TREM2 is required for microglial instruction of astrocytic synaptic engulfment in neurodevelopment

Variants in the microglial receptor TREM2 confer risk for multiple neurodegenerative diseases. However, it remains unknown how this receptor functions on microglia to modulate these diverse neuropathologies. To understand the role of TREM2 on microglia more generally, we investigated changes in microglial function in Trem2−/− mice. We found that loss of TREM2 impairs normal neurodevelopment, resulting in reduced synapse number across the cortex and hippocampus in 1-month-old mice. This reduction in synapse number was not due directly to alterations in interactions between microglia and synapses. Rather, TREM2 was required for microglia to limit synaptic engulfment by astrocytes during development. While these changes were largely normalized later in adulthood, high fat diet administration was sufficient to reinitiate TREM2-dependent modulation of synapse loss. Together, this identifies a novel role for microglia in instructing synaptic pruning by astrocytes to broadly regulate appropriate synaptic refinement, and suggests novel candidate mechanisms for how TREM2 and microglia could influence synaptic loss in brain injury and disease

Relevance of laboratory testing for the diagnosis of primary immunodeficiencies: a review of case-based examples of selected immunodeficiencies

The field of primary immunodeficiencies (PIDs) is one of several in the area of clinical immunology that has not been static, but rather has shown exponential growth due to enhanced physician, scientist and patient education and awareness, leading to identification of new diseases, new molecular diagnoses of existing clinical phenotypes, broadening of the spectrum of clinical and phenotypic presentations associated with a single or related gene defects, increased bioinformatics resources, and utilization of advanced diagnostic technology and methodology for disease diagnosis and management resulting in improved outcomes and survival. There are currently over 200 PIDs with at least 170 associated genetic defects identified, with several of these being reported in recent years. The enormous clinical and immunological heterogeneity in the PIDs makes diagnosis challenging, but there is no doubt that early and accurate diagnosis facilitates prompt intervention leading to decreased morbidity and mortality. Diagnosis of PIDs often requires correlation of data obtained from clinical and radiological findings with laboratory immunological analyses and genetic testing. The field of laboratory diagnostic immunology is also rapidly burgeoning, both in terms of novel technologies and applications, and knowledge of human immunology. Over the years, the classification of PIDs has been primarily based on the immunological defect(s) ("immunophenotype") with the relatively recent addition of genotype, though there are clinical classifications as well. There can be substantial overlap in terms of the broad immunophenotype and clinical features between PIDs, and therefore, it is relevant to refine, at a cellular and molecular level, unique immunological defects that allow for a specific and accurate diagnosis. The diagnostic testing armamentarium for PID includes flow cytometry - phenotyping and functional, cellular and molecular assays, protein analysis, and mutation identification by gene sequencing. The complexity and diversity of the laboratory diagnosis of PIDs necessitates many of the above-mentioned tests being performed in highly specialized reference laboratories. Despite these restrictions, there remains an urgent need for improved standardization and optimization of phenotypic and functional flow cytometry and protein-specific assays. A key component in the interpretation of immunological assays is the comparison of patient data to that obtained in a statistically-robust manner from age and gender-matched healthy donors. This review highlights a few of the laboratory assays available for the diagnostic work-up of broad categories of PIDs, based on immunophenotyping, followed by examples of disease-specific testing

L'INDEMNITY CLAUSE NEI CONTRATTI DI CESSIONE DI PARTECIPAZIONI SOCIALI

\u201cIndemnity clauses in sale and purchase agreement under Italian law\u201d This work is a comparative analysis of the problems arising from indemnity clauses in sale and purchase agreements under Italian Law. In a contract for the sale of shares of a s.p.a or a s.r.l., the seller usually provides representations and warranties by which he guarantees to the buyer the presence of certain characteristics of the target company\u2019s assets. The collateral asset, financial and income provided for this purpose is usually integrated and completed by indemnity clauses, through which the parties regulate the activation and the limits of the guarantees, as well as the consequences and remedies arising from their breach of these representations and warranties. In particular, the content of indemnity clauses may consist of an obligation to: a) indemnify and hold the buyer harmless from any current or potential contingent liability (usually existing at the last balance sheet date); b ) indemnify the buyer for any undeclared debt or loss of assets; c) compensate for any loss or damage suffered by the target that would not have occurred if the financial situation of the company were correctly represented and described in the business warranties contained in the sale and purchase agreement. The thesis contains three sections: (i) a description of the main theoretical problems arising from the application of indemnity clauses, typical of the common law systems, to the Italian legal system; (ii) an exam of the different ways in which an indemnity clause could be drafted by the parties in the most common cases, as well as the interpretative issues involved; (iii) a study of the strong difficulty to frame the indemnity clause under the categories of the Italian legal system (such as, for example, damages, price adjustment, penalty clauses) with an attempt to understand how to recognize the indemnity clause its own juridical autonomy. Granting such autonomy and, as the author tried to do, identifying a set of rules which could be used to regulate the indemnity clause appears to be necessary. This is not only in the light of the difficult application of Italian law to the issues created by the breach of business warranties in sale and purchase agreements, but also in the light of the cross-border and transnational scenario in which the indemnity clause is usually used and operates

Of Omenn and mice

Omenn syndrome (OS) is a peculiar immunodeficiency in which profound T and B cell defects are associated with severe autoimmune-like manifestations . Although the molecular and biochemical basis of OS have been elucidated, the mechanisms leading to T cell infiltration of peripheral tissues such as skin and gut still remain unsolved. Two murine models with hypomorphic mutations in rag genes reproducing OS features and a murine model of lymphopenia-derived autoimmunity with similar immunopathology were recently described. The aim of this review is to integrate clues on the roles of impaired thymic development and lymphopenia in the pathogenesis of autoimmunity