Immunomodulatory activity of extracellular Hsp70 mediated via paired receptors Siglec-5 and Siglec-14.

The intracellular chaperone heat-shock protein 70 (Hsp70) can be secreted from cells, but its extracellular role is unclear, as the protein has been reported to both activate and suppress the innate immune response. Potential immunomodulatory receptors on myelomonocytic lineage cells that bind extracellular Hsp70 are not well defined. Siglecs are Ig-superfamily lectins on mammalian leukocytes that recognize sialic acid-bearing glycans and thereby modulate immune responses. Siglec-5 and Siglec-14, expressed on monocytes and neutrophils, share identical ligand-binding domains but have opposing signaling functions. Based on phylogenetic analyses of these receptors, we predicted that endogenous sialic acid-independent ligands should exist. An unbiased screen revealed Hsp70 as a ligand for Siglec-5 and Siglec-14. Hsp70 stimulation through Siglec-5 delivers an anti-inflammatory signal, while stimulation through Siglec-14 is pro-inflammatory. The functional consequences of this interaction are also addressed in relation to a SIGLEC14 polymorphism found in humans. Our results demonstrate that an endogenous non-sialic acid-bearing molecule can be either a danger-associated or self-associated signal through paired Siglecs, and may explain seemingly contradictory prior reports on extracellular Hsp70 action.

Novel nonsense gain-of-function NFKB2 mutations associated with a combined immunodeficiency phenotype.

NF-κB signaling through its NFKB1-dependent canonical and NFKB2-dependent noncanonical pathways plays distinctive roles in a diverse range of immune processes. Recently, mutations in these 2 genes have been associated with common variable immunodeficiency (CVID). While studying patients with genetically uncharacterized primary immunodeficiencies, we detected 2 novel nonsense gain-of-function (GOF) NFKB2 mutations (E418X and R635X) in 3 patients from 2 families, and a novel missense change (S866R) in another patient. Their immunophenotype was assessed by flow cytometry and protein expression; activation of canonical and noncanonical pathways was examined in peripheral blood mononuclear cells and transfected HEK293T cells through immunoblotting, immunohistochemistry, luciferase activity, real-time polymerase chain reaction, and multiplex assays. The S866R change disrupted a C-terminal NF-κΒ2 critical site affecting protein phosphorylation and nuclear translocation, resulting in CVID with adrenocorticotropic hormone deficiency, growth hormone deficiency, and mild ectodermal dysplasia as previously described. In contrast, the nonsense mutations E418X and R635X observed in 3 patients led to constitutive nuclear localization and activation of both canonical and noncanonical NF-κΒ pathways, resulting in a combined immunodeficiency (CID) without endocrine or ectodermal manifestations. These changes were also found in 2 asymptomatic relatives. Thus, these novel NFKB2 GOF mutations produce a nonfully penetrant CID phenotype through a different pathophysiologic mechanism than previously described for mutations in NFKB2.

Cardiovascular Risk Factors and Echocardiographic Findings in a Predominantly Black Population with Rheumatoid Arthritis and Heart Failure.

Among White rheumatoid arthritis (RA) cohorts, heart failure with preserved ejection fraction (HFpEF) is the most prevalent type of heart failure (HF). We aimed to assess the type of HF affecting Black RA patients. 64 patients with RA-HF were compared to age-, sex-, and race-matched RA patients without HF. Left ventricular ejection fraction (LVEF), wall motion abnormalities, left ventricle (LV) mass, and wall thickness were reviewed. 87.3% were Black, 84.4% were women, with a mean age of 69.6 ± 1.38 (± SEM) and BMI (kg/m 2) 29.6 ± 1.07. RA-HF patients had higher rates of hypertension (HTN), chronic kidney disease, and atrial fibrillation. 66.7% had ≥3 cardiovascular risk factors compared to RA patients without HF. 2D-echocardiograms of RA-HF revealed that 62.3% had LVEF ≥50%, 37% had diastolic dysfunction, and 43.1% had wall motion abnormalities. LV mass and relative wall thickness measurements indicated LV eccentric remodeling. The odds ratio for HF was 4.7 (1.5-14.53 CI), p<0.01, among RA-HTN group and 3.5 (1.091-11.7 CI) p<0.01 among smokers. In our predominantly Black RA-HF patients, HFpEF was the most common type of HF. HTN was associated with the highest OR for HF. Eccentric hypertrophic remodeling, a known poor prognostic indicator for cardiovascular events, was found. Further studies are required to confirm our findings.