Natural killer cells and innate lymphoid cells 1 tune anxiety-like behavior and memory in mice via interferon-γ and acetylcholine.

The mechanisms of communication between the brain and the immune cells are still largely unclear. Here, we characterize the populations of resident natural killer (NK) cells and innate lymphoid cells (ILC) 1 in the meningeal dura layer of adult mice. We describe that ILC1/NK cell-derived interferon-γ and acetylcholine can contribute to the modulation of brain homeostatic functions, shaping synaptic neuronal transmission and neurotransmitter levels with effects on mice behavior. In detail, the interferon-γ plays a role in the formation of non-spatial memory, tuning the frequency of GABAergic neurotransmission on cortical pyramidal neurons, while the acetylcholine is a mediator involved in the modulation of brain circuitries that regulate anxiety-like behavior. These findings disclose mechanisms of immune-to-brain communication that modulate brain functions under physiological conditions.

COVID-19 Severity, Cardiological Outcome, and Immunogenicity of mRNA Vaccine on Adult Patients With 22q11.2 DS.

BACKGROUND: The contemporaneous presence of immune defects and heart diseases in patients with 22q11.2 deletion syndrome (22q11.3DS) might represent risk factors for severe coronavirus 2019 disease (COVID-19). OBJECTIVE: To analyze severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outcome in 22q11.2DS patients and immunogenicity of different doses of mRNA SARS-CoV-2 vaccine. METHODS: Longitudinal observational study on SARS-CoV-2 outcome in 60 adults with 22q11.2DS (March 2020-June 2022). Anti-Spike, and anti-receptor binding domain (RBD) antibody responses, generation of Spike-specific memory B cells (MBCs) and Spike-specific T cells at different time points before and after the mRNA BNT162b2 vaccination were evaluated in 16 22q11.2DS patients. RESULTS: We recorded a 95% rate of vaccination, with almost all patients being immunized with the booster dose. Twenty-one patients had SARS-CoV-2 infection. Three patients were infected before vaccine availability, 6 after receiving 2 doses of vaccine, and 12 after one booster dose. The SARS-CoV-2- infection had a mild course, except in one unvaccinated patient with several comorbidities who died from acute respiratory distress syndrome (fatality rate 5%). Infected patients had more frequently moderate/severe intellectual disability, lymphopenia, and lower CD4+ count. Despite major congenital heart diseases, COVID-19 did not impact cardiological conditions. The BNT162b2 vaccine induced S1-immunoglobulin G (IgG) responses, low serum S1-IgA, and slightly impaired specific MBCs response. Specific T-cell responses observed were related to lymphocytes and CD4+ T cell counts. CONCLUSIONS: The SARS-CoV-2 infection had a mild course in most patients with 22q11.2DS, even in patients with major cardiovascular diseases. Immunization induced Spike-specific IgG responses and generated specific MBCs and memory T cells. The weaker memory responses in patients with lymphopenia suggested the need for additional doses.

Identification of a Novel Mutation in TNFAIP3 in a Family With Poly-Autoimmunity.

Haploinsufficiency of A20 (HA20) is an inflammatory disease caused by mutations in the TNFAIP3 gene classically presenting with Behcet's-like disease. A20 acts as an inhibitor of inflammation through its effect on NF-kB pathway. Here we describe four consanguineous patients (three sisters and their mother) with a predominantly autoimmune phenotype, including thyroiditis, type I diabetes, hemolytic anemia and chronic polyarthritis. All patients had recurrent oral ulcers, with only 1 patient presenting also recurrent fever episodes, as a classical autoinflammatory feature. Next generation sequencing identified a novel heterozygous frameshift mutation (p.His577Alafs*95) that causes a premature stop codon in the zinc finger domain of A20, leading to a putative haploinsufficiency of the protein. Functional analyses confirmed the pathogenicity of the mutation. The variant was associated with decreased levels of A20 in blood cells. Accordingly, ex-vivo lipopolysaccharide (LPS)-stimulated patients' peripheral blood mononuclear cells (PBMCs) showed higher levels of p65 NF-kB phosphorylation, as well as increased production of the proinflammatory cytokines IL-1ß, IL-6 and TNF-α. Moreover, in agreement with recent observations, demonstrating a role for A20 in inhibiting STAT1 and IFNγ pathways, markedly higher circulating levels of the two IFNγ-inducible chemokines CXCL9 and CXCL10 were detected in all patients. Supporting the findings of a hyperactivation of IFNγ signaling pathway in HA20 patients, patients' monocytes showed higher levels of STAT1 without stimulation, as well as higher phosphorylated (active) STAT1 levels following IFNγ stimulation. In conclusion, our study show that in the clinical spectrum of HA20 autoimmune features may predominate over autoinflammatory features and demonstrate, from a molecular point of view, the involvement of A20 in modulating not only the NF-kB, but also the IFNγ pathway.

COVID-19-Associated Multisystem Inflammatory Syndrome in a Neonate with Atypical Coronary Artery Involvement.

OBJECTIVE: The study aimed to report a novel coronavirus disease 2019 (COVID-19)-associated multisystem inflammatory syndrome in children (MIS-C) in a neonate found to have an atypical diffuse thickening in coronary artery walls whose diagnosis required a multi-imaging approach. STUDY DESIGN: A neonate presented at birth with multiple organ involvement and coronary artery anomalies. A diagnosis of MIS-C associated with COVID-19 was supported by maternal severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection during pregnancy, and by the presence of both immunoglobulin (Ig)-G against SARS-CoV-2 and spike-specific memory B-cells response in the neonatal blood. Other plausible causes of the multiple organ involvement were excluded. RESULT: At admission, a severe coronary artery dilatation was identified on echocardiography, supporting the diagnosis of the MIS-C Kawasaki-like disease; however, coronary artery internal diameters were found to be normal using cardiac computed tomography angiography. At discharge, comparing the two imaging techniques each other, the correct diagnosis resulted to be an abnormal thickening in coronary arterial walls. These findings suggest that the inflammatory process affecting the coronary arterial wall in MIS-C could result not only in typical coronary artery lesions such as dilatation of the lumen or aneurysms development but also in abnormal thickening of the coronary artery wall. CONCLUSION: Our case provides an alert for pediatric cardiologists about the complexity to assess coronary artery involvement in MIS-C and raises the question that whether an abnormal vascular remodeling, with normal inner diameters, is to be considered like coronary artery dilatation for risk stratification. KEY POINTS: · COVID-19 associated MIS-C can present in neonates with multiple organ involvement.. · Coronary artery assessment in neonatal MIS-C could be complex, and a multi-imaging approach could be required.. · Beside the typical coronary artery lesions, such as dilatation of the lumen or aneurysms, also abnormal thickening of the coronary artery wall can occur..

SARS-CoV-2 Vaccine Induced Atypical Immune Responses in Antibody Defects: Everybody Does their Best.

BACKGROUND: Data on immune responses to SARS-CoV-2 in patients with Primary Antibody Deficiencies (PAD) are limited to infected patients and to heterogeneous cohorts after immunization. METHODS: Forty-one patients with Common Variable Immune Deficiencies (CVID), six patients with X-linked Agammaglobulinemia (XLA), and 28 healthy age-matched controls (HD) were analyzed for anti-Spike and anti-receptor binding domain (RBD) antibody production, generation of Spike-specific memory B-cells, and Spike-specific T-cells before vaccination and one week after the second dose of BNT162b2 vaccine. RESULTS: The vaccine induced Spike-specific IgG and IgA antibody responses in all HD and in 20% of SARS-CoV-2 naive CVID patients. Anti-Spike IgG were detectable before vaccination in 4 out 7 CVID previously infected with SARS-CoV-2 and were boosted in six out of seven patients by the subsequent immunization raising higher levels than patients naïve to infection. While HD generated Spike-specific memory B-cells, and RBD-specific B-cells, CVID generated Spike-specific atypical B-cells, while RBD-specific B-cells were undetectable in all patients, indicating the incapability to generate this new specificity. Specific T-cell responses were evident in all HD and defective in 30% of CVID. All but one patient with XLA responded by specific T-cell only. CONCLUSION: In PAD patients, early atypical immune responses after BNT162b2 immunization occurred, possibly by extra-follicular or incomplete germinal center reactions. If these responses to vaccination might result in a partial protection from infection or reinfection is now unknown. Our data suggests that SARS-CoV-2 infection more effectively primes the immune response than the immunization alone, possibly suggesting the need for a third vaccine dose for patients not previously infected.

IgA Antibodies and IgA Deficiency in SARS-CoV-2 Infection.

A large repertoire of IgA is produced by B lymphocytes with T-independent and T-dependent mechanisms useful in defense against pathogenic microorganisms and to reduce immune activation. IgA is active against several pathogens, including rotavirus, poliovirus, influenza virus, and SARS-CoV-2. It protects the epithelial barriers from pathogens and modulates excessive immune responses in inflammatory diseases. An early SARS-CoV-2 specific humoral response is dominated by IgA antibodies responses greatly contributing to virus neutralization. The lack of anti-SARS-Cov-2 IgA and secretory IgA (sIgA) might represent a possible cause of COVID-19 severity, vaccine failure, and possible cause of prolonged viral shedding in patients with Primary Antibody Deficiencies, including patients with Selective IgA Deficiency. Differently from other primary antibody deficiency entities, Selective IgA Deficiency occurs in the vast majority of patients as an asymptomatic condition, and it is often an unrecognized, Studies are needed to clarify the open questions raised by possible consequences of a lack of an IgA response to SARS-CoV-2.

Follow-up evaluation of the immunological status of children admitted for acute cerebral nervous system infections: a retrospective study.

BACKGROUND: Acute Cerebral Nervous System Infections (ACNS) may cause death or severe complications even to promptly treated children. The role of the immune system in influencing the course and the outcome of meningitis has been studied but it is not yet completely understood. The aim of the research is to ascertain whether children who experienced ACNS infection had a normal immune system. METHODS: Patients under 18 years of age admitted at Bambino Gesù Children from January 2006 till June 2016 for meningitis were asked to participate to the follow-up study. The immune status was evaluated both clinically and by laboratory investigations. RESULTS: Most of the patients over 3 years at follow up had at least one immunological alteration at follow-up evaluation (74%). Considering ACNS infection etiology, certain pathogens were almost exclusive of patients affected by some immunological alteration, regardless of their age. DISCUSSION: Our preliminary results indicate that sub-clinical immunological defects may be associated to ACNS pediatric infections. Moreover, to the best of our knowledges, this is the first study correlating pathogens to immune evaluation in ACNS infections. It is, however, important to underline the high frequency of persistent immunological alterations in the analyzed patients. Further studies are needed to confirm our conclusions. CONCLUSIONS: We recommend an immunological assessment at follow up evaluation in children who experienced an ACNS infection.

Spleen development is modulated by neonatal gut microbiota.

The full development of the mammalian immune system occurs after birth upon exposure to non self-antigens. The gut is the first site of bacterial colonization where it is crucial to create the appropriate microenvironment able to balance effector or tolerogenic responses to external stimuli. It is a well-established fact that at mucosal sites bacteria play a key role in developing the immune system but we ignore how colonising bacteria impact the maturation of the spleen. Here we addressed this issue. Taking advantage of the fact that milk SIgA regulates bacterial colonization of the newborn intestine, we generated immunocompetent mice born either from IgA pro-efficient or IgA deficient females. Having demonstrated that SIgA in maternal milk modulates neonatal gut microbiota by promoting an increased diversity of the colonizing species we also found that immunocompetent pups, not exposed to milk SIgA, fail to properly develop the FDC network and primary follicles in the spleen compromising the response to T-dependent antigens. The presence of a less diverse microbiota with a higher representation of pathogenic species leads to a fast replenishment of the marginal zone and the IgM plasma cell compartment of the spleen as well as IgA plasma cells in the gut.