Rosacea is a complex inflammatory condition characterized by papulopustular lesions and erythema on the central face for which there is no cure. The development of rosacea is influenced by both external triggers and genetics, but the common pathophysiology is overactivation of the immune system. Here, we review the current data on proinflammatory cytokines and dysregulation of the neurovascular system as targetable components of rosacea. Amelioration of cutaneous and gastrointestinal dysbiosis and other external factors impacts the immune state and has been observed to improve rosacea. While multiple treatments exist, many patients do not achieve their goals for rosacea control and highlights an unmet need for dermatologic care. Current interventions encompass topical/oral drugs, light devices, and avoidance of triggers management. Additional understanding of the underlying pathogenesis may help us develop novel targeted therapeutic strategies to improve rosacea.

Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory disease caused by mutations in effectors and regulators of cytotoxicity in cytotoxic T cells (CTL) and natural killer (NK) cells. The complexity of the immune system means that in vivo models are needed to efficiently study diseases like HLH. Mice with defects in the genes known to cause primary HLH (pHLH) are available. However, these mice only develop the characteristic features of HLH after the induction of an immune response (typically through infection with lymphocytic choriomeningitis virus). Nevertheless, murine models have been invaluable for understanding the mechanisms that lead to HLH. For example, the cytotoxic machinery (e.g., the transport of cytotoxic vesicles and the release of granzymes and perforin after membrane fusion) was first characterized in the mouse. Experiments in murine models of pHLH have emphasized the importance of cytotoxic cells, antigen-presenting cells (APC), and cytokines in hyperinflammatory positive feedback loops (e.g., cytokine storms). This knowledge has facilitated the development of treatments for human HLH, some of which are now being tested in the clinic.

In vitro studies have shown that deletion of nef and deleterious mutation in the Nef dimerization interface attenuates HIV replication and associated pathogenesis. Humanized rodents with human immune cells and lymphoid tissues are robust in vivo models for investigating the interactions between HIV and the human immune system. Here, we demonstrate that nef deletion impairs HIV replication and HIV-induced immune dysregulation in the blood and human secondary lymphoid tissue (human spleen) in bone marrow-liver-thymus-spleen (BLTS) humanized mice. Furthermore, we also show that nef defects (via deleterious mutations in the dimerization interface) impair HIV replication and HIV-induced immune dysregulation in the blood and human spleen in BLTS-humanized mice. We demonstrate that the reduced replication of nef-deleted and nef-defective HIV is associated with robust antiviral innate immune response, and T helper 1 response. Our results support the proposition that Nef may be a therapeutic target for adjuvants in HIV cure strategies.

BACKGROUND: Immune thrombocytopenia (ITP) and Evans syndrome (ES) are manifestations of immune dysregulation. Genetic variants in immune-related genes have been identified in patients with ITP and especially ES. We aimed to explore familial autoimmunity in patients with ITP and ES to understand possible contributions to chronicity.
METHODS: We assessed family history in two ways: via patient report for ITP and ES and by population-based analysis using the Utah Population Database (UPDB) for ITP. A total of 266 patients with ITP and 21 patients with ES were identified via chart review, and 252 of the 266 patients with ITP were also identified in the UPDB.
RESULTS: Chart review showed familial autoimmunity in 29/182 (15.9%) and 25/84 (29.8%) of patients with newly diagnosed+persistent (nd+p) ITP and chronic ITP (cITP), respectively, (p = .009). The UPDB analysis revealed that autoimmunity in relatives of patients with nd+pITP was higher than in relatives of controls (odds ratio [OR]: 1.69 [1.19-2.41], p = .004), but was not significantly increased in relatives of patients with cITP (OR 1.10 [0.63-1.92], p = .734). Incomplete family history in medical records likely contributed to the observed discrepancy.
CONCLUSIONS: The findings suggest that familial autoimmunity may have a stronger association with the development of ITP rather than its duration. Twelve (57.1%) patients with ES reported autoimmunity in their relatives. UPDB analysis was omitted due to the small number of patients with ES. The use of population databases offers a unique opportunity to assess familial health and may provide clues about contributors to immune dysregulation features within families.

There are approximately 500 congenital disorders that impair immune cell development and/or function. Patients with these disorders may present with a wide range of symptoms, including increased susceptibility to infection, autoimmunity, autoinflammation, lymphoproliferation, and/or atopy. Flow cytometry-based immune phenotyping of T and B lymphocytes plays an essential role in the evaluation of patients with these presentations. In this review, we describe the clinical utility of flow cytometry as part of a comprehensive evaluation of immune function and how this testing may be used as a diagnostic tool to identify underlying aberrant immune pathways, monitor disease activity, and assess infection risk.

Dengue infection is caused by the dengue virus (DENV) and is transmitted to humans by infected female Aedes aegypti and Aedes albopictus mosquitoes. There are nearly 100 million new dengue cases yearly in more than 120 countries, with a five-fold increase in incidence over the past four decades. While many patients experience a mild illness, a subset suffer from severe disease, which can be fatal. Dysregulated immune responses are central to the pathogenesis of dengue, and haematologic manifestations are a prominent feature of severe disease. While thrombocytopaenia and coagulopathy are major causes of bleeding in severe dengue, leucocyte abnormalities are emerging as important markers of prognosis. In this review, we provide our perspective on the clinical aspects and pathophysiology of haematologic manifestations in dengue. We also discuss the key gaps in our current practice and areas to be addressed by future research.

The interferon regulatory factor 2 binding protein 2 (IRF2BP2) is a transcriptional regulator, functioning a transcriptional corepressor by interacting with the interferon regulatory factor-2. The ubiquitous expression of IRF2BP2 by diverse cell types and tissues suggests its potential involvement in different cell signalling pathways. Variants inIRF2BP2have been recently identified to cause familial common variable immunodeficiency (CVID) characterized by immune dysregulation. This study investigated three rare novel variants inIRF2BP2, identified in patients with primary antibody deficiency and autoimmunity by whole exome-sequencing (WES). Following transient overexpression of EGFP-fused mutants in HEK293 cells and transfection in Jurkat cell lines, we used fluorescence microscopy, real-time PCR and Western blotting to analyze their effects on IRF2BP2 expression, subcellular localization, nuclear translocation of IRF2, and the transcriptional activation of NFκB1(p50). We found altered IRF2BP2 mRNA and protein expression levels in the mutants compared to the wild type after IRF2BP2 overexpression. In confocal fluorescence microscopy, variants in the C-terminal RING finger domain showed an irregular aggregate formation and distribution instead of the expected nuclear localization compared to the variants in the N-terminal zinc finger domain and their wildtype counterpart. Immunoblotting revealed an impaired IRF2 and NFκB1 (p50) nuclear localization in the mutants compared to the IRF2BP2 wildtype counterpart. LPS stimulation reduced IRF2BP2 mRNA expression in the variants compared to the wild type. Our findings significantly contribute to understanding the clinical significance of IRF2BP2 mutations in the pathogenesis of immunodeficiency and immune dysregulation. We observed impairment of the nuclear translocation of IRF2 and NFκB1 (p50) due to the upregulation of IRF2BP2, potentially affecting specific gene expressions involved in immune regulation.

To reveal the effects of waterborne copper stress on gene expression changes, molecular pathways, and physiological functions in Coilia nasus, juvenile fish were equally divided into two experimental groups, and the copper levels were 1.61 ± 0.03 mg/L (copper-exposed group) and 0 mg/L (control group), respectively. After 4 h, gill tissue samples were collected for transcript sequencing analysis, and two libraries were constructed from the copper treatment group (Cu) and the control group (C) and sequenced using Illumina sequencing technology. The results showed that approximately 40.2-46.0 M clean reads were obtained from each library, and the percentage of uniquely mapped transcripts ranged from 80.57 to 84.93%. A total of 3915 differentially expressed genes (DEGs) were identified under waterborne copper stress, among which 1300 genes were up-regulated, and 2615 genes were down-regulated. Twelve DEGs were randomly selected for quantitative RT-PCR (qRT-PCR) analysis, and the results confirmed that the transcriptome analysis was reliable. Furthermore, the DEGs were subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and the results showed that most of the DEGs were involved in metabolic pathways, including steroid biosynthesis, glutathione metabolism, and peroxisome proliferator-activated receptor (PPAR) signaling pathways. Furthermore, due to the waterborne copper levels, gsk-3β was significantly up-regulated, while other metabolism-related genes (tor, pi3k, lpl, aqp7, fabp3) were significantly down-regulated. In addition, the copper-exposed group significantly reduced the expression of some immunity genes (ifn-γ, stat1, cxcl10, and tgf-β), and enhanced the expression of il-1β and tnf-α. In summary, these results indicated that copper causes metabolic disorders and insufficient energy supply in the body, and induces oxidative stress, which results in reduced immune functions.

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by immune system dysfunction that can lead to serious health issues and mortality. Recent investigations highlight the role of gut microbiota alterations in modulating inflammation and disease severity in SLE. This review specifically summaries the variations in gut microbiota composition across various murine models of lupus. By focusing on these differences, we aim to elucidate the intricate relationship between gut microbiota dysbiosis and the development and progression of SLE in preclinical settings.

OBJECTIVE: The majority of indeterminate pediatric acute liver failure (PALF) cases are secondary to immune dysregulation, labeled activated T-cell hepatitis (TCHep). We aimed to describe a cohort of children with acute severe hepatitis and PALF and define how clinical immune labs may help identify the TCHep group.
METHODS: Retrospective review of children with acute hepatitis and PALF between March 2020 and August 2022. Patients were classified as known diagnosis, indeterminate hepatitis (IND-Hep), or TCHep (defined by liver biopsy with predominant CD8 T-cell inflammation or development of aplastic anemia).
RESULTS: 124 patients were identified: 83 with known diagnoses, 16 with TCHep, and 25 with IND-Hep. Patients with TCHep had significantly increased median total bilirubin levels (7.5 mg/dL (IQR 6.8-8.9) vs 1.5 mg/dL (IQR 1.0-3.6), p < 0.0001), soluble interleukin-2 receptor levels (4512 IU/mL (IQR 4073-5771) vs 2997 IU/mL (IQR 1957-3237), p = 0.02), and percent of CD8+ T-cells expressing perforin (14.5 % (IQR 8.0-20.0) vs 1.0 % (IQR 0.8-1.0), p = 0.004) and granzyme (37.5 % (IQR 15.8-54.8) vs 4.0 % (IQR 2.5-5.5), p = 0.004) compared to IND-Hep patients. Clinical flow cytometry showed that TCHep patients had significantly increased percent CD8+ T cells (29.0 % (IQR 24.5-33.5) vs 23.6 % (IQR 19.8-25.8), p = 0.04) and HLA-DR+ (16.0 % (IQR 14.5-24.5) vs 2.7 (1.8-5.3), p < 0.001) compared to IND-Hep patients indicative of increase in CD8+ T cells that are activated.
CONCLUSIONS: Peripheral blood clinical immune studies demonstrate increased markers of CD8 T-cell activation, proliferation, and cytotoxic function for TCHep patients. These readily available immune function labs can be used to help distinguish patients with TCHep from those with other causes. This provides a non-invasive tool for early detection of potential TCHep before progression to liver failure.