Innate and adaptive immune defects associated with lower SARS-CoV-2 BNT162b2 mRNA vaccine response in elderly people

The immune factors associated with impaired SARS-CoV-2 vaccine response in the elderly are mostly unknown. We studied old and young people vaccinated with SARS-CoV-2 BNT162b2 mRNA before and after the first and second dose. Aging was associated with a lower anti-RBD IgG levels and a decreased magnitude and polyfunctionality of SARS-CoV-2 specific T cell response. The dramatic decrease in thymic function in the elderly, which fueled alteration in T cell homeostasis, and lower CD161+ T cell levels were associated with decreased T cell response two months after vaccination. Additionally, a deficient dendritic cell (DC) homing, activation and Toll like receptor (TLR)-mediated function, along with a proinflammatory functional profile in monocytes, were observed in the elderly, which was also related to lower specific T cell response after vaccination. These findings might be relevant for the improvement of the current vaccination strategies and for the development of new vaccine prototypes.

Detection of Pneumocystis jirovecii and Toxoplasma gondii in patients with lung infections by a duplex qPCR assay

Pneumocystis pneumonia (PCP) and pulmonary toxoplasmosis (PT) are caused by Pneumocystis jirovecii and Toxoplasma gondii. The clinical symptoms and imaging of PCP and PT are indistinguishable. A duplex qPCR was developed to differentiate between these two pathogens. In testing 92 clinical samples to validate the performance of this method for P. jirovecii detection, it identified 31 positive samples for P. jirovecii infection, consistent with clinical diagnosis. Among the remainder of the 61 clinical samples with suspected PCP, yet showing as negative by the conventional PCR diagnosis approach, 6 of them proved positive using our new assay. Our new approach also produced similar results in identification of T. gondii infections, giving a result of 2 positive and 20 negative in clinical samples. An investigation was undertaken on the prevalence of P. jirovecii and T. gondii infections using 113 samples from lung infection patients. 9% (10/113) were shown to be positive with infections of P. jirovecii, 2% with T. gondii (2/113) and 5% (6/113) were co-infected with both pathogens. Although this duplex qPCR can detect individual P. jirovecii and T. gondii infection, and co-infection of both pathogens, further large-scale investigations are needed to validate its performance, especially in T. gondii detection. Our assay provides a rapid and accurate tool for PCP and PT diagnosis in immunocompromised population and clinical surveillance of these infections in patients with no immune defects.

Toll-like Receptor 3 Deficiency in a Child with Recurrent Infections and Diabetes Mellitus

There are more than 400 different primary immune deficiencies worldwide. Amongst them, patients with humoral immunodeficiency are more common. Most of the innate immune defects, affect the phagocytic system. There are a few cases of toll-like receptor deficiency with innate immune defects, like TLR3 mutations, which usually present with Herpes simplex encephalitis. Herein, we report a two-year old boy with TLR3 deficiency, who was presented with recurrent infections and type one diabetes mellitus.

SOCS Proteins in Immunity, Inflammatory Diseases, and Immune-Related Cancer

Cytokine signaling represents one of the cornerstones of the immune system, mediating the complex responses required to facilitate appropriate immune cell development and function that supports robust immunity. It is crucial that these signals be tightly regulated, with dysregulation underpinning immune defects, including excessive inflammation, as well as contributing to various immune-related malignancies. A specialized family of proteins called suppressors of cytokine signaling (SOCS) participate in negative feedback regulation of cytokine signaling, ensuring it is appropriately restrained. The eight SOCS proteins identified regulate cytokine and other signaling pathways in unique ways. SOCS1–3 and CISH are most closely involved in the regulation of immune-related signaling, influencing processes such polarization of lymphocytes and the activation of myeloid cells by controlling signaling downstream of essential cytokines such as IL-4, IL-6, and IFN-γ. SOCS protein perturbation disrupts these processes resulting in the development of inflammatory and autoimmune conditions as well as malignancies. As a consequence, SOCS proteins are garnering increased interest as a unique avenue to treat these disorders.

Acquired Pure Red Cell Aplastic in one of the Monozygotic Twins with Common Variable Immunodeficiency

BackgroundCommon variable immunodeficiency (CVID) is the most prevalent primary immune defects in adults. It has become clear that most cases of CVID have a polygenic rather than a monogenic inheritance. CVID patients are prone to recurrent infection, and an increased incidence of certain autoimmune and neoplastic disorders. Monozygotic twins share identical genetic basis and may serve as a powerful model for study on genetic defects.Case presentationHere, we report a case of monozygotic twins were diagnosed with CVID at their 30s’. They featured a partly similar profile of clinical manifestations, including severe, recurring infections and bone pain. Interestingly, only the elder brother developed pure red cell aplastic (PRCA), and relieved after 5-month’s treatment with 100 mg/d of cyclosporine treatment. Whole-exome sequencing (WES) was utilized to investigate genetic defects.ConclusionsThe results suggest that a combination effect of deleterious variations maybe the cause, such as VDR, NHEJ1, DOCK5, NOD2 and C3, which were predicted by bioinformatics analysis. The potential combinatorial effects in CVID is inferred from their roles in T and B cell signal pathways activation.

Aspergillus-Associated Endophenotypes in Bronchiectasis

Bronchiectasis is a chronic condition of global relevance resulting in permanent and irreversible structural airway damage. Bacterial infection in bronchiectasis is well studied; however, recent molecular studies identify fungi as important pathogens, either independently or in association with bacteria. Aspergillus species are established fungal pathogens in cystic fibrosis and their role is now increasingly being recognized in noncystic fibrosis bronchiectasis. While the healthy airway is constantly exposed to ubiquitously present Aspergillus conidia in the environment, anatomically damaged airways appear more prone to colonization and subsequent infection by this fungal group. Aspergilli possess diverse immunopathological mechanistic capabilities and when coupled with innate immune defects in a susceptible host, such as that observed in bronchiectasis, it may promote a range of clinical manifestations including sensitization, allergic bronchopulmonary aspergillosis, Aspergillus bronchitis, and/or invasive aspergillosis. How such clinical states influence “endophenotypes” in bronchiectasis is therefore of importance, as each Aspergillus-associated disease state has overlapping features with bronchiectasis itself, and can evolve, depending on underlying host immunity from one type into another. Concurrent Aspergillus infection complicates the clinical course and exacerbations in bronchiectasis and therefore dedicated research to better understand the Aspergillus-host interaction in the bronchiectasis airway is now warranted.

Case Report: Post-Partum Complications of NFκB1 Deficiency Underscore a Need to Better Understand Primary Immunodeficiency Management During Pregnancy

Nuclear factor κappa-B (NFκB) is a family of transcription factors involved in regulating inflammation and immunity. Mutations in the NFκB1 pathway are associated with primary immune defects and underlie the most common monogenic etiology of common variable immunodeficiency (CVID). However, little is known about how NFκB1 defects or primary immunodeficiency (PID) complicate pregnancy. We present a previously healthy 34-year-old patient who suffered from poor wound healing and sterile sepsis during the post-partum period of each of her three pregnancies. She was otherwise asymptomatic, but her daughter developed Evans Syndrome (ES) with hypogammaglobulinemia prompting expanded genetic testing which revealed a novel monoallelic variant in NFκB1. This case highlights that pregnancy-related complications of PID can be difficult to recognize and may portend adverse patient outcomes. For these reasons, guidance regarding diagnosis and management of women of childbearing age with PID is warranted.

Treatment of relapsed/refractory CLL with Venetoclax-Rituximab during the COVID-19 pandemic: A daily-life experience in southern Italy.

With more than 3 million proven infections and 100.000 associated deaths in Italy, the COVID-19 pandemic poses extraordinary challenges to health-care professionals and especially to those caring for patients with haematologic malignancies (1-2). Given the multiple immune defects characterizing chronic lymphocytic leukaemia (CLL), it is considered that patients with this form of leukemia have a high-risk of suffering severe forms of COVID-19 (3-4).

Toll-Like Receptor Signaling in the Establishment and Function of the Immune System

Toll-like receptors (TLRs) are pattern recognition receptors that play a central role in the development and function of the immune system. TLR signaling promotes the earliest emergence of hematopoietic cells during development, and thereafter influences the fate and function of both primitive and effector immune cell types. Aberrant TLR signaling is associated with hematopoietic and immune system dysfunction, and both loss- and gain-of- function variants in TLR signaling-associated genes have been linked to specific infection susceptibilities and immune defects. Herein, we will review the role of TLR signaling in immune system development and the growing number of heritable defects in TLR signaling that lead to inborn errors of immunity.

Single dose of BNT162b2 mRNA vaccine against SARS-CoV-2 induces high frequency of neutralising antibody and polyfunctional T-cell responses in patients with myeloproliferative neoplasms

Encouraging results have been observed from initial studies evaluating vaccines targeting the novel beta coronavirus which causes severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, concerns have been raised around the efficacy of these vaccines in immunosuppressed populations, including patients with haematological malignancy. Myeloproliferative neoplasms (MPN), in particular myelofibrosis (MF), are associated with heterogenous immune defects which are influenced by patient age, disease subtype and the use of cytoreductive therapies. Patients with a WHO defined diagnosis of an MPN presenting to our clinic were recruited following first injection of 30μg BNT162b2. A positive anti-S IgG ELISA was seen in 76.1% (16) of patients following vaccination with positive neutralising antibodies detected in 85.7% (18) of patients. A memory T cell response was observed in 80% (16) of patients, with a CD4+ T cell response in 75% (15) and a CD8+ T cell response in 35% (7). These results, for the first time, provide some reassurance regarding the initial immune response to the BNT162b2 vaccine amongst patients with MPN, with response rates similar to that observed in the general population.