How to dissect the plasticity of antigen-specific immune response: a tissue perspective.

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.

Respiratory Syncityal Virus A and B: three bronchiolitis seasons in a third level hospital in Italy.

BACKGROUND: Respiratory syncytial virus (RSV) is the main cause of hospitalization for bronchiolitis among infants. RSV is classified into two subtypes, A and B, whose predominance alternates during different epidemic seasons. The clinical impact of viral factors is controversial and many evidences suggest a critical role for the immune host response. Premature children are at the highest risk for severe RSV infection. The main aim of this study is to identify the different RSV subtypes circulating in the last three epidemic seasons and to evaluate whether any of them was associated with poor prognosis in term and preterm infants. METHODS: We performed a retrospective analysis of medical records for all patients aged less than one year which were hospitalized during the winter season between November 2015 and April 2018 with clinical diagnosis of bronchiolitis and nasopharyngeal aspirates positive for RSV. RESULTS: We enrolled 422 children, of which 50 were born preterm. During the analysis period, we observed a significant increase in the rates of oxygen supplementation and admission to intensive care unit. The evidence shows an alternating pattern in the prevalence of RSV subtypes among term born; in each epidemic season, the prevalent serotype is the cause of the majority of the cases requiring intensive care. Conversely, RSV-A is always prevalent in preterm children and caused most of the cases requiring intensive care. CONCLUSIONS: During the 3 seasons analyzed, we observed an alternating prevalence of RSV A and B. While there are no differences in severity between RSV A and B in term population, RSV-A is prevalent and causes most of the severe cases in the premature group. Furthermore, an increase in RSV-related oxygen therapy and PICU admission has been documented not only in the premature population. Considering the absence of appropriate therapeutic strategies, our work emphasizes the importance of implementing prophylaxis measures against RSV and highlights the urgent need to gain knowledge about immune response to the virus, also in premature children.

The EPIICAL project: an emerging global collaboration to investigate immunotherapeutic strategies in HIV-infected children.

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 in vivo 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.

Premature ageing of the immune system relates to increased anti-lymphocyte antibodies (ALA) after an immunization in HIV-1-infected and kidney-transplanted patients.

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.

Autoimmunity in multiple sclerosis: study of a wide spectrum of autoantibodies.

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 (P < 0.001). 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 (< 20 years) was associated with a lower autoantibody frequency (P < 0.01) Primary and secondary progressive MS had a higher antibody frequency than relapsing-remitting (P < 0.05) or benign (P < 0.001) MS. Up to 86% of patients were autoantibody-positive during the acute stage, but only 30% of them remained positive during the remission stage (P < 0.001). 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.

Chorea in primary antiphospholipid syndrome.

A 12-year-old girl with chorea, thrombocytopenia and false positive VDRL had negative serological tests for SLE, but high titre of antiocardiolipine antibodies. Primary antiphospholipid antibody syndrome is rarely complicated by chorea, but should be taken into consideration in patients who do not fulfill the diagnostic criteria for SLE.