Granzymes are a family of serine proteases that were once thought to function exclusively as mediators of cytotoxic lymphocyte‐induced target cell death. However, non‐apoptotic roles for granzymes, including granzyme K (GzK), have been proposed. As recent studies have observed elevated levels of GzK in the plasma of patients diagnosed with clinical sepsis, we hypothesized that extracellular GzK induces a proinflammatory response in endothelial cells. In the present study, extracellular GzK proteolytically activated protease‐activated receptor‐1 leading to increased interleukin 6 and monocyte chemotactic protein 1 production in endothelial cells. Enhanced expression of intercellular adhesion molecule 1 along with an increased capacity for adherence of THP‐1 cells was also observed. Characterization of downstream pathways implicated the mitogen‐activated protein kinase p38 pathway for intercellular adhesion molecule 1 expression, and both the p38 and the extracellular signal‐regulated protein kinases 1 and 2 pathways in cytokine production. GzK also increased tumour necrosis factor α‐induced inflammatory adhesion molecule expression. Furthermore, the physiological inhibitor of GzK, inter‐α‐inhibitor protein, significantly inhibited GzK activity in vitro. In summary, extracellular GzK promotes a proinflammatory response in endothelial cells.

Caspase recruitment domain (CARD) protein-B cell CLL/lymphoma 10 (BCL10)-MALT1 paracaspase (MALT1) [CBM] complexes are critical signaling adaptors that facilitate immune and inflammatory responses downstream of both cell surface and intracellular receptors. Germline mutations that alter the function of members of this complex (termed CBMopathies) cause a broad array of clinical phenotypes, ranging from profound combined immunodeficiency to B-cell lymphocytosis. With an increasing number of patients being described in recent years, the clinical spectrum of diseases associated with CBM-opathies is rapidly expanding and becoming unexpectedly heterogeneous. Here we review major discoveries that have shaped our understanding of CBM complex biology, and we provide an overview of the clinical presentation, diagnostic approach, and treatment options for those carrying germline mutations affecting CARD9,

We report three new cases of a germline heterozygous gain-of-function missense (p.(Met1141Lys)) mutation in the C2 domain of phospholipase C gamma 2 (PLCG2) associated with symptoms consistent with previously described auto-inflammation and phospholipase Cγ2 (PLCγ2)-associated antibody deficiency and immune dysregulation (APLAID) syndrome and pediatric common variable immunodeficiency (CVID). Functional evaluation showed platelet hyper-reactivity, increased B cell receptor-triggered calcium influx and ERK phosphorylation. Expression of the altered p.(Met1141Lys) variant in a PLCγ2knockout DT40 cell line showed clearly enhanced BCR-triggered influx of external calcium when compared to controltransfected cells. Our results further expand the molecular basis of pediatric CVID and phenotypic spectrum of PLCγ2-related defects. Keywords Germline PLCγ2 mutations . PLCγ2 C2 domainHighlights A hypermorphic missense mutation in the C2 domain of PLCG2 is associated with pediatric CVID

STAT6 (signal transducer and activator of transcription 6) is a transcription factor that plays a central role in the pathophysiology of allergic inflammation. We have identified 16 patients from 10 families spanning three continents with a profound phenotype of early-life onset allergic immune dysregulation, widespread treatment-resistant atopic dermatitis, hypereosinophilia with esosinophilic gastrointestinal disease, asthma, elevated serum IgE, IgE-mediated food allergies, and anaphylaxis. The cases were either sporadic (seven kindreds) or followed an autosomal dominant inheritance pattern (three kindreds). All patients carried monoallelic rare variants in STAT6 and functional studies established their gain-of-function (GOF) phenotype with sustained STAT6 phosphorylation, increased STAT6 target gene expression, and TH2 skewing. Precision treatment with the anti–IL-4Rα antibody, dupilumab, was highly effective improving both clinical manifestations and immunological biomarkers. This study identifies heterozygous GOF variants in STAT6 as a novel autosomal dominant allergic disorder. We anticipate that our discovery of multiple kindreds with germline STAT6 GOF variants will facilitate the recognition of more affected individuals and the full definition of this new primary atopic disorder.

Cardiac fibrosis is observed across diverse etiologies of heart failure. Granzyme B (GzmB) is a serine protease involved in cell-mediated cytotoxicity in conjunction with the pore-forming protein, perforin. Recent evidence suggests that GzmB also contributes to matrix remodeling and fibrosis through an extracellular, perforin-independent process. However, the role of GzmB in the onset and progression of cardiac fibrosis remains elusive. The present study investigated the role of GzmB in the pathogenesis of cardiac fibrosis. GzmB was elevated in fibrotic human hearts and in angiotensin II-induced murine cardiac fibrosis. Genetic deficiency of GzmB reduced angiotensin II-induced cardiac hypertrophy and fibrosis, independently of perforin. GzmB deficiency also reduced microhemorrhage, inflammation, and fibroblast accumulation in vivo. In vitro, GzmB cleaved the endothelial junction protein, vascular endothelial (VE)-cadherin, resulting in the disruption of endothelial barrier function. Together, these results suggest a perforin-independent, extracellular role for GzmB in the pathogenesis of cardiac fibrosis.

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STAT6 (Signal transducer and activator of transcription 6) is a transcription factor that plays a central role in the pathophysiology of allergic inflammation. STAT6 mediates the biological effects of IL-4, a cytokine necessary for type 2 differentiation of T cells and B cell survival, proliferation and class switching to IgE. We have identificated two unrelated patients with a phenotype notable for their early-life onset of profound allergic immune dysregulation, widespread treatment-resistant atopic dermatitis, hypereosinophilia with esosinophilic esophagitis, elevated serum IgE, IgE-mediated food allergies, and vascular anomalies of the brain. Both patients harbored heterozygous de novo missense variants in the DNA binding domain of STAT6 (c.1144G>C, p.E382Q; and c.1256A>G, p.D419G). Functional studies established that both variants caused a gain-of-function (GOF) phenotype associated with enhanced phosphorylation and transcriptional activity of STAT6, in addition to increased transcript abundance of known STAT6 target genes and other genes implicated in allergic disease. JAK inhibitors decreased the enhanced STAT6 responses associated with both these STAT6 GOF variants. This study identifies heterozygous GOF variants in STAT6 as a novel autosomal dominant allergic disorder. We anticipate that our discovery of the first humans with germline STAT6 GOF variants will facilitate the recognition of more affected individuals and the full definition of this new primary atopic disorder.