Clinical and experimental immunology最新文献

Neutrophils are short-lived cells of the innate immune system and represent 50-70% of the circulating leucocytes. Their primary role is antimicrobial defence which they accomplish through rapid migration to sites of inflammation followed by phagocytosis, degranulation, and the release of neutrophil extracellular traps (NETosis). While previously considered terminally differentiated cells, they have been shown to have great adaptability and to play a role in conditions ranging from cancer to autoimmunity. This review focuses on their role in allergic disease. In particular: their role as potential amplifiers of type 1 hypersensitivity reactions leading to anaphylaxis; their involvement in alternative pathways of food and drug allergy; their role in allergic rhinitis and asthma and neutrophil dysfunction in atopic dermatitis. The use of potential biomarkers and therapeutic targets is also discussed with a view to guiding future research.

Oral vaccines have several advantages compared with parenteral administration: they can be relatively cheap to produce in high quantities, easier to administer, and induce intestinal mucosal immunity that can protect against infection. These characteristics have led to successful use of oral vaccines against rotavirus, polio, and cholera. Unfortunately, oral vaccines for all three diseases have demonstrated lower performance in the highest-burden settings where they are most needed. Rotavirus vaccines are estimated to have >85% effectiveness against hospitalization in children <12 months in countries with low child mortality, but only ~65% effectiveness in countries with high child mortality. Similarly, oral polio vaccines have lower immunogenicity in developing country settings compared with high-resource settings. Data are more limited for oral cholera vaccines, but suggest lower titers among children compared with adults, and, for some vaccines, lower efficacy in endemic settings compared with non-endemic settings. These disparities are likely multifactorial, and available evidence suggests a role for maternal factors (e.g. transplacental antibodies, breastmilk), host factors (e.g. genetic polymorphisms-with the best evidence for rotavirus-or previous infection), and environmental factors (e.g. gut microbiome, co-infections). Overall, these data highlight the rather ambiguous and often contradictory nature of evidence on factors affecting oral vaccine response, cautioning against broad extrapolation of outcomes based on one population or one vaccine type. Meaningful impact on performance of oral vaccines will likely only be possible with a suite of interventions, given the complex and multifactorial nature of the problem, and the degree to which contributing factors are intertwined.

Low titers to pneumococcal vaccine are a frequent finding in pediatric patients with recurrent oto-sinopulmonary infections. To characterize the pre- and post-immunization antibody trend for each serotype included in the pneumococcal 13-valent conjugate vaccine, in a cohort of pediatric patients with recurrent oto-sinopulmonary infections, this retrospective review identified 182 patients with recurrent oto-sinopulmonary infections (131 required an immune workup and 99 had low pneumococcal titers leading to a pneumococcal 13-valent conjugate vaccine booster). Baseline pneumococcal serotype-specific antibody titers at the initial visit and 6 weeks after the vaccine booster were obtained. An adequate response to the pneumococcal conjugate vaccine was deemed to be a 4-fold increase over baseline and/or a post-immunization titer of 1.3 µg/ml or greater. Overall, The pneumococcal 13-valent conjugate vaccine booster provided a significant improvement in the number of protective titers, increasing from 3.6 serotypes at baseline to 11.1 serotypes at 6 weeks (P < 0.001). This increase correlated with improved clinical outcomes (81% showed no signs of recurrent infection after the first booster and 94% after a second booster). Post-immunization antibody concentrations were significantly higher than at baseline for all serotypes (P < 0.05), and only 8, 9N, and 12F did not exhibit a greater than 4-fold increase (P > 0.05) 6 weeks following booster. There were no differences between patients at different ages in post-immunization titer levels for all serotypes. In pediatric patients with recurrent oto-sinopulmonary infections, an additional pneumococcal booster proved to be effective in the protection of these children against further infections, across all age groups.

Introduction: The apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is crucial for inflammasome assembly and activation of several inflammasomes, including NLRP3. ASC aggregates are detected in human sera post pyroptotic cell death, but their inflammasome origin remains unclear.

Method: This study aimed to develop a method to detect ASC aggregates originating from NLRP3 inflammasomes. Initially, human monocytes, macrophages, and THP-1 ASC reporter cells were employed to validate the detection of ASC/NLRP3-positive events through flow cytometry.

Results: The presence of ASC/NLRP3 specks was confirmed in cell supernatants from monocytes and macrophages treated with LPS and nigericin or ATP. Flow cytometry analysis identified double-positive specks in patient sera from inflammatory conditions when compared with healthy controls. Elevated ASC/NLRP3 specks were observed in conditions such as cryopyrin-associated periodic syndrome and Schnitzler's syndrome.

Conclusion: We validated fluorescence-activated cell sorting as a reliable method for detecting ASC/NLRP3 specks in human sera, with potential diagnostic and monitoring applications in certain systemic autoinflammatory diseases.

Introduction: Systemic lupus erythematosus (SLE) patients exhibit B-cell abnormalities. Although there are concerns about reduced antibody responses to SARS-CoV-2 vaccines, detailed data on B-cell-specific responses in SLE remain scarce. Understanding the responsiveness to novel vaccine antigens, and boosters number, is important to avoid unnecessarily prolonged isolation of immunocompromised individuals. We assessed humoral and antigen-specific B-cell subset responses, including changes in isotype switching, prior to and after several doses of SARS-CoV-2 vaccines.

Methods: Blood samples were obtained prior to and after SARS-CoV-2 vaccination from cross-sectional and longitudinal cohorts of previously uninfected patients with SLE (n = 93). Healthy participants receiving SARS-CoV-2 vaccines were recruited as controls (n = 135). We measured serum antibody titres, their neutralizing capacity, and vaccine-specific memory B-cell subsets.

Results: Impaired IgG, IgA, and neutralizing responses against the original and various SARS-CoV-2 variants were observed following two doses of vaccine in SLE patients. Follow-up booster doses increased humoral responses compared to baseline, but they remained lower, with poorer neutralisation capacity against most strains, compared to healthy individuals after three or more doses. Analysis of memory B-cell subsets in SLE patients revealed an increase of SARS-CoV-2-specific isotype unswitched IgM+ over SARS-CoV-2-specific isotype switched IgG+/IgA+ memory B-cells compared to healthy individuals. Culturing healthy naive B-cells with high levels of IFNα, a hallmark of SLE pathogenesis, prevented B-cells from switching to IgG under IgG-polarizing conditions.

Conclusion: SLE patients' protection against SARS-CoV-2 is overall impaired compared to healthy individuals and is associated with a class switch defect possibly due to chronic exposure of B-cells to IFNα.

Introduction: Immune checkpoint inhibition (ICI) is highly effective for the treatment of melanoma, but intrinsic resistance is present in a subgroup of patients. TGF-β pathway activity may play a role in this resistance by preventing T-cells from entering the tumor microenvironment, causing immune escape. We investigated the association of TGF-β signal transduction pathway activity with resistance to ICI treatment in advanced melanoma. Furthermore, other pathway activities were analyzed to better understand their potential role in ICI resistance.

Method: The activity of 8 signaling pathways (TGF-β, Hedgehog, MAPK, AR, NOTCH, PI3K, JAK/STAT1-2, and NFkB) was analyzed from tumor tissue from patients with advanced melanoma. Pathway activity scores (PAS) were explored for associations with survival and response to ICI in 34 patients (19 non-responders and 15 responders). A second, independent method to investigate the predictive value of TGF-β pathway activation was conducted by determining levels of phosphorylated SMAD2.

Results: The mean TGF-β PAS of responders vs non-responders was 53.9 vs 56.8 (P = 0.265). No significant relation with progression-free survival was detected for TGF-β activity (P = 0.078). No association between pSMAD2 staining and treatment response or survival was identified. In contrast, Hedgehog scores of responders versus non-responders were 35.7 vs 41.6 (P = 0.038). High Hedgehog PAS was the sole significant predictor of resistance to ICI (OR 0.88, P = 0.033) and worse progression-free survival (HR 1-1.1, P = 0.012).

Conclusion: TGF-β pathway activation showed no significant relation with treatment response to ICI or survival in patients with advanced melanoma. Hedgehog PAS was identified as a possible biomarker associated with both treatment response and survival.

Juvenile systemic lupus erythematosus (JSLE) is an autoimmune condition which causes significant morbidity in children and young adults and is more severe in its presentation than adult-onset SLE. While many aspects of immune dysfunction have been studied extensively in adult-onset SLE, there is limited and contradictory evidence of how cytotoxic CD8+ T cells contribute to disease pathogenesis and studies exploring cytotoxicity in JSLE are virtually non-existent. Here, we report that CD8+ T cell cytotoxic capacity is reduced in JSLE versus healthy controls, irrespective of treatment or disease activity. Transcriptomic and serum metabolomic analysis identified that this reduction in cytotoxic CD8+ T cells in JSLE was associated with upregulated type I interferon (IFN) signalling, mitochondrial dysfunction, and metabolic disturbances when compared to controls. Greater interrogation of the influence of these pathways on altered cytotoxic CD8+ T cell function demonstrated that JSLE CD8+ T cells had enlarged mitochondria and enhanced sensitivity to IFN-α leading to selective apoptosis of effector memory (EM) CD8+ T cells, which are enriched for cytotoxic mediator-expressing cells. This process ultimately contributes to the observed reduction in CD8+ T cell cytotoxicity in JSLE, reinforcing the growing evidence that mitochondrial dysfunction is a key pathogenic factor affecting multiple immune cell populations in type I IFN-driven rheumatic diseases.

Introduction: Wound healing causes heavy economic burdens for families and society, becoming a critical issue in the global healthcare system. While the role of immune cells in the wound healing process is well-established, the involvement of B cells remains poorly understood. This study aims to elucidate the essentiality of B cells in wound repair. Our findings demonstrate a rise in B cell population during the early stage of wound healing, which further intensifies during the later stage.

Methods: We employed anti-CD20 antibodies to deplete B cells in mice and created a whole skin excisional wound mice model, analyzing wound closure over 12 days. B cells were isolated from the animals' spleen and co-cultured with macrophages from bone marrow. The polarization of M1 and M2 macrophages was analyzed by real-time qPCR and flow cytometry.

Results: The wound healing process in mice was observed to be considerably delayed following the elimination of B cells. The wounds exhibited a state of inflammation primarily characterized by the presence of pro-inflammatory M1 macrophages. The decrease in M2 macrophages within the local wound area resulted in impairment of the wound repair mechanism. B cell-macrophage co-culture system revealed that B cells effectively induce the polarization of macrophages towards M2-like phenotype. Furthermore, we found that follicular B cells play predominant role in modulating the polarization of M2 macrophages.

Conclusion: Consequently, our findings indicate that B cells can be recruited to the wound site and facilitate the polarization of M2-like macrophages, thereby accelerating the healing process during wound healing.