Clinical Reviews in Allergy & Immunology最新文献

The recurrence of inflammatory skin diseases represents a significant challenge in clinical practice, primarily mediated by immune memory. In inflammatory skin diseases, immune memory encompasses adaptive immune memory, trained immunity, and inflammatory memory, which are conducted by adaptive immune cells, innate immune cells, and structural cells, respectively. Adaptive immune memory is established through gene rearrangement, leading to antigen-specific immune memory. In contrast, trained immunity and inflammatory memory are formed through epigenetic and metabolic reprogramming, resulting in non-specific immune memory. Different types of immune memory work synergistically to aggravate localized inflammation in recurrent inflammatory skin diseases. However, immune memory in specific cells, such as macrophages, may also play an immunoregulatory role under certain conditions. We reviewed the immune memory mechanisms in different inflammatory skin diseases and discussed future strategies for targeted regulation of the molecular mechanisms underlying immune memory, such as targeted biological agents and epigenetic modifications. Additionally, we explored the potential for precise regulation of immune memory and its application in personalized treatment for recurrent inflammatory skin diseases.

Melanocytes are essential for regulating pigmentation and providing photoprotection in human skin. Originating from neural crest cells, these cells migrate to the basal layer of the epidermis and hair follicles during embryogenesis. Melanosomes, the specialized, membrane-bound organelles are essential for melanin synthesis. Beyond their role in pigmentation, melanocytes exhibit complex immune functions, expressing a variety of immune-related markers and receptors, such as pattern recognition receptors (PRRs), major histocompatibility complex class II (MHC-II) molecules, CD40, intercellular adhesion molecule 1 (ICAM-1), and programmed death-ligand 1 (PD-L1). These receptors allow melanocytes to detect environmental signals and engage in the innate immune response. Furthermore, melanocytes release various immunomodulatory substances, including proinflammatory cytokines, chemokines, and damage-associated molecular patterns (DAMPs), contributing to immune regulation. The immune functions of melanocytes are significantly influenced by external factors such as ultraviolet radiation (UVR), the microbiome, and oxidative stress. In different skin diseases, these immune functions may vary. For example, vitiligo, a common hypopigmentary disorder, is primarily driven by an autoimmune response targeting melanocytes, giving rise to depigmentation and the appearance of white patches. In contrast, melanoma, a form of skin cancer that arises from melanocytes, is closely linked to UV exposure. This review highlights the diverse immunobiological functions of melanocytes and their implications in dermatology.

N6-methyladenosine (m⁶A), a prevalent and essential RNA modification, serves a key function in driving autoimmune disease pathogenesis. By modulating immune cell development, activation, migration, and polarization, as well as inflammatory pathways, m⁶A is crucial in forming innate defenses and adaptive immunity. This article provides a comprehensive overview of m⁶A modification features and reveals how its dysregulation affects the intensity and persistence of immune responses, disrupts immune tolerance, exacerbates tissue damage, and promotes the development of autoimmunity. Specific examples include its contributions to systemic autoimmune disorders like lupus and rheumatoid arthritis, as well as conditions that targeting specific organs like multiple sclerosis and type 1 diabetes. Furthermore, this review explores the therapeutic promise of target m⁶A-related enzymes ("writers," "erasers," and "readers") and summarizes recent advances in intervention strategies. By focusing on the mechanistic and therapeutic implications of m⁶A modification, this review sheds light on its role as a promising tool for both diagnosis and treatment in autoimmune disorders, laying the foundation for advancements in customized medicine.

Historically, lactate has been considered merely a metabolic byproduct. However, recent studies have revealed that lactate plays a much more dynamic role, acting as an immune signaling molecule that influences cellular communication, through the process of "lactate shuttling." Lactylation, a novel post-translational modification, is directly derived from lactate and represents an emerging mechanism through which lactate exerts its effects on cellular function. It has been shown to directly affect immune cells by modulating the activation of pro-inflammatory and anti-inflammatory pathways. This modification influences the expression of key immune-related genes, thereby impacting immune cell differentiation, cytokine production, and overall immune response. In this review, we focused on the role of lactate and lactylation in the dysregulation of immune responses in psoriasis and its relapse. Additionally, we discuss the potential applications of targeting lactate metabolism and lactylation modifications in the treatment of psoriasis, alongside the investigation of artificial intelligence applications in advancing lactate and lactylation-focused drug development, identifying therapeutic targets, and enabling personalized medical decision-making. The significance of this review lies in its comprehensive exploration of how lactate and lactylation contribute to immune dysregulation, offering a novel perspective for understanding the metabolic and epigenetic changes associated with psoriasis. By identifying the roles of these pathways in modulating immune responses, this review provides a foundation for the development of new therapeutic strategies that target these mechanisms.

Uveitis involves a complex interplay of immune cell infiltration and cytokine imbalances, with Th17 cells playing a central role in this process. Th17 cells contribute to disease pathogenesis by promoting inflammation, recruiting additional immune cells, and directly damaging retinal tissues. This review discusses the current knowledge on therapeutic strategies targeting Th17-related cytokines, including cytokine blockade, small molecule inhibitors, and immunomodulatory approaches. Traditionally, Th17-related cytokines have been viewed as pro-inflammatory agents in uveitis. However, emerging research has highlighted the capacity of the Th17 response to express immunoregulatory cytokines, notably IL-10, IL-24, and TGF-β. This suggest that the Th17 response may have a dualistic role that includes immune suppression. In this review, we will discuss this paradoxical nature of Th17 cells in immune regulation and inflammation that they can both promote and mitigate uveitis. We expected that a deeper understanding of these mechanisms is imperative for the innovation of novel therapeutics that could consider the dual role of Th17 response in the pathogenesis of uveitis. By finely tuning the Th17 response to preserve retinal integrity and function, these new treatments could bring significant benefits to patients with uveitis. This review aims to shed light on the complexities of the Th17 response in uveitis and its implications for future therapeutic strategies.

Interleukin (IL)-17, a pro-inflammatory cytokine, plays a pivotal role in immune regulation by bridging innate and adaptive responses. Beyond its canonical involvement in T helper-17 cells-mediated immunity, IL-17 contributes significantly to the pathogenesis of systemic autoinflammatory diseases (SAIDs) including Familial Mediterranean Fever (FMF), nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3)-associated autoinflammatory diseases, and synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome. Dysregulated IL-17 signaling drives inflammasome activation, neutrophil recruitment, and chronic tissue inflammation. IL-17 inhibitors have demonstrated efficacy in refractory SAIDs, though challenges such as increased infection risks, paradoxical inflammatory reactions, and uncertainties regarding long-term safety persist. Currently, there is insufficient data to support the use of IL-17 inhibitors as first-line treatments, and their role in managing SAIDs is yet to be fully defined. This review highlights the mechanistic role of IL-17 in SAIDs and emerging therapeutic strategies, including IL-17-targeted monotherapies and combination approaches with IL-1 or tumor necrosis factor (TNF) inhibitors. Future research should focus on biomarker development, combination therapies, and long-term studies to optimize the safety and efficacy of IL-17-targeted therapies in SAIDs.

The pathology of urticaria is complex. Recently, researchers have widely focused on the role that the coagulation/fibrinolysis system plays in the pathology of urticaria. The potential of coagulation/fibrinolysis biomarkers as disease severity or treatment response biomarkers remains uncertain, lacking comprehensive analysis in previous studies. Hence, we performed a scoping review to thoroughly analyze coagulation/fibrinolysis biomarkers that may predict disease progression and treatment response of urticaria. Data from 71 studies showed that chronic spontaneous urticaria (CSU) was the most-studied subtype (39 articles), with D-dimers being the most researched marker (56 articles). Twenty-one biomarkers were investigated, and ten biomarkers were significantly correlated with disease severity. Specifically, D-dimers (26 articles) and prothrombin fragment 1 + 2 (F₁₊₂) (12 articles) plasma levels increased with exacerbation and decreased with remission. Biomarkers such as D-dimer also correlated significantly with inflammatory cytokines and complement, suggesting interactions among coagulation, immunity, and inflammation in the pathology of urticaria. While these biomarkers may predict treatment response, more evidence is needed. Additionally, anticoagulants such as warfarin, heparin sodium and tranexamic acid have been proved effective for urticaria. This review emphasizes that some coagulation/fibrinolysis biomarkers (such as D-dimer and F₁₊₂) may be not only indicators of disease status but also potential predictors of treatment response. It aims to assist researchers and practitioners in gaining a better understanding of the close relationships among coagulation/fibrinolysis biomarkers, the condition of urticaria (especially chronic urticaria, CU), and its prognosis. It also provides new directions for future research on exploring treatment methods via the coagulation/fibrinolysis pathways.

Hereditary angioedema (HAE) has been recognized for almost 150 years. The newest form of HAE, where C1 inhibitor levels are normal (HAE-nC1INH), was first described in 2000. Over the last two decades, new types of apparent non-mast cell-mediated angioedema with normal quantity and activity of C1INH have been described, in some cases with proven genetic pathogenic variants that co-segregate with angioedema expression within families. Like HAE due to C1INH deficiency, HAE-nC1INH patients are at risk of serious morbidity and mortality. Therefore, proactive management and treatment of HAE-nC1INH patients after an expert physician diagnosis is critically important. The underlying pathophysiology responsible for the angioedema has also been clarified in some of the HAE-nC1INH types. While several clinical guidelines and practice parameters including HAE-nC1INH have been published, we have made substantial progress in our understanding encompassing diagnostic criteria, pathophysiology, and treatment outcomes. HAE International (HAEi) and the US HAE Association (HAEA) convened a symposium of global HAE-nC1INH experts to synthesize our current knowledge in the area. Given the paucity of high-level evidence in HAE-nC1INH, all recommendations are based on expert opinion. This review and expert opinion on the best practice approach to diagnosing and treating HAE-nC1INH will support physicians to better manage patients with HAE-nC1INH.

22q11.2 deletion and duplication syndromes are complex genetic syndromes composed of a wide spectrum of clinical manifestations, mostly affecting cardiovascular, endocrine, neurodevelopmental, and immune functioning. 22q11.2 deletion syndrome (22q11.2 DS) is more common and widely recognized compared to the duplication counterpart. Most of the literature focuses on delineating the genetic, molecular, and clinical impact of 22q11.2 DS, and less information focuses on the 22q11.2 duplication syndrome (22q11.2 DupS). We will cover both variants in this review and shed light on the less reported atypical 22q11.2 deletions and duplications. Variants in multiple genes in the 22q11.2 region, especially the TBX1 and DGCR8 genes, have been linked to the clinical phenotypes of 22q11.2 DS and 22q11.2 DupS. Variations in genes on the non-deleted homologous chromosome in the critical 22q11.2 region can further influence phenotypes by revealing recessive diseases. This effect has been documented for several genes in this area, such as SNAP29 and GP1BB. Neural crest development is usually impacted leading to various cardiovascular defects including Tetralogy of Fallot and truncus arteriosus. It can also cause palatal defects, especially velopharyngeal deficiency, considered another hallmark of 22q11DS. Individuals may also present with hypocalcemia and thyroid dysfunction due to impaired parathyroid gland formation and thyroid dysgenesis, respectively. Immunodeficiencies result from impaired T-cell development due to thymic hypoplasia, also a consequence of abnormal neural crest development. Humoral defects are also now increasingly recognized in these individuals. Psychiatric, neurocognitive, and developmental features are common, but severity varies across affected individuals. Other systems like the genitourinary, gastrointestinal, skeletal, and hematological are also involved. Monitoring and treating all the possible clinical manifestations require a multi-disciplinary approach to effectively address the plethora of clinical findings. The complex nature of the treatment guidelines reflects the clinical heterogeneity of these genetic variations. Further research is required to continue exploring the mechanisms relating to the impact of genetic aberrations in the 22q11.2 region on various clinical parameters. This will hopefully guide future updates to the current clinical practice guidelines to continue tailoring them to the individual needs of each affected person.

Androgenetic alopecia (AGA), a leading cause of progressive hair loss, affects up to 50% of males aged 50 years, causing significant psychological burden. Current treatments, such as anti-androgen drugs and minoxidil, show heterogeneous effects, even with long-term application. Meanwhile, the large-scale adoption of other adjuvant therapies has been slow, partly due to insufficient mechanistic evidence. A major barrier to developing better treatment for AGA is the incomplete understanding of its pathogenesis. The predominant academic consensus is that AGA is caused by abnormal expression of androgens and their receptors in individuals with a genetic predisposition. Emerging evidence suggests the contributing role of factors such as immune responses, oxidative stress, and microbiome changes, which were not previously given due consideration. Immune-mediated inflammation and oxidative stress disrupt hair follicles' function and damage the perifollicular niche, while scalp dysbiosis influences local metabolism and destabilizes the local microenvironment. These interconnected mechanisms collectively contribute to AGA pathogenesis. These additional aspects enhance our current understanding and confound the conventional paradigm, bridging the gap in developing holistic solutions for AGA. In this review, we gather existing evidence to discuss various etiopathogenetic factors involved in AGA and their possible interconnections, aiming to lay the groundwork for the future identification of therapeutic targets and drug development. Additionally, we summarize the advantages and disadvantages of AGA research models, ranging from cells and tissues to animals, to provide a solid basis for more effective mechanistic studies.