Clinical and experimental immunology最新文献

Recognizing the need for innovative therapeutic approaches in the management of autoimmune diseases, our current investigation explores the potential of autologous extracellular vesicles (EVs), derived from the blood of rheumatoid arthritis patients, to serve as therapeutic vectors to improve drug delivery. We found that circulating EVs derived from arthritic mice (collagen-induced arthritis model) express the joint/synovia homing receptor, αVβ3 integrin. Importantly, both autologous labeled EVs, derived from the blood of arthritic mice (collagen antibody-induced arthritis model) and healthy mice-derived EVs, exhibit targeted migration toward inflamed synovia without infiltrating healthy joints, as demonstrated by an in vivo imaging system. Furthermore, EVs derived from plasma of rheumatoid arthritis patients show an overexpression of αV integrin and are effectively taken up by lipopolysaccharides/tumor necrosis factor alpha (TNFα)-induced activated human synovial cell line in vitro, although interestingly the uptake of healthy EVs was found to be significantly increased. Notably, arthritic mice-derived circulating EVs, strongly express murine glucose transporter 1, which in turn can facilitate their binding to glucose-coated gold nanoparticles (previously shown to be conjugated with drugs for improved drug delivery). The significance of our results, lies in the identification of autologous tissue homing EVs as promising vectors, offering a novel avenue to enhance targeted delivery of anti-inflammatory/rheumatic drugs in rheumatoid arthritis treatment.

Introduction: STAT3 orchestrates crucial immune responses through its pleiotropic functions as a transcription factor. Patients with germline monoallelic dominant negative or hypermorphic STAT3 variants, who present with immunodeficiency and/or immune dysregulation, have revealed the importance of balanced STAT3 signaling in lymphocyte differentiation and function, and immune homeostasis. Here, we report a novel missense variant of unknown significance in the DNA binding domain of STAT3 in a patient who experienced hypogammaglobulinemia, lymphadenopathy, hepatosplenomegaly, immune thrombocytopenia, eczema and enteropathy over a 35-year period.

Methods: In vitro demonstration of prolonged STAT3 activation due to delayed de-phosphorylation, and enhanced transcriptional activity, confirmed this to be a novel pathogenic STAT3 gain-of-function variant. Peripheral blood lymphocytes from this patient, and patients with confirmed STAT3 Gain-of-function Syndrome, were collected to investigate mechanisms of disease pathogenesis.

Results: B cell dysregulation was evidenced by a loss of class-switched memory B cells and a significantly expanded CD19hiCD21lo B cell population, likely influenced by a skewed CXCR3+ TFH population. Interestingly, unlike STAT3 dominant negative variants, cytokine secretion by activated peripheral blood STAT3 GOF CD4+ T cells and frequencies of Treg cells were intact, suggesting CD4+ T cell dysregulation likely occurs at sites of disease rather than the periphery.

Conclusion: This study provides an in-depth case study in confirming a STAT3 gain-of-function variant and identifies lymphocyte dysregulation in peripheral blood of patients with STAT3 Gain-of-function Syndrome. Identifying cellular biomarkers of disease provide a flow cytometric based screen to guide validation of additional novel STAT3 gain-of-function variants as well as provide insights into putative mechanisms of disease pathogenesis.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces pneumonia and acute respiratory failure in coronavirus disease 2019 (COVID-19) patients with inborn errors of immunity to type I interferon (IFN-I). The impact of SARS-CoV-2 infection varies widely, ranging from mild respiratory symptoms to life-threatening illness and organ failure, with a higher incidence in men than in women. Approximately 3-5% of critical COVID-19 patients under 60 and a smaller percentage of elderly patients exhibit genetic defects in IFN-I production, including X-chromosome-linked TLR7 and autosomal TLR3 deficiencies. Around 15-20% of cases over 70 years old, and a smaller percentage of younger patients, present with preexisting autoantibodies neutralizing type I interferons. Additionally, innate errors affecting the control of the response to type I interferon have been associated with pediatric multisystem inflammatory syndrome (MIS-C). Several studies have described rare errors of immunity, such as XIAP deficiency, CYBB, SOCS1, OAS1/2, and RNASEL, as underlying factors in MIS-C susceptibility. However, further investigations in expanded patient cohorts are needed to validate these findings and pave the way for new genetic approaches to MIS-C. This review aims to present recent evidence from the scientific literature on genetic and immunological abnormalities predisposing individuals to critical SARS-CoV-2 infection through IFN-I. We will also discuss multisystem inflammatory syndrome in children (MIS-C). Understanding the immunological mechanisms and pathogenesis of severe COVID-19 may inform personalized patient care and population protection strategies against future serious viral infections.

Granulomatosis with polyangiitis (GPA) is a B-cell-mediated, relapsing, autoimmune disease. There is a need for novel therapeutic approaches and relapse markers to achieve durable remission. B cells express immune regulatory molecules that modulate their activation and maintain tolerance. While recent studies show dysregulation of these molecules in other autoimmune diseases, data on their expression in GPA are limited. This study aimed to map the expression of surface immune regulatory molecules on circulating B-cell subsets in GPA and correlate their expression with clinical parameters. Immune regulatory molecule expression on circulating B-cell subsets was comprehensively examined in active GPA (n = 16), GPA in remission (n = 16), and healthy controls (n = 16) cross-sectionally using a 35-color B-cell-specific spectral flow cytometry panel. Our supervised and unsupervised in-depth analysis revealed differential expression of inhibitory and stimulatory immune molecules on distinct B-cell populations in GPA, with the most notable differences observed in active GPA. These differences include the upregulation of FcγRIIB on nonmature B cells, downregulation of CD21 and upregulation of CD86 on antigen-experienced B cells, and elevated CD22 expression on various populations. Additionally, we found a strong association between FcγRIIB, BTLA, and CD21 expression on specific B-cell populations and disease activity in GPA. Together, these findings provide novel insights into the immune regulatory molecule expression profile of B cells in GPA and could potentially form the foundation for new therapeutic approaches and disease monitoring markers.

HYCOs are hybrid molecules consisting of activators of the transcription factor Nrf2 conjugated to carbon monoxide (CO)-releasing moieties. These 'dual action' compounds (HYCOs) have been designed to mimic the activity of heme oxygenase-1 (HO-1), a stress inducible cytoprotective enzyme that degrades heme to CO which expression is regulated by Nrf2. HYCOs have recently shown efficacy in ameliorating experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. However, the mechanism(s) of action of HYCOs still remains to be fully investigated. Here, we assessed the effects of HYCO-3, a prototype of these hybrids, on myeloid-derived cells, microglial cells and T lymphocytes obtained from EAE-immunized mice. HYCO-3 exerted immunomodulatory effects on all the examined cell populations by inhibiting the generation of pro-inflammatory cytokines and nitric oxide, and downregulating antigen-presenting capacity of these cells. The observed effects support the view that HYCOs are promising candidates to be developed for the treatment of autoimmune and chronic inflammatory disorders.

Despite its wide use to treat various inflammatory diseases, infliximab becomes ineffective in some patients due to inadequate drug levels and production of anti-drug antibodies (ADA). The aim of this study was to compare the prevalence and ADA levels in a large cohort of patients. ADA and infliximab (IFX) through levels measured by enzyme-linked immunosorbent assay were collected from 505 patients within a period of 4 years. The results indicate that (i) 13.5% of patients produce ADA, (ii) male patients were more likely to produce ADA at levels above 10 000 ng/ml than female patients, (iii) ADA levels were lower when associated with immunosuppressant drugs, (iv) there was an inverse relationship between ADA presence and IFX detection, and (v) no correlation was observed between ADA levels and number of injections or brand of IFX administered. This study improves our understanding of the factors promoting IFX immunogenicity and highlights the need to develop personalized treatment strategies.

F-BAR domain only protein 1 (FCHO1) contributes as a critical component to an essential cellular process, clathrin-mediated endocytosis. Clathrin-mediated endocytosis involves cellular membrane invagination followed by cargo protein recruitment and adaptor protein assembly to form endocytic vesicles and maintains several cellular functions, such as signaling, differentiation, nutrition, absorption, and secretion. We aimed to determine the clinical/immunological findings of FCHO1 deficiency to generate an appropriate medical approach. We present clinical/immunological/genetic findings of two FCHO1 deficiency patients together with recently reported 17 patients. We found two different variants in the patients, one previously defined and one novel homozygous mutation [c.306C > A (p.Tyr102Ter)]. Recurrent sinopulmonary infections occurred in all patients, with viral (63.1%) and fungal (52.6%) infections frequently reported. Lymphopenia and CD4 + T cell lymphopenia are present in 77.7% (14/18) and 100% of patients, respectively. CD8+ T cell number is low in half. Hypogammaglobulinemia and low IgM are present in 83.3% (15/18) and 61.1% (11/18) of patients, respectively. Neurological disorders (Guillian-Barre Syndrome, Moya-Moya disease, encephalitis, and cranial infarction) are common [n = 6 (31.5%)]. Malignancy is present in four (21%) patients, three suffered from diffuse large B cell lymphoma, and one developed Hodgkin lymphoma. Additional clinical and laboratory results from more patients helped to define the characteristics of FCHO1 deficiency. The early application of molecular genetic analysis in CID patients is crucial. Since all transplanted patients were alive, allogeneic hematopoietic stem cell transplantation emerged as a potential curative therapy.

Introduction: To evaluate the characteristics of hematological parameters and peripheral inflammatory markers (PIMs) in migraine, including chronic migraine (CM) and episodic migraine (EM), and to explore their underlying mechanisms.

Method: A total of 88 subjects were enrolled, 58 with migraine (28 with CM and 30 with EM) and 30 healthy controls. All subjects were matched for age, gender, and body mass index, and peripheral blood was collected. Hematological parameters and PIMs were compared between migraineurs and healthy controls. The patients underwent hematological laboratory testing and calculated the PIMs. PIMs included neutrophil/lymphocyte ratio, lymphocyte/monocyte ratio (LMR), neutrophil/monocyte ratio, platelet/lymphocyte ratio, and platelet/monocyte ratio (PMR) ratio.

Result: Monocyte counts in migraine patients were significantly lower compared with healthy controls, while LMR and PMR were significantly higher. Statistically significant differences were observed in monocyte counts, LMR, and PMR among the three groups of CM, EM, and HC patients. Post hoc Bonferroni t-test showed that monocyte counts were significantly lower in the EM group compared with the HC group, while LMR and PMR were significantly higher. Comparison between the EM and CM groups showed that LMR was significantly higher in the EM group. Differences in monocyte counts, LMR, and PMR between the CM and HC groups were not statistically significant. Receiver operating characteristic curve analysis indicated that the area under the curve (AUC) for the diagnosing migraine using the combination of Mon, LMR, and PMR was 0.707, and the AUC for the diagnosis of EM was 0.758. The AUC value of PMR for diagnosing CM was 0.669, while the AUC for the combination of LMR and platelet/lymphocyte ratio in distinguishing CM and EM was 0.705.

Conclusion: Our findings indicate that migraine and its subtypes exhibit abnormalities in monocyte counts and PIMs, which possess diagnostic predictive value for differentiating migraine and its subtypes. This suggests that systemic inflammation may play a role in the pathogenesis of migraine.