Clinical and experimental immunology最新文献

The human response to vaccination exhibits considerable variability due to a complex interplay of heritable and environmental factors. This review examines the current understanding of the role of human genetics in vaccine responses, encompassing both rare adverse events following immunization as well as immunogenicity and efficacy. We highlight recent studies including from the coronavirus disease 2019 (COVID-19) pandemic, which provided a unique opportunity to study vaccine genetics at scale for a newly emerging infection and revealed significant associations between HLA alleles and responses to SARS-CoV-2 vaccines. Understanding genetic contributions to vaccine responses holds promise for enhancing vaccine safety and efficacy, and the development of personalized vaccination strategies.

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.

CD40-CD40L interaction is crucial for the interplay between B and T cells and determines B-cell fate. Here, we investigated the effects of CD40-CD40L inhibition on B-cell subsets and cytokine production using the non-depleting monoclonal anti-CD40 antibody CFZ534. CFZ534 had no impact on B-cell viability but inhibited TLR9-agonistic (CpG-ODN) CD40L- as well as CD40L-mediated proliferation. The plasmablast subset was reduced after stimulation with CpG-ODN + CD40L, but this effect was completely restored by CFZ534-mediated CD40 blockade. IgG as well as IgM-secreting cells were significantly reduced in the presence of CFZ534 upon CD40L stimulation. CpG-ODN, but not CD40L, induced Granzyme B production in B cells after CD40-blockade and CpG-ODN/CD40L stimulation. Moreover, we found that IL-10 and Granzyme B were produced by separate B-cell subsets. Hence, CD40-blockade mediated by CFZ534 increased Granzyme B production and decreased IL-10 production in CD24hiCD38hi B cells with a transitional phenotype and led to a significant decrease in the expression of the pro-inflammatory cytokines IL-6, IL-12p35, and IL-23p19 and TNFα in a B and CD4 + TH-cell co-culture system. Based on these preclinical results, CD40 blockade by the Fc-silent, non-depleting monoclonal antibody CFZ534 exerts an anti-inflammatory effect on B cells, including hampering the IgG class switch without affecting their viability.

Large-scale population studies are important to monitor and evaluate aspects of a vaccination programme including vaccine coverage, real-world effectiveness, and post-licensure vaccine safety. These types of epidemiological studies often come under the remit of public health agencies, such as the UK Health Security Agency (UKHSA) in England, which are required to undertake surveillance of vaccine-preventable diseases, including via seroepidemiological studies and data linkage studies using national-level electronic healthcare data. An individual-level national vaccine register with an accurate denominator can be the key to gaining insights into vaccine coverage, effectiveness, and safety. During the coronavirus disease 2019 pandemic, England's first vaccine register was developed. This enabled timely estimates of real-world vaccine effectiveness in the whole population of England, as well as enabling epidemiological investigations of rare potential risks from vaccines in specific populations. Population-based research studies, including prospective cohort studies, are complementary to surveillance and combined, enable more comprehensive assessments. As there was an unprecedented investment into research studies and infrastructure during the pandemic, the scale of these studies meant they were able to contribute to vaccine programme evaluations in a way that had not been possible for previous vaccine programmes. In this review, we summarise the different large-scale surveillance and research studies that have been used to evaluate and inform vaccine policy from the time of the first data linkage studies undertaken in England in the 1990s to the present-day post-COVID-19 pandemic.

During the coronavirus disease 2019 (COVID-19) pandemic a rare new paediatric inflammatory condition (paediatric inflammatory multisystem syndrome temporally associated with COVID-19 (PIMS-TS)/MIS-C) was identified which correlated with previous or recent SARS-CoV-2 infection. PIMS-TS led to severe multiorgan inflammation, suggestive of disruption of central tolerance and thymus function. Here we investigated the possible role of the thymus in paediatric PIMS-TS. We confirmed that human thymus explants can be infected with SARS-CoV-2 in vitro. Comparison of T-cell populations in blood from PIMS-TS patients and age-matched healthy control children showed that although the overall proportions of CD4 and CD8 T-cell populations were decreased in PIMS-TS patients, the proportion of naïve cells in the CD4 population was higher in the PIMS-TS group. In PIMS-TS patients, the number of TREC in Peripheral blood mononuclear cells (PBMC) correlated strongly with the proportion of naïve CD4 and CD8 T cells, whereas this correlation was not present in healthy children. Sequencing rearranged TCRβ and TCRɑ transcripts from FACS-sorted CD4+CD8-CD3+ and CD4-CD8+CD3+ from blood from PIMS-TS, healthy children, and additionally paediatric severe COVID-19 patients showed that while all three groups showed similar diversity and distribution, the repertoire of the PIMS-TS and COVID-19 groups had distinctive patterns of TCR gene segment usage and VJ combinatorial usage compared to healthy controls (TRBV11-2 × TRBJ2-7, TRBV11-2 × TRBJ1-1, TRBV11-2 × TRBJ2-5, TRBV11-2 × TRBJ2-1; TRBV29-1 × TRBJ2-7, TRBV29-1 × TRBJ1-1 enriched in PIMS-TS; TRBV7-9 × TRBJ1-2, TRAV9-2 × TRAJ30, and TRAV26-1 × TRAJ39 enriched in COVID-19). The non-productive TCR rearrangements in the PIMS-TS group were also enriched for TRBV11-2, and showed bias towards distal (5'TRAV to 3'TRAJ) TCRɑ gene segment usage, suggesting involvement of the thymus in PIMS-TS.

Background: Radiation therapy has long been a cornerstone of cancer treatment. More recently, immune checkpoint blockade has also been applied across a variety of cancers, often leading to remarkable response rates. However, photon-based radiotherapy-which accounts for the vast majority-is also known to frequently induce profound lymphopenia, which might limit the efficacy of immune system-based combinations. Proton beam therapy is known to produce a less drastic lymphopenia, which raises the possibility of greater synergy with immunotherapy. In this study, we aimed to explore the exact nature of the differential impact of the two radiation modalities upon the immune system.

Methods: We used multiparametric flow cytometry and deep sequencing of rearranged TCRb loci to investigate a cohort of 20 patients with gastrointestinal tumors who received either therapy and developed lymphopenia.

Results: Proton-treated patients remained relatively stable throughout treatment by most metrics considered, whereas those who received photons saw a profound depletion in naïve T cells, an increase in effector/memory populations, and a loss of TCR diversity. The repertoires of photon-treated patients underwent an oligoclonal expansion after their lymphocyte count nadirs, particularly of CD8+ Temra cells, driving this reduction in diversity. Across the entire cohort, this reduction in post-nadir diversity is inversely correlated with the overall survival time of those patients who died.

Conclusion: This raises the possibility that increased adoption of proton-based or other lymphocyte-sparing radiotherapy regimes may lead to better survival in cancer patients.

Heterozygous loss-of-function mutations in the TNFAIP3 gene lead to A20 haploinsufficiency (HA20). A20 protein is a negative feedback regulator of NF-κB signaling. Traditionally, HA20 is associated with Behçet's disease-like symptoms, however, recent findings suggest it may also manifest with a broader array of autoimmune diseases. Here, we describe a novel TNFAIP3 variant in a Dutch family, predominantly presenting with polyautoimmunity rather than autoinflammatory manifestations. We evaluated two patients from a Dutch family with autoimmune symptoms. Whole-exome sequencing (WES) identified a heterozygous c.608T>G (p.Leu203Arg) missense variant in TNFAIP3, located within the OTU domain. Functional analyses included immunoblotting of peripheral blood mononuclear cells (PBMCs) and an overexpression model using transfected HEK293T cells. A20 protein expression was evaluated, while phosphoflow cytometry assessed phosphorylation of key signaling molecules in the NF-κB, STAT and mTOR pathways. Inflammatory cytokine production was measured in cell culture supernatants. Overexpression of this missense A20 variant in HEK293T enhanced NF-κB signaling, reflected by increased TRAF6 expression and IκBα phosphorylation. Patient-derived PBMCs demonstrated reduced A20 expression, increased phosphorylation within the NF-κB, STAT1, and mTOR pathways, and elevated production of pro-inflammatory cytokines. These molecular alterations suggest disrupted immune regulation contributing to the observed autoimmune phenotype. The identification of this novel TNFAIP3 variant contributing to HA20 expands the clinical spectrum to include predominant autoimmune manifestations. In addition to NF-κB and STAT1 activation, we discovered mTOR pathway activation, shedding new light on A20's function and progression toward autoimmunity. Furthermore, the involvement of mTOR pathway also provides new therapeutic possibilities.

Background: Growing evidence links immune dysfunction, notably impaired IFNγ production, to chronic pulmonary aspergillosis (CPA), but understanding of the immune phenotype in CPA patients remains limited.

Methods: To investigate this, we recruited 25 CPA patients and 25 controls with bronchiectasis, isolating immune cells from peripheral blood for detailed flow cytometric phenotyping at resting state and after ex vivo stimulation with the TLR2/Dectin-1 agonist Zymosan.

Results: CPA patients exhibited pronounced neutrophilia and a reduced frequency of conventional dendritic cell (DC) subsets at baseline compared to bronchiectasis controls. Post-stimulation, DC and monocyte subsets in CPA patients showed significantly lower expression of activation markers. Notably, cDC1s displayed reduced IL-12p40, TNFα, and CD86 expression. CPA patients with a history of tuberculosis (TB) had significantly higher frequencies of activated cDC1s. Machine learning analysis validated these immunological parameters as predictive of CPA status.

Conclusion: Our findings suggest that immune dysfunction in CPA involves DC and monocyte impairments, potentially contributing to IFNγ deficiency through reduced IL-12 production and co-stimulatory capacity in cDC1s. These results also hint at the presence of innate immune memory in CPA patients with prior TB. Our study advances understanding of the immune dysfunction underlying CPA.

Background: Idiopathic inflammatory myopathy (IIM) is a progressive autoimmune disease characterized by interstitial lung disease (ILD) with limited therapeutics available. Pirfenidone (PFD), a medication utilized for the treatment of idiopathic pulmonary fibrosis, exhibits notable antioxidant, anti-inflammatory, and inhibition of collagen synthesis. This study aims to clarify its efficacy and mechanism in treating IIM-ILD.

Methods: A murine myositis-associated interstitial lung disease (MAILD) model was used to assess the therapeutic effect of PFD. The serum levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) were detected by enzyme-linked immunosorbent assay (ELISA). Pirfenidone was utilized to disrupt neutrophil extracellular traps (NETs) formation in vitro, and its inhibitory effect on NETs was assessed through immunohistochemistry of citrullinated histone H3 and myeloperoxidase in the lung tissue and the serum cfDNA level in mice. Immunohistochemical and western blot were utilized to examine alterations in epithelial-mesenchymal transition (EMT) and NOD-like receptor protein 3 (NLRP3) inflammasome markers.

Results: Pirfenidone treatment inhibited pulmonary inflammation and fibrosis in the MAILD model. Pirfenidone intervention reduced NETs formation in vitro. Pirfenidone treatment significantly reduces NETs infiltration in the lung tissue and the level of cfDNA in the serum of mice. Additionally, PFD downregulated EMT and NLRP3-related proteins in vivo. Pirfenidone treatment also notably reduced serum levels of IL-1β, IL-6, and TNF-α. After NETs stimulation, A549 cells exhibited EMT and activation of NLRP3 inflammasome. Pirfenidone attenuated EMT in A549 cells and suppressed the activation of NLRP3 inflammasome.

Conclusion: Pirfenidone alleviates ILD in a murine MAILD model by inhibiting NETs formation and NLRP3 inflammasome activation, suggesting that PFD might be a potential therapeutic agent for IIM-ILD.