Summary
Generation of antigen‐specific humoral responses following vaccination or infection requires the maturation and function of highly specialized immune cells in secondary lymphoid organs (SLO), ...such as lymph nodes or tonsils. Factors that orchestrate the dynamics of these cells are still poorly understood. Currently, experimental approaches that enable a detailed description of the function of the immune system in SLO have been mainly developed and optimized in animal models. Conversely, methodological approaches in humans are mainly based on the use of blood‐associated material because of the challenging access to tissues. Indeed, only few studies in humans were able to provide a discrete description of the complex network of cytokines, chemokines and lymphocytes acting in tissues after antigenic challenge. Furthermore, even fewer data are currently available on the interaction occurring within the complex micro‐architecture of the SLO. This information is crucial in order to design particular vaccination strategies, especially for patients affected by chronic and immune compromising medical conditions who are under‐vaccinated or who respond poorly to immunizations. Analysis of immune cells in different human tissues by high‐throughput technologies, able to obtain data ranging from gene signature to protein expression and cell phenotypes, is needed to dissect the peculiarity of each immune cell in a definite human tissue. The main aim of this review is to provide an in‐depth description of the current available methodologies, proven evidence and future perspectives in the analysis of immune mechanisms following immunization or infections in SLO.
In this review we aim to dissect novel technologies to analyze the immune system plasticity at tissue level. Such tools are needed in order to ‘study immune compartments as one inter‐dependent functional unit'. Our purpose is to highlight the advantages and the limitations of the most widely used approaches focusing on the importance of tissues analysis and the need of a computational approach.
Summary
Low‐affinity immunoglobulin (Ig)G with potential autoreactivity to lymphocytes and hypergammaglobulinaemia have been described previously in HIV‐1‐infected patients. Whether such antibodies ...increase after challenging the immune system, for example with an immunization, is not known. In the present study, the modulation of antibodies with low affinity and potential autoreactivity was evaluated after 2012–13 seasonal flu vaccination with a simple empirical laboratory test measuring the titres of anti‐lymphocyte antibodies (ALA) in two different models of secondary immunodeficiency: HIV‐1 vertically infected patients (HIV) and patients treated with immunosuppressive therapies after kidney transplantation (KT) compared to healthy individuals (HC). In parallel, the activation status of B cells and their degree of immune senescence was evaluated by measuring the B cell interleukin (IL)‐21R expression/plasma IL‐21 levels and the frequencies of mature‐activated (MA) and double‐negative (DN) B cells. A significant increase of ALA titres was observed after vaccination in HIV and KT but not in HC, and this correlated directly with the frequencies of both MA and DN and inversely with the B cell IL‐21R expression. This suggests that the quality of an immune response triggered by flu vaccination in HIV and KT may depend upon the activation status of B cells and on their degree of immune senescence. Further investigations are needed to verify whether high frequencies of MA and DN may also relate to increase autoimmunity after immunization in high‐risk populations.
The EPIICAL (Early-treated Perinatally HIV-infected Individuals: Improving Children's Actual Life with Novel Immunotherapeutic Strategies) project arises from the firm belief that perinatally ...infected children treated with suppressive antiretroviral therapy (ART) from early infancy represent the optimal population model in which to study novel immunotherapeutic strategies aimed at achieving ART-free remission. This is because HIV-infected infants treated within 2-3 months of life have a much reduced viral reservoir size, and rarely show HIV-specific immunity but preserve normal immune development. The goal of EPIICAL is the establishment of an international collaboration to develop a predictive platform using this model to select promising HIV therapeutic vaccine candidates, leading to prioritisation or deprioritisation of novel immunotherapeutic strategies. To establish this platform, the EPIICAL Consortium aims to: develop predictive models of virological and immunological dynamics associated with response to early ART and to treatment interruption using available data from existing cohorts/studies of early-treated perinatally HIV-infected children; optimise methodologies to better characterise immunological, virological and genomic correlates/profiles associated with viral control; test novel immunotherapeutic strategies using
proof-of-concept (PoC) studies with the aim of inducing virological, immunological and transcriptomic correlates/profiles equivalent to those defined by the predictive model. This approach will strengthen the capacity for discovery, development and initial testing of new therapeutic vaccine strategies through the integrated efforts of leading international scientific groups, with the aim of improving the health of HIV-infected individuals.
As the global COVID-19 pandemic progresses, it is paramount to gain knowledge on adaptive immunity to SARS-CoV-2 in children to define immune correlates of protection upon immunization or infection. ...We analyzed anti-SARS-CoV-2 antibodies and their neutralizing activity (PRNT) in 66 COVID-19-infected children at 7 (±2) days after symptom onset. Individuals with specific humoral responses presented faster virus clearance and lower viral load associated with a reduced in vitro infectivity. We demonstrated that the frequencies of SARS-CoV-2-specific CD4+CD40L+ T cells and Spike-specific B cells were associated with the anti-SARS-CoV-2 antibodies and the magnitude of neutralizing activity. The plasma proteome confirmed the association between cellular and humoral SARS-CoV-2 immunity, and PRNT+ patients show higher viral signal transduction molecules (SLAMF1, CD244, CLEC4G). This work sheds lights on cellular and humoral anti-SARS-CoV-2 responses in children, which may drive future vaccination trial endpoints and quarantine measures policies.
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•Antibody neutralization is inversely associated with SARS-CoV-2 in nasopharyngeal swabs•Antigen-specific B cells positively associate with anti-SARS-CoV-2 humoral immunity•SARS-CoV-2 neutralizing antibodies are present in patients with higher specific T cells•Antigen-specific B and T cells are features of SARS-CoV-2 immunity in children
Cotugno et al. show that neutralizing antibodies affect SARS-CoV-2 viral load in infected children. Antigen-specific B and T cells are positively associated with virus neutralization. This information provides a basis for defining SARS-CoV-2 adaptive responses in children.
Background
Although SARS‐CoV‐2 immunizations have started in most countries, children are not currently included in the vaccination programs; thus, it remains crucial to define their anti‐SARS‐CoV‐2 ...immune response in order to minimize the risk for other epidemic waves. This study sought to provide a description of the virology ad anti‐SARS‐CoV‐2 immunity in children with distinct symptomatology.
Methods
Between March and July 2020, we recruited 15 SARS‐CoV‐2 asymptomatic (AS) and 51 symptomatic (SY) children, stratified according to WHO clinical classification. We measured SARS‐CoV‐2 viral load using ddPCR and qPCR in longitudinally collected nasopharyngeal swab samples. To define anti‐SARS‐CoV‐2 antibodies, we measured neutralization activity and total IgG load (DiaSorin). We also evaluated antigen‐specific B and CD8+T cells, using a labeled S1+S2 protein and ICAM expression, respectively. Plasma protein profiling was performed with Olink.
Results
Virological profiling showed that AS patients had lower viral load at diagnosis (p = .004) and faster virus clearance (p = .0002) compared with SY patients. Anti‐SARS‐CoV‐2 humoral and cellular response did not appear to be associated with the presence of symptoms. AS and SY patients showed similar titers of SARS‐CoV‐2 IgG, levels of neutralizing activity, and frequency of Ag‐specific B and CD8+ T cells, whereas pro‐inflammatory plasma protein profile was found to be associated with symptomatology.
Conclusion
We demonstrated the development of anti‐SARS‐CoV‐2 humoral and cellular response with any regard to symptomatology, suggesting the ability of both SY and AS patients to contribute toward herd immunity. The virological profiling of AS patients suggested that they have lower virus load associated with faster virus clearance.
Summary From the use of antiretroviral therapy to prevent mother-to-child transmission to the possibility of HIV cure hinted at by the Mississippi baby experience, paediatric HIV infection has been ...pivotal to our understanding of HIV pathogenesis and management. Daily medication and indefinite antiretroviral therapy is recommended for children infected with HIV. Maintenance of life-long adherence is difficult and the incidence of triple-class virological failure after initiation of antiretroviral therapy increases with time. This challenge shows the urgent need to define novel strategies to provide long-term viral suppression that will allow safe interruption of antiretroviral therapy without viral rebound and any associated complications. HIV-infected babies treated within a few days of birth have a unique combination of a very small pool of integrated viruses, a very high proportion of relatively HIV resistant naive T cells, and an unparalleled capacity to regenerate an immune repertoire. These features make this group the optimum model population to investigate the potential efficacy of immune-based therapies. If successful, these investigations could change the way we manage HIV infection.
OBJECTIVE:To identify predictors of faster time to virological suppression among infants starting combination antiretroviral therapy (cART) early in infancy.
DESIGN:Cohort study of infants from ...Europe and Thailand included in studies participating in the European Pregnancy and Paediatric HIV Cohort Collaboration.
METHODS:Infants with perinatal HIV starting cART aged less than 6 months with at least 1 viral load measurement within 15 months of cART initiation were included. Multivariable interval-censored flexible parametric proportional hazards models were used to assess predictors of faster virological suppression, with timing of suppression assumed to lie in the interval between last viral load at least 400 and first viral load less than 400 copies/ml.
RESULTS:Of 420 infants, 59% were female and 56% from Central/Western Europe, 26% United Kingdom/Ireland, 15% Eastern Europe and 3% Thailand; 46 and 54% started a boosted protease inhibitor-based or nonnucleoside reverse transcriptase inhibitor-based regimen, respectively. At cART initiation, the median age, CD4% and viral load were 2.9 interquartile range (IQR)1.4–4.1 months, 34 (IQR24–45)% and 5.5 (IQR4.5–6.0) log10 copies/ml, respectively. Overall, an estimated 89% (95% confidence interval86–92%) achieved virological suppression within 12 months of cART start. In multivariable analysis, younger age adjusted hazard ratio (aHR)0.84 per month older; P < 0.001, higher CD4% (aHR1.11 per 10% higher; P = 0.010) and lower log10 viral load (aHR0.85 per log10 higher; P < 0.001) at cART initiation independently predicted faster virological suppression.
CONCLUSION:We observed a significant independent effect of age at cART initiation, even within a narrow 6 months window from birth. These findings support the earliest feasible cART initiation in infants and suggest that early therapy influences key virological and immunological parameters that could have important consequences for long-term health.
The aim of this study was to assess the frequency of organ- and nonorgan-specific autoantibodies in MS patients and evaluate whether the presence of autoantibodies is an indicator of disease activity ...and/or a prognosis factor. One hundred and five definite MS patients in different stages and with different course and 75 blood donors were tested for the autoantibodies TgA, TMA/TPO-A, PCA, ANA, aCl, SMA, AMA and ANCA. All patients were screened for the LAC. Autoantibodies to at least one autoantigen were found in 66.6% MS patients and in 13.3% controls (P50.001). The frequency of TgA, TMA/TPO-A, ANA, aCl and SMA was statistically higher in patients than in controls. Circulating ANCAs were found in seven MS, a never reported finding. An early onset of MS (520 years) was associated with a lower autoantibody frequency (P50.01). Primary and secondary progressive MS had a higher antibody frequency than relapsing-remitting (P50.05) or benign (P50.001) MS. Up to 86% of patients were autoantibody-positive during the acute stage, but only 30% of them remained positive during the remission stage (P50.001). A generalised immune dysregulation occurs in MS patients, mostly during the acute stages and in the progressive courses, involving activation of both autoreactive Th1-cells (mainly linked to CNS lesions) and B-cells via Th2 cells.
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