Expert Review of Clinical Immunology最新文献

Introduction: Inborn errors of immunity with atopic phenotypes (IEIwA) represent a growing and complex subset of monogenic disorders that manifest primarily through severe and multifaceted allergic symptoms. These conditions bridge the fields of immunodeficiency and atopy, posing significant diagnostic and therapeutic challenges.

Areas covered: A literature search was performed via the online database PubMed, including all publication years 2021-2024, with the objective of identifying the most recent advancements in the field of IEIwA. This review provides an updated synthesis of the immunogenetic mechanisms underlying IEIwA, categorizing them by pathophysiological pathways, including impaired T cell receptor signaling, cytokine dysregulation, T cell repertoire restrictions, regulatory T cell dysfunction, metabolic abnormalities, and skin barrier defects. Advances in genomic technologies, especially whole-exome/genome sequencing, have refined the classification and recognition of these disorders. Moreover, the review highlights red flags that may aid in differentiating monogenic IEIwA from multifactorial allergic conditions. Emerging targeted therapies, such as monoclonal antibodies and small molecules, offer new avenues for precision medicine, though curative treatments like hematopoietic stem cell transplantation remain essential for many conditions.

Expert opinion: This review underscores the need for heightened awareness, early recognition, and tailored management strategies to improve outcomes in patients with IEIwA.

Introduction: Interleukin-17 (IL-17), a proinflammatory cytokine primarily produced by Th17 cells, plays a complex role in transplant immunology. Its involvement in graft-versus-host disease (GvHD) and immune regulation following hematopoietic cell transplantation (HCT) has garnered significant clinical interest, though findings remain inconsistent.

Areas covered: This narrative review summarizes clinical studies in human HCT recipients investigating IL-17 cytokine levels, Th17 cell activity, and IL-17 gene polymorphisms associated with transplant outcomes. While several studies report associations between elevated IL-17 or Th17 levels and increased GvHD risk, results vary widely due to differences in study design, patient populations, and measurement methods.

Expert opinion: IL-17 is a promising, though context-dependent, biomarker and therapeutic target in HCT. Its dual roles in promoting inflammation and supporting antimicrobial defense complicate therapeutic modulation. Future studies should focus on standardized assays, multi-omics approaches, and longitudinal designs to clarify its clinical utility. Tailored strategies that modulate IL-17 without impairing immune reconstitution or graft-versus-leukemia effects are likely to guide future interventions.

Introduction: T regulatory cells (Tregs) are key modulators of the immune system with dual roles. While protective against autoimmunity, Tregs can exhibit immunosuppressive capabilities, allowing the tumor to evade immune recognition and destruction, and favoring tumor progression. Targeting Tregs to reduce their immunosuppressive ability offers a promising strategy to boost anti-tumor immunity and improve cancer treatment outcomes.

Areas covered: This review explores the role of Tregs in the immune system, delves into their contribution to cancer and tumor progression, and highlights therapeutic strategies targeting Tregs, along with innovative delivery systems.

Expert opinion: Targeting tumor-infiltrating regulatory T cells (Tregs) represents a promising but complex approach in cancer immunotherapy. However, its success is limited by the risk of autoimmunity, inefficient intratumoral delivery, and patient immune heterogeneity. Precision strategies integrating biomarker-guided stratification, single-cell, and spatial profiling can improve selectivity and therapeutic outcomes. Identifying tumor-specific Treg markers and distinguishing stable, suppressive Tregs from more plastic or 'fragile' subsets are essential for advancing targeted immunotherapies. Partial functional reprogramming of tumor-resident Tregs, rather than their complete depletion, offers a strategy to weaken their suppressive capacity while retaining peripheral immune regulation, thus promoting local anti-tumor responses without disrupting tolerance.

Background: In response to the clinical dilemma of insufficient immune treatment response rate for lung adenocarcinoma (LUAD), this study aims to analyze the regulatory mechanism of the TCF3/VEGFA axis on CD8⁺ T cells' function.

Research design and methods: Bioinformatics analysis predicted the upstream transcription factors of VEGFA. Dual luciferase and ChIP assays verified the binding relationship between VEGFA and TCF3. WB detected the expression of VEGFA, NF-κB-related markers and PD-L1. Flow cytometry and immunofluorescence detected the expression of PD-L1. The cytotoxicity efficiency of CD8⁺ T cells was evaluated in a co-cultivation system. A subcutaneous LUAD mouse model was constructed to verify the role of TCF3/VEGFA in vivo.

Results: VEGFA was transcriptionally activated by its upstream transcription factor TCF3 (p < 0.05). Overexpressing TCF3 weakened the inhibitory effect of VEGFA knockdown on NF-κB-related markers and PD-L1 expression and the promotion of CD8⁺ T cell cytotoxicity (p < 0.05). in vivo experiments also confirmed that overexpressing TCF3 reversed the anti-tumor effect of VEGFA knockdown (p < 0.05).

Conclusions: This article reveals that the TCF3/VEGFA axis enhances the expression of PD-L1 in LUAD by activating the NF-κB signaling pathway, thereby weakening the cytotoxicity of CD8⁺ T cells.

Introduction: Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipids, immune cells, and fibrous components within the arterial wall. While traditionally considered a lipid-driven process, growing evidence suggests that immune mechanisms play a central role in all stages of atherogenesis.

Areas covered: This review summarizes the most relevant evidence supporting the immunoinflammatory basis of plaque development, progression, and destabilization. Both innate and adaptive immune responses contribute to endothelial dysfunction, immune cell recruitment, cytokine production, and the activation of inflammasome pathways, which amplify vascular inflammation. Crucially, the interplay between inflammation and thrombosis, termed thromboinflammation, plays a pivotal role in plaque instability and clinical events.

Expert opinion: We critically examine the limitations of the classic dichotomy between stable and unstable plaques, proposing instead a tripartite classification: active, dormant, and inactive plaques, analogous to the states of volcanic activity. Even clinically 'stable' plaques may exhibit silent yet ongoing immunometabolic and thromboinflammatory activity, contributing to residual cardiovascular risk. Advanced imaging, molecular diagnostics, and inflammation-sensitive biomarkers (e.g. high-sensitivity C-reactive protein, IL-6) can help detect subclinical plaque activity. Finally, the concept of 'thromboinflammaging' emphasizes the impact of age-related immune dysregulation on vascular pathology. This evolving paradigm supports immunomodulation as a cornerstone in precision cardiovascular medicine.

Background: Chronic nonbacterial osteomyelitis (CNO) is an autoinflammatory bone disease characterized by sterile bone inflammation. While monogenic causes are rare and typically present with early-onset, distinct skin or lytic bone lesions, the contribution of COX-pathway genes remains underexplored. TBXAS1 gene variants are classically associated with Ghosal hematodiaphyseal dysplasia (GHDD), which causes osteosclerosis and hematologic abnormalities.

Research design and methods: In this single-center, cross-sectional study, whole-exome sequencing first revealed the TBXAS1 variants in the index case, a 6-year-old boy with multifocal CNO and good clinical response to NSAIDs. Afterward, we performed next-generation sequencing (NGS) of the TBXAS1 gene in a single-center CNO cohort.

Results: Among 16 patients within the CNO cohort, NGS revealed two siblings with the same variants who were also presented with CNO, but without signs of osteosclerosis or hematologic involvement.

Conclusions: These findings suggest a potential link between TBXAS1 deficiency and a distinct, milder CNO phenotype potentially mediated by the COX pathway. However, it remains uncertain whether TBXAS1 mutations define a new CNO subtype or represent an attenuated form of GHDD. Further functional and genetic studies targeting COX-pathway-related genes are needed to clarify the role of TBXAS1 in the pathogenesis of CNO and to identify novel disease mechanisms.

Introduction: Difficult-to-treat psoriatic arthritis (D2T-PsA) is increasingly recognized as a complex clinical entity characterized by persistent disease burden despite multiple targeted therapies. Its identification is essential to improve patient outcomes and to guide the development of new therapeutic strategies.

Areas covered: In this perspective article, we discuss the evolving concept of D2T-PsA, including its epidemiology, clinical characterization, and underlying pathophysiological mechanisms. We highlight the role of gender differences, psychosocial comorbidities, and central sensitization in shaping disease persistence and patient-reported impact. We also examine the limitations of current disease activity indices (DAPSA, PsAID, PASDAS) in capturing heterogeneity and the need for multidimensional frameworks. A structured literature search was conducted in PubMed/MEDLINE and Scopus databases (January 2020-June 2025), restricted to English-language publications, using combinations of the terms psoriatic arthritis, difficult-to-treat, refractory, and difficult-to-manage. Additional references were identified from conference abstracts and relevant bibliographies.

Expert opinion: Recognizing D2T-PsA as a distinct, multifactorial entity is critical to advancing personalized medicine. Future directions will involve harmonizing EULAR and GRAPPA frameworks, integrating biomarker discovery, digital tools, and adaptive trial designs, and embedding patient perspectives. This multidimensional approach is expected to transform treatment from empirical cycling toward precision care in psoriatic arthritis.

Introduction: In inflammatory bowel diseases (IBD), human intestinal myofibroblasts (HIMF) gets activated due to chronic inflammation and start accumulating excessive extracellular matrix (ECM). ECM drives the significant clinical problem of intestinal fibrosis and stricture formation in Crohn's disease (CD) and Ulcerative colitis (UC) patients that require surgical intervention in a large group of the population.

Areas covered: In this review, we delineate the role of transglutaminase 2 (TG2), a matrix bound, calcium (Ca) dependent enzyme, as an important effector in the pathogenesis of chronic inflammatory diseases. We discuss the role of TG2 in fibrotic diseases with a focus on intestinal fibrosis and TG2 as a potential target for therapy of stricturing CD. This review additionally covers the progress in our mechanistic understanding of TG2 as a marker and driver for intestinal fibrosis and stricture formation in IBD patients.

Expert opinion: TG2 may play a central role in promoting inflammation independent progression of fibrosis, potentially explaining the lack of efficacy of traditional anti-inflammatory drugs in fibrotic diseases. The anti-fibrotic potential of TG2 specific inhibitors in stricturing Crohn's disease are just starting to be explored. Further investigations are needed to identify novel mechanisms for TG2 specific inhibitors in the intestine.

Introduction: IgG4-related disease (IgG4-RD) is a chronic immune-mediated fibroinflammatory disorder characterized by dense lymphoplasmacytic infiltration and storiform fibrosis, often resulting in organ dysfunction. Although glucocorticoids provide initial clinical improvement, relapse is common, underscoring the need for targeted therapies. B-cell depletion therapy has emerged as a promising approach, shedding light on the roles of plasmablasts and cytotoxic T lymphocytes in disease pathogenesis.

Areas covered: This review summarizes recent advances in immunological mechanisms of IgG4-RD, focusing on plasmablasts, activated B cells, cytotoxic T lymphocytes, T follicular helper (Tfh) cells, macrophages, dendritic cells, other immune cells, and fibroblasts. We highlight how single-cell RNA sequencing and highly multiplex immunofluorescence have uncovered novel immune subsets and their interactions. These technologies have identified previously unrecognized populations, including GZMK⁺ cytotoxic Tfh cells, MKI67⁺ B cells, and double-negative type 3 B cells, offering unprecedented resolution into disease mechanisms.

Expert opinion: Single-cell technologies have revolutionized our understanding of IgG4-RD immunopathogenesis and potentially revealed disease heterogeneity across clinical phenotypes. These insights hold promise for biomarker development and precision therapeutic strategies. Future directions should include spatial transcriptomics and proteomics, improved animal models, and translational efforts to bridge mechanistic discoveries with targeted treatment for this complex multi-organ disease.

Background: Aims of this study were to evaluate the serum level of autoantibodies against G-protein-coupled receptors for Angiotensin II type 1 (anti-AT1R) and endothelin receptor type A (anti-ETAR) in systemic sclerosis (SSc) patients and healthy controls (HC) and to evaluate the associations of these antibodies with microvascular complication of SSc, such as digital ulcers (DUs), subclinical renal vasculopathy and early pulmonary vasculopathy.

Research design and methods: Sixty-four SSc patients and 20 HC were tested for anti-AT1R and anti-ETAR.

Results: SSc patients had higher anti-AT1R [7.78 ng/ml (IQR 6.14;12.16) vs 3.25 ng/ml (IQR 2.60;4.70), p < 0.001] and anti-ETAR [0.16 OD (IQR 0.14;0.17) vs 0.10 OD (IQR 0.10;0.12), p < 0.001] than HC. SSc patients with DUs had higher anti-AT1R [10.79 ng/ml (IQR 7.32;14.15) vs 6.76 ng/ml (IQR 5.88;7.88), p < 0.001] and anti-ETAR [0.16 OD (IQR 0.15;0.18) vs 0.15 OD (IQR 0.13;0.16), p < 0.01] than SSc patients without DUs. We found a positive correlation between renal resistive index (RRI) and anti-AT1R (r = 0.357, p < 0.01) or anti-ETAR (r = 0.442, p < 0.001) and a negative correlation between tricuspid annular plane systolic excursion/pulmonary arterial systolic pressure (TAPSE/sPAP) and anti-AT1R (r = -0.436, p < 0.001) or anti-ETAR (r =  -0.334, p < 0.01).

Conclusions: Anti-AT1R and anti-ETAR may play a pathogenic role in endothelial dysfunction.