Clinical and experimental immunology最新文献

Increasing evidence supports the involvement of inborn errors of immunity in severe infections, but little is known about the prevalence of these genetic defects in children with sepsis. Due to the limited understanding of the molecular and immunological mechanisms driving sepsis, genetic testing is rarely used in routine diagnostics to identify genetic susceptibility to the condition. We performed a prospective observational study on previously healthy children hospitalized for severe infections, including sepsis. Patients underwent immunophenotyping and whole-exome sequencing, followed by in silico analysis to identify potentially causal variants. We assembled a cohort of 194 previously healthy children, including 149 (77%) patients with severe infection and 45 (23%) with sepsis. Our cohort was marked by a high frequency of respiratory tract infections (35%), bloodstream infections (20%), and central nervous system infections (16%). The genetic investigation identified 28 potentially causal variants, 18 (64%) are classified as variants with uncertain significance, and 10 (36%) are likely pathogenic variants. Of 45 patients with sepsis, 6 (13%) had potentially causal genetic variants. Similarly, 22/149 (15%) patients with severe infection presented potentially causal genetic variants. Whole-exome sequencing predicted the impairment of various immune mechanistic pathways such as immune dysregulation defects, antibody deficiencies, and combined immunodeficiencies (18% each). We found no clear association between genetic variants and the studied parameters: organ failure, microbe identification, immunoglobulin levels, and lymphocyte subset numbers. Although whole-exome sequencing is a valuable tool for detecting inborn errors of immunity underlying sepsis and unexplained severe infections, it could be selectively recommended for patients with a strong clinical suspicion of genetic abnormalities, balancing its diagnostic value with its cost and complexity.

Fc receptors (FcR) play a key role in coordinating responses from both the innate and adaptive immune system. The inhibitory Fc gamma receptor (FcγRIIB/CD32B; referred to as FcγRII/CD32 in mice) restrains the immune response, specifically through regulating immunoglobulin G (IgG) effector functions. FcγRII-deficient mice demonstrate elevated incidence and severity of autoimmunity and increased responses to immunization and infections. To explore the potential of FcγRIIB as a target for augmenting vaccines, we tested the ability of monoclonal antibodies (mAb) against mouse FcγRII and human FcγRIIB to enhance humoral responses in preclinical models. We used wild-type (WT), FcγR-deficient, and human FcγRIIB transgenic (Tg) mice with either a functional intracellular domain (hFcγRIIB Tg) or lacking immunoreceptor tyrosine-based inhibitory motif (ITIM) signalling capacity (NoTIM). Targeting mouse FcγRII and human FcγRIIB with antibodies significantly augmented humoral immune responses against experimental antigens and enhanced tumour clearance in vivo. Surprisingly, mAbs without a functional Fc (N297Q; referred to as Fc-null) lacked efficacy. Similarly, blocking FcγRII in mice lacking activating FcγRs failed to enhance immune responses. Conversely, blocking both signalling-competent and signalling-defective (NoTIM) FcγRIIB in Tg mice with a WT, but not Fc-null, FcγRIIB mAb equally enhanced immunity. These data indicate the redundancy of inhibitory signalling in potentiating immune responses in vivo. Collectively, our data suggest that mAb-targeting of FcγRIIB stabilizes mAb Fc and enhances immune responses via Fc-mediated crosslinking of activating FcγRs, irrespective of the inhibitory function of FcγRIIB. These findings support a strategy to boost immune responses in immunization protocols.

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.

Potent inflammatory responses stemming from innate and T cell activation are initiated during acute human immunodeficiency virus infection. Suppression of the virus replication by antiretroviral therapy reduces but does not normalize immune activation. By now, it is clear that residual immune activation can persist even after years of antiretroviral therapy and associates with increased risks for co-morbidities, thereby raising interest for strategies that can resolve the residual immune activation in people with human immunodeficiency virus on antiretrovirals. This brief review reports the human studies with various drugs with anti-inflammatory properties and their effects on measures of systemic immune activation on people with human immunodeficiency virus. Along with the possible reasons for conflicting outcomes, considerations for ongoing and future approaches are outlined.

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.

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.

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.