OTULIN haploinsufficiency predisposes to environmentally directed inflammation.

Recently, OTULIN haploinsufficiency was linked to enhanced susceptibility to infections accompanied by local necrosis and systemic inflammation. The pathogenesis observed in haploinsufficient patients differs from the hyperinflammation seen in classical OTULIN-related autoinflammatory syndrome (ORAS) patients and is characterized by increased susceptibility of dermal fibroblasts to alpha toxin-inflicted cytotoxic damage. Immunological abnormalities were not observed in OTULIN haploinsufficient patients, suggesting a non-hematopoietic basis.

CTLA4-Ig Effectively Controls Clinical Deterioration and Immune Condition in a Murine Model of Foxp3 Deficiency.

Purpose: FOXP3 deficiency results in severe multisystem autoimmunity in both mice and humans, driven by the absence of functional regulatory T cells. Patients typically present with early and severe autoimmune polyendocrinopathy, dermatitis, and severe inflammation of the gut, leading to villous atrophy and ultimately malabsorption, wasting, and failure to thrive. In the absence of successful treatment, FOXP3-deficient patients usually die within the first 2 years of life.

Homozygous DBF4 mutation as a cause of severe congenital neutropenia.

Background: Severe congenital neutropenia presents with recurrent infections early in life as a result of arrested granulopoiesis. Multiple genetic defects are known to block granulocyte differentiation; however, a genetic cause remains unknown in approximately 40% of cases.

Objective: We aimed to characterize a patient with severe congenital neutropenia and syndromic features without a genetic diagnosis.

DNA replication-associated inborn errors of immunity.

Inborn errors of immunity are a heterogeneous group of monogenic immunologic disorders caused by mutations in genes with critical roles in the development, maintenance, or function of the immune system. The genetic basis is frequently a mutation in a gene with restricted expression and/or function in immune cells, leading to an immune disorder. Several classes of inborn errors of immunity, however, result from mutation in genes that are ubiquitously expressed.

Disrupted Ca homeostasis and immunodeficiency in patients with functional IP receptor subtype 3 defects.

Calcium signaling is essential for lymphocyte activation, with genetic disruptions of store-operated calcium (Ca) entry resulting in severe immunodeficiency. The inositol 1,4,5-trisphosphate receptor (IPR), a homo- or heterotetramer of the IPR1-3 isoforms, amplifies lymphocyte signaling by releasing Ca from endoplasmic reticulum stores following antigen stimulation. Although knockout of all IPR isoforms in mice causes immunodeficiency, the seeming redundancy of the isoforms is thought to explain the absence of variants in human immunodeficiency.

Common variable immunodeficiency in two kindreds with heterogeneous phenotypes caused by novel heterozygous mutations.

NFKB1 haploinsufficiengcy was first described in 2015 in three families with common variable immunodeficiency (CVID), presenting heterogeneously with symptoms of increased infectious susceptibility, skin lesions, malignant lymphoproliferation and autoimmunity. The described mutations all led to a rapid degradation of the mutant protein, resulting in a p50 haploinsufficient state. Since then, more than 50 other mutations have been reported, located throughout different domains of NFKB1 with the majority situated in the N-terminal Rel homology domain (RHD).

A Novel Homozygous Stop Mutation in IL23R Causes Mendelian Susceptibility to Mycobacterial Disease.

Purpose: Mendelian susceptibility to mycobacterial disease (MSMD) is caused by inborn errors of IFN-γ immunity. The most frequent genetic defects are found in IL12 or a subunit of its receptor. IL23R deficiency in MSMD has only been reported once, in two pediatric patients from the same kindred with isolated disseminated Bacille Calmette-Guérin disease.

A disease-associated missense mutation in CYP4F3 affects the metabolism of leukotriene B4 via disruption of electron transfer.

Background: Cytochrome P450 4F3 (CYP4F3) is an ω-hydroxylase that oxidizes leukotriene B4 (LTB4), prostaglandins, and fatty acid epoxides. LTB4 is synthesized by leukocytes and acts as a chemoattractant for neutrophils, making it an essential component of the innate immune system. Recently, involvement of the LTB4 pathway was reported in various immunological disorders such as asthma, arthritis, and inflammatory bowel disease.

Monogenic Adult-Onset Inborn Errors of Immunity.

Inborn errors of immunity (IEI) are a heterogenous group of disorders driven by genetic defects that functionally impact the development and/or function of the innate and/or adaptive immune system. The majority of these disorders are thought to have polygenic background. However, the use of next-generation sequencing in patients with IEI has led to an increasing identification of monogenic causes, unravelling the exact pathophysiology of the disease and allowing the development of more targeted treatments.

Case Report: VEXAS Syndrome: From Mild Symptoms to Life-Threatening Macrophage Activation Syndrome.

Recently, a novel disorder coined VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome was identified in patients with adult-onset inflammatory syndromes, often accompanied by myelodysplastic syndrome1. All patients had myeloid lineage-restricted somatic mutations in UBA1 affecting the Met41 residue of the protein and resulting in decreased cellular ubiquitylation activity and hyperinflammation. We here describe the clinical disease course of two VEXAS syndrome patients with somatic UBA1 mutations of which one with a mild phenotype characterized by recurrent rash and symmetric polyarthritis, and another who was initially diagnosed with idiopathic multicentric Castleman disease and developed macrophage activation syndrome as a complication of the VEXAS syndrome.

Increased IL-10-producing regulatory T cells are characteristic of severe cases of COVID-19.

Objectives: The pandemic spread of the coronavirus SARS-CoV-2 is due, in part, to the immunological properties of the host-virus interaction. The clinical presentation varies from individual to individual, with asymptomatic carriers, mild-to-moderate-presenting patients and severely affected patients. Variation in immune response to SARS-CoV-2 may underlie this clinical variation.

Adult-Onset ANCA-Associated Vasculitis in SAVI: Extension of the Phenotypic Spectrum, Case Report and Review of the Literature.

STING-associated vasculopathy with onset in infancy (SAVI) is an autosomal dominant disorder due to gain-of-function mutations in , also known as , encoding for STING. It was reported as a vasculopathy of infancy. However, since its description a wider spectrum of associated manifestations and disease-onset has been observed.

Defective Sec61α1 underlies a novel cause of autosomal dominant severe congenital neutropenia.

Background: The molecular cause of severe congenital neutropenia (SCN) is unknown in 30% to 50% of patients. SEC61A1 encodes the α-subunit of the Sec61 complex, which governs endoplasmic reticulum protein transport and passive calcium leakage. Recently, mutations in SEC61A1 were reported to be pathogenic in common variable immunodeficiency and glomerulocystic kidney disease.

A Rare Case of Angioimmunoblastic T-Cell Lymphoma with Epstein-Barr Virus-Negative Reed-Sternberg-Like B-Cells, Chylous Ascites, and Chylothorax.

Angioimmunoblastic T-cell lymphoma is a rare non-Hodgkin lymphoma with dismal prognosis. The median age of presentation ranges from 62 to 69 years with generalized lymphadenopathy, B symptoms, and hepatosplenomegaly as the most prevalent symptoms. The combination of B-cell and T-cell proliferations is common in AITL and the B-cell component may resemble Reed-Sternberg-like B-cells.

Inappropriate costimulation and aberrant DNA methylation as therapeutic targets in angioimmunoblastic T-cell lymphoma.

Angioimmunoblastic T-cell lymphoma (AITL) is one of the most common subtypes of peripheral T-cell lymphoma. Advances in understanding the mutational landscape of AITL have not resulted in improved prognosis nor consensus regarding optimal first-line and second-line treatment. The recently proposed multistep tumorigenesis model for AITL provides a theoretical framework of AITL oncogenesis.

Food-Derived Bioactives Can Protect the Anti-Inflammatory Activity of Cortisol with Antioxidant-Dependent and -Independent Mechanisms.

In chronic inflammatory diseases the anti-inflammatory effect of glucocorticoids (GCs) is often decreased, leading to GC resistance. Inflammation is related with increased levels of reactive oxygen species (ROS), leading to oxidative stress which is thought to contribute to the development of GC resistance. Plant-derived compounds such as flavonoids are known for their ability to protect against ROS.