively drive allergic disease. These pathogenic Th2 (pTh2) cells have been identified across a wide range of human allergic conditions, including conjunctivitis, allergic rhinitis, chronic rhinosinusitis, atopic dermatitis, IgE-mediated food allergy, and eosinophilic gastrointestinal disorders such as eosinophilic esophagitis, underscoring their broad clinical relevance. The molecular requirements for early pTh2 differentiation, as well as the transcriptional networks and epigenetic mechanisms that regulate their maturation, remain incompletely understood. Moreover, pTh2 cells themselves display considerable heterogeneity, circulating in the blood, and residing in secondary lymphoid organs, and peripheral tissues. This review highlights recent advances in the heterogeneity, differentiation, and molecular regulation of pTh2 cells, with a particular focus on their roles in eosinophilic asthma. We review the signalling pathways that drive pTh2 differentiation, their transcriptional and epigenetic regulation, and the diverse subpopulations they encompass. These insights offer a foundation for developing targeted therapies to mitigate type 2-driven allergic inflammation.

Incomplete genotype-phenotype correlations challenge the management of non-SCID FOXN1 immunodeficiency. We describe the detailed clinical course of three distinct newborns with four novel FOXN1 mutations identified by TREC-NBS. For comprehensive immune characterization advanced flow cytometry-based immunophenotyping was employed alongside high-resolution single-cell RNA sequencing. In our cohort, we detected heterozygous FOXN1 mutations in P1 (c.1178delG; p.Gly393Alafs*157) and P2 (c.830+1G>T; p.?), and compound heterozygous FOXN1-mutations in P3 (c.1318C>T; p.Gln440* and c.668T>G; p.?). Despite slow and partial recovery from T-cell lymphocytopenia in P3, clinical signs for classical ´nude SCID` were incomplete. Compared to a healthy cord blood control, a distinct B-cell population was identified in the FOXN1-deficient patients expressing immature B-cell markers and lower HLA-II mRNA levels. In summary, our cohort of three newborns with four novel FOXN1 variants highlights heterogeneous immunological courses and broader thymic dysfunction implications in this rare disease. Structured management strategies are essential for those identified by NBS-programs.

Objectives: Placentation is influenced by decidual Natural Killer (dNK)¹ cells. Defective placentation can lead to recurrent pregnancy loss (RPL)² or placenta accreta spectrum (PAS)³ disorders. Interaction between Programmed Cell Death Protein 1 (PD-1)⁴ on NK cells and Programmed Cell Death 1 Ligand (PD-L1)⁵ can alter the cytokine expression and cytotoxic potential of NK cells. This study compares dNK and PD-1⁺ dNK cell number, number of extravillous trophoblast (EVT)⁶ and PD-L1⁺ EVTs in two patient groups that experienced either RPL or PAS disorder to a control group.

Methods: For this retrospective case-control study tissue from in total 77 abortion samples (healthy women, women with RPL and PAS disorder) were immunohistochemically stained and the above-mentioned cells and receptors were counted and statistically compared between the three groups with either Kruskal Wallis or ANOVA and corresponding posthoc tests.

Results: The number of EVTs was reduced in the RPL group. There were more dNK and PD-1⁺dNK cells as well as a higher ratio of dNK cells compared to EVTs in the RPL group compared to the control group. Furthermore, the proportion of PD-L1⁺ cells in all EVT cells was higher in the RPL group compared to the control group.

Conclusion: Our findings show that both PD-1 and PD-L1 are differentially expressed on dNK cells and EVTs in the RPL group compared to the control group. Hereby suggesting that PD-1/PD-L1 interaction might influence NK cell function and therefore might be relevant for women experiencing RPL. This may be in terms of cytokine microenvironment or cell-cell-interaction.