Patients with systemic sclerosis show phenotypic and functional defects in neutrophils

BACKGROUND Systemic sclerosis (SSc) is a multiorgan autoimmune disease characterized by inflammation, vascular modification, and progressive fibrosis of the skin and several visceral organs. Innate and adaptive immune cells, including myeloid, B and T cells, are believed to be central to the pathogenesis of SSc. However, the role and functional state of neutrophil granulocytes (neutrophils) are ill-defined in SSc. METHODS We performed a prospective study of neutrophils freshly isolated from SSc patients and healthy donors (HD) by measuring in these neutrophils (i) functional cell surface markers, including CD16, CD62L, CD66b, CD66c, CXCR1, CXCR2, and CXCR4; (ii) cytokine-activated intracellular signal transducer and activator of transcription (STAT) pathways, such as phosphorylated STAT3 (pSTAT3), pSTAT5, and pSTAT6; (iii) production of neutrophil extracellular traps (NET) and intracellular myeloperoxidase (MPO); and (iv) phagocytosis of bacteria by the neutrophils. RESULTS Neutrophils of SSc patients expressed lower CD16 and CD62L and higher pSTAT3 and pSTAT6 compared to HD. Moreover, neutrophils of SSc patients lacked CXCR1 and CXCR2, the receptors responding to the potent neutrophil chemoattractant CXCL8. Neutrophils of SSc patients were also deficient in MPO levels, NET formation and phagocytosis of bacteria. CONCLUSIONS Neutrophils of patients with SSc display several functional defects affecting cell migration, NET formation, and phagocytosis of bacteria

IL-4 receptor engagement in human neutrophils impairs their migration and extracellular trap formation

Background Type 2 immunity serves to resist parasitic helminths, venoms, and toxins, but the role and regulation of neutrophils during type 2 immune responses are controversial. Helminth models suggested a contribution of neutrophils to type 2 immunity, whereas neutrophils are associated with increased disease severity during type 2 inflammatory disorders, such as asthma. Objective We sought to evaluate the effect of the prototypic type 2 cytokines IL-4 and IL-13 on human neutrophils. Methods Human neutrophils from peripheral blood were assessed without or with IL-4 or IL-13 for (1) expression of IL-4 receptor subunits, (2) neutrophil extracellular trap (NET) formation, (3) migration toward CXCL8 in vitro and in humanized mice, and (4) CXCR1, CXCR2, and CXCR4 expression, as well as (5) in nonallergic versus allergic subjects. Results Human neutrophils expressed both types of IL-4 receptors, and their stimulation through IL-4 or IL-13 diminished their ability to form NETs and migrate toward CXCL8 in vitro. Likewise, in vivo chemotaxis in NOD-scid-Il2rg−/− mice was reduced in IL-4–stimulated human neutrophils compared with control values. These effects were accompanied by downregulation of the CXCL8-binding chemokine receptors CXCR1 and CXCR2 on human neutrophils on IL-4 or IL-13 stimulation in vitro. Ex vivo analysis of neutrophils from allergic patients or exposure of neutrophils from nonallergic subjects to allergic donor serum in vitro impaired their NET formation and migration toward CXCL8, thereby mirroring IL-4/IL-13–stimulated neutrophils. Conclusion IL-4 receptor signaling in human neutrophils affects several neutrophil effector functions, which bears important implications for immunity in type 2 inflammatory disorders

Biased IL-2 signals induce Foxp3-rich pulmonary lymphoid structures and facilitate long-term lung allograft acceptance in mice

Transplantation of solid organs can be life-saving in patients with end-stage organ failure, however, graft rejection remains a major challenge. In this study, by pre-conditioning with interleukin-2 (IL-2)/anti-IL-2 antibody complex treatment biased toward IL-2 receptor α, we achieved acceptance of fully mismatched orthotopic lung allografts that remained morphologically and functionally intact for more than 90 days in immunocompetent mice. These allografts are tolerated by the actions of forkhead box p3 (Foxp3)$^{+}$ regulatory T (Treg) cells that home to the lung allografts. Although counts of circulating Treg cells rapidly return to baseline following cessation of IL-2 treatment, Foxp3$^{+}$ Treg cells persist in peribronchial and peribronchiolar areas of the grafted lungs, forming organized clusters reminiscent of inducible tertiary lymphoid structures (iTLS). These iTLS in lung allografts are made of Foxp3$^{+}$ Treg cells, conventional T cells, and B cells, as evidenced by using microscopy-based distribution and neighborhood analyses. Foxp3-transgenic mice with inducible and selective deletion of Foxp3$^{+}$ cells are unable to form iTLS in lung allografts, and these mice acutely reject lung allografts. Collectively, we report that short-term, high-intensity and biased IL-2 pre-conditioning facilitates acceptance of vascularized and ventilated lung allografts without the need of immunosuppression, by inducing Foxp3-controlled iTLS formation within allografts

Scuola/Università e mercato del lavoro: la transizione che non c’è. Quello che raccontano i percorsi di formazione e le esperienze di lavoro dei nostri studenti

La ricerca di nessi di causalità nella analisi delle dinamiche dei mercati del lavoro è sempre ardua, e ancora di più se ci si concentra sui fenomeni specificamente connessi al rapporto tra studio e lavoro, su cui intervengono molteplici variabili difficilmente inquadrabili negli schemi teorici utilizzati per spiegare i comportamenti legati alle scelte (individuali e politiche) che ruotano intorno al lavoro. Di fronte a tale incertezza emerge l’importanza dell’osservazione del dato di realtà per spiegare, comprendere e valutare anche le diverse opzioni di regolazione, che d’altra parte, almeno nel nostro Paese, raramente discendono da una adeguata base di conoscenza empirica dei fenomeni su cui intervengono

Contributo allo studio della funzione del contratto collettivo: il caso dell'apprendistato

Nel più ampio discorso intorno alla funzione del contratto collettivo, il caso dell'apprendistato è particolarmente emblematico. Lo studio delle origini delle relazioni industriali e della contrattazione collettiva e, in particolare, del modo in cui dell'apprendistato era governato e regolato dalle parti sociali, cioè come sistema (di governo) dell'incontro tra domanda e offerta di lavoro, dimostra efficacemente come il contratto collettivo storicamente abbia svolto una funzione istituzionale ben più ampia di quella meramente normativa di regolazione dei rapporti di lavoro individuali

Interleukin-4 receptor engagement impairs the migration and effector functions of neutrophils

Type 2 immunity serves to resist parasitic helminths, venoms, and toxins, but the role and regulation of neutrophils during type 2 immune responses are controversial. Helminth models suggested a contribution of neutrophils to type 2 immunity, whereas neutrophils are associated with increased disease severity during type 2 inflammatory disorders, such as asthma

La formazione dei lavoratori nei contratti collettivi tra vecchi e nuovi modelli

Il presente contributo ha l’obiettivo di verificare in che modo gli attori della rappresentanza sindacale e datoriale, per il tramite della contrattazione collettiva, hanno regolato la materia della formazione e della qualificazione e riqualificazione professionale dei lavoratori. Dal punto di vista metodologico, l’indagine procede con l’analisi di venti contratti collettivi nazionali del lavoro, individuati tra quelli più applicati, e di cinquanta accordi collettivi aziendali stipulati tra il 2012 e il 2022. Ad esito della ricerca è possibile rilevare un crescente interesse delle parti sociali verso la materia della formazione profes- sionale e segnalare le principali tendenze e modelli di regolazione