Precision medicine: The use of tailored therapy in primary immunodeficiencies.

Primary immunodeficiencies (PID) are rare, complex diseases that can be characterised by a spectrum of phenotypes, from increased susceptibility to infections to autoimmunity, allergy, auto-inflammatory diseases and predisposition to malignancy. With the introduction of genetic testing in these patients and wider use of next-Generation sequencing techniques, a higher number of pathogenic genetic variants and conditions have been identified, allowing the development of new, targeted treatments in PID. The concept of precision medicine, that aims to tailor the medical interventions to each patient, allows to perform more precise diagnosis and more importantly the use of treatments directed to a specific defect, with the objective to cure or achieve long-term remission, minimising the number and type of side effects.

Recurrent pyogenic infections caused by a novel Gln1420* mutation in the C3 gene.

C3 is a crucial protein of the complement system. Congenital C3 deficiency is extremely rare and manifests through recurrent, severe infections and should always be considered as a differential diagnosis of recurrent pyogenic infections. We report a case of a patient with a novel C3 gene mutation, responsible for complete C3 deficiency with impaired complement system activation and recurrent infections.

Case Report: Wide Spectrum of Manifestations of Ligase IV Deficiency: Report of 3 Cases.

DNA ligase IV deficiency is a rare autosomal recessive disorder associated with impaired DNA repair mechanisms. Most patients with DNA repair defects present with neurologic deficits, combined immunodeficiency, bone marrow failure, and/or hematologic neoplasia. We present 3 unrelated cases of ligase IV deficiency with different clinical presentations.

Case Report: Primary Immunodeficiencies, Massive EBV+ T-Cell Lympoproliferation Leading to the Diagnosis of ICF2 Syndrome.

In immunocompromised patients, EBV may elicit B-cell transformation and proliferation. A 5-year-old microcephalic boy was admitted with fever and non-malignant polymorphic T-cell lymphoproliferative disease associated with EBV. A presumptive diagnosis of primary immunodeficiency with inability to control EBV was made and next-generation sequencing led to the identification of a novel ZBTB24 mutation (ICF2-syndrome).

Variants in STXBP3 are Associated with Very Early Onset Inflammatory Bowel Disease, Bilateral Sensorineural Hearing Loss and Immune Dysregulation.

Background And Aims: Very early onset inflammatory bowel disease [VEOIBD] is characterized by intestinal inflammation affecting infants and children less than 6 years of age. To date, over 60 monogenic aetiologies of VEOIBD have been identified, many characterized by highly penetrant recessive or dominant variants in underlying immune and/or epithelial pathways. We sought to identify the genetic cause of VEOIBD in a subset of patients with a unique clinical presentation.

A Novel TRAF3IP2 Mutation Causing Chronic Mucocutaneous Candidiasis.

Inborn errors of the IL-17-mediated signaling have been associated with chronic mucocutaneous candidiasis (CMC). We describe a patient with CMC, atopic dermatitis, enamel dysplasia, and recurrent parotitis harboring a novel compound heterozygous mutation of TRAF3IP2, leading to autosomal recessive ACT1 deficiency and deficient IL-17 signaling.

Haploidentical α/β T-cell and B-cell depleted stem cell transplantation in severe mevalonate kinase deficiency.

Objective: Mevalonic aciduria represents the most severe form of mevalonate kinase deficiency (MKD). Patients with mevalonic aciduria have an incomplete response even to high doses of anti-cytokine drugs such as anakinra or canakinumab and stem cell transplantation (SCT) represents a possible therapy for this severe disease.

Methods: We report the first two children affected by severe MKD who received haploidentical α/β T-cell and B-cell depleted SCT.

Phosphorylated full-length Tau interacts with 14-3-3 proteins via two short phosphorylated sequences, each occupying a binding groove of 14-3-3 dimer.

Protein-protein interactions (PPIs) remain poorly explored targets for the treatment of Alzheimer's disease. The interaction of 14-3-3 proteins with Tau was shown to be linked to Tau pathology. This PPI is therefore seen as a potential target for Alzheimer's disease.

Fragment-based Differential Targeting of PPI Stabilizer Interfaces.

Stabilization of protein-protein interactions (PPIs) holds great potential for therapeutic agents, as illustrated by the successful drugs rapamycin and lenalidomide. However, how such interface-binding molecules can be created in a rational, bottom-up manner is a largely unanswered question. We report here how a fragment-based approach can be used to identify chemical starting points for the development of small-molecule stabilizers that differentiate between two different PPI interfaces of the adapter protein 14-3-3.

Selectivity via Cooperativity: Preferential Stabilization of the p65/14-3-3 Interaction with Semisynthetic Natural Products.

Natural compounds are an important class of potent drug molecules including some retrospectively found to act as stabilizers of protein-protein interactions (PPIs). However, the design of synthetic PPI stabilizers remains an understudied approach. To date, there are limited examples where cooperativity has been utilized to guide the optimization of a PPI stabilizer.

Design of Drug-Like Protein-Protein Interaction Stabilizers Guided By Chelation-Controlled Bioactive Conformation Stabilization.

Protein-protein interactions (PPIs) of 14-3-3 proteins are a model system for studying PPI stabilization. The complex natural product Fusicoccin A stabilizes many 14-3-3 PPIs but is not amenable for use in SAR studies, motivating the search for more drug-like chemical matter. However, drug-like 14-3-3 PPI stabilizers enabling such studies have remained elusive.

Nuclear Magnetic Resonance Spectroscopy Insights into Tau Structure in Solution: Impact of Post-translational Modifications.

Although Tau is an intrinsically disordered protein, some level of structure can still be defined, corresponding to short stretches of dynamic secondary structures and a preferential global fold described as an ensemble of conformations. These structures can be modified by Tau phosphorylation, and potentially other post-translational modifications. The analytical capacity of Nuclear Magnetic Resonance (NMR) spectroscopy provides the advantage of offering a residue-specific view of these modifications, allowing to link specific sites to a particular structure.

Set-up and screening of a fragment library targeting the 14-3-3 protein interface.

Protein-protein interactions (PPIs) are at the core of regulation mechanisms in biological systems and consequently became an attractive target for therapeutic intervention. PPIs involving the adapter protein 14-3-3 are representative examples given the broad range of partner proteins forming a complex with one of its seven human isoforms. Given the challenges represented by the nature of these interactions, fragment-based approaches offer a valid alternative for the development of PPI modulators.

Adoption of a Turn Conformation Drives the Binding Affinity of p53 C-Terminal Domain Peptides to 14-3-3σ.

The interaction between the adapter protein 14-3-3σ and transcription factor p53 is important for preserving the tumor-suppressor functions of p53 in the cell. A phosphorylated motif within the C-terminal domain (CTD) of p53 is key for binding to the amphipathic groove of 14-3-3. This motif is unique among 14-3-3 binding partners, and the precise dynamics of the interaction is not yet fully understood.

Fatal Meningitis in Patient with X-Linked Chronic Granulomatous Disease Caused by Virulent Granulibacter bethesdensis.

Granulibacter bethesdensis is a pathogen reported to cause recurrent lymphadenitis exclusively in persons with chronic granulomatous disease. We report a case of fatal meningitis caused by a highly virulent G. bethesdensis strain in an adolescent in Europe who had chronic granulomatous disease.

X-linked agammaglobulinemia (XLA):Phenotype, diagnosis, and therapeutic challenges around the world.

Background: X-linked agammaglobulinemia is an inherited immunodeficiency recognized since 1952. In spite of seven decades of experience, there is still a limited understanding of regional differences in presentation and complications. This study was designed by the Primary Immunodeficiencies Committee of the World Allergy Organization to better understand regional needs, challenges and unique patient features.

[H Factor Deficiency: A Case with an Atypical Presentation].

We report a case of an 18-month-old boy with H factor deficiency with atypical presentation: recurrent acute otitis media and several maternal family members with autoimmune disorders (vitiligo, thyroiditis and immune trombocytopenia). Blood tests revealed low C3 and AH50, as well as low properdin and H factor. I factor was normal.

Invasive Meningococcal Disease Unraveling a Novel Mutation in the C5 Gene in a Portuguese Family.

Although bacterial meningitis is a rare presentation of a congenital immunodeficiency, invasive meningococcal disease is classically associated with complement deficiencies. We report a patient from a consanguineous kindred presenting with an invasive meningococcal disease caused by serogroup B meningococcus that revealed an underlying C5 deficiency caused by a novel mutation in the C5 gene.

Plerixafor for the Treatment of WHIM Syndrome.

WHIM syndrome (warts, hypogammaglobulinemia, infections, and myelokathexis), a primary immunodeficiency disorder involving panleukopenia, is caused by autosomal dominant gain-of-function mutations in CXC chemokine receptor 4 (CXCR4). Myelokathexis is neutropenia caused by neutrophil retention in bone marrow. Patients with WHIM syndrome are often treated with granulocyte colony-stimulating factor (G-CSF), which can increase neutrophil counts but does not affect cytopenias other than neutropenia.

Novel Mutation in a Patient With APLAID and Cutis Laxa.

The auto-inflammation and phospholipase Cγ2 (PLCγ2)-associated antibody deficiency and immune dysregulation (APLAID) syndrome is a rare primary immunodeficiency caused by a gain-of-function mutation S707Y in the gene previously described in two patients from one family. The APLAID patients presented with early-onset blistering skin lesions, posterior uveitis, inflammatory bowel disease (IBD) and recurrent sinopulmonary infections caused by a humoral defect, but lacked circulating autoantibodies and had no cold-induced urticaria, contrary to the patients with the related PLAID syndrome. We describe a new APLAID patient who presented with vesiculopustular rash in the 1st weeks of life, followed by IBD, posterior uveitis, recurrent chest infections, interstitial pneumonitis, and also had sensorineural deafness and cutis laxa.

Backbone chemical shift assignments of human 14-3-3σ.

14-3-3 proteins are a group of seven dimeric adapter proteins that exert their biological function by interacting with hundreds of phosphorylated proteins, thus influencing their sub-cellular localization, activity or stability in the cell. Due to this remarkable interaction network, 14-3-3 proteins have been associated with several pathologies and the protein-protein interactions (PPIs) established with a number of partners are now considered promising drug targets. The activity of 14-3-3 proteins is often isoform specific and to our knowledge only one out of seven isoforms, 14-3-3[Formula: see text], has been assigned.