RESUMEN
IL-12 is a pro-inflammatory cytokine that induces the production of interferon-γ (IFNγ) and favours the differentiation of T helper 1 (Th1) cells. In the presence of IL-12 human Treg cells acquire a Th1-like phenotype with reduced suppressive activity in vitro. Primary biliary cholangitis (PBC) is an autoimmune cholestatic liver disease characterised by high Th1 and Th17 infiltrating cells, reduced frequencies of Treg cells, and a genetic association with IL-12 signalling. Herein, we sought to evaluate the IL-12 signalling pathway in PBC pathology, by studying human samples from patients with PBC, alongside those with primary Sjögren's syndrome (pSS)(autoimmune disease with IL-12 signalling gene association), primary sclerosing cholangitis (PSC) (cholestatic liver disease without IL-12 gene association) and healthy individuals. Our data revealed that TLR stimulation of PBC (nâ¯=â¯17) and pSS monocytes (nâ¯=â¯6) resulted in significant induction of IL12A mRNA (pâ¯<â¯0.05, pâ¯<â¯0.01, respectively) compared to PSC monocytes (nâ¯=â¯13) and at similar levels to HC monocytes (nâ¯=â¯8). PSC monocytes expressed significantly less IL-12p70 (108â¯pg/ml, mean) and IL-23 (358â¯pg/ml) compared to HC (458â¯pg/ml and 951â¯pg/ml, respectively) (pâ¯<â¯0.01, pâ¯<â¯0.05). Treg cells from patients with PBC (nâ¯=â¯16) and pSS (nâ¯=â¯3) but not PSC (nâ¯=â¯10) and HC (nâ¯=â¯8) responded to low dose (10â¯ng/ml) IL-12 stimulation by significant upregulation of IFNγ (mean 277 and 254â¯pg/ml, respectively) compared to PSC and HC Treg cells (mean 22 and 77â¯pg/ml, respectively)(pâ¯<â¯0.05). This effect was mediated by the rapid and strong phosphorylation of STAT4 on Treg cells from patients with PBC and pSS (pâ¯<â¯0.05) but not PSC and HC. In the liver of patients with PBC (nâ¯=â¯7) a significantly higher proportion of IL-12Rß2+Tregs (16% on average) was detected (pâ¯<â¯0.05) compared to other liver disease controls (5%)(nâ¯=â¯18) which also showed ex vivo high IFNG and TBET expression. CONCLUSION: Our data show an increased sensitivity of PBC and pSS Treg cells to low dose IL-12 stimulation, providing ongoing support for the importance of the IL12-IL-12Rß2-STAT4 pathway on Treg cells in disease pathogenesis and potentially treatment.
Asunto(s)
Colangitis Esclerosante/inmunología , Interferón gamma/inmunología , Subunidad p35 de la Interleucina-12/inmunología , Cirrosis Hepática Biliar/inmunología , Síndrome de Sjögren/inmunología , Linfocitos T Reguladores/inmunología , Adulto , Autoinmunidad , Estudios de Casos y Controles , Diferenciación Celular , Colangitis Esclerosante/genética , Colangitis Esclerosante/patología , Femenino , Regulación de la Expresión Génica , Humanos , Interferón gamma/genética , Interleucina-12/genética , Interleucina-12/inmunología , Subunidad p35 de la Interleucina-12/genética , Interleucina-23/genética , Interleucina-23/inmunología , Cirrosis Hepática Biliar/genética , Cirrosis Hepática Biliar/patología , Activación de Linfocitos , Masculino , Persona de Mediana Edad , Monocitos/inmunología , Monocitos/patología , Fenotipo , Factor de Transcripción STAT4/genética , Factor de Transcripción STAT4/inmunología , Síndrome de Sjögren/genética , Síndrome de Sjögren/patología , Linfocitos T Reguladores/patología , Células TH1/inmunología , Células TH1/patología , Células Th17/inmunología , Células Th17/patologíaRESUMEN
BACKGROUND & AIMS: Autoimmune pancreatitis (AIP) is a fibroinflammatory condition affecting the pancreas and could present as a multisystem disorder. Diagnosis and management can pose a diagnostic challenge in certain groups of patients. We report our experience of managing this condition in a tertiary pancreaticobiliary centre in the North East of England. METHODS: Patients were identified from a prospectively maintained database of patients diagnosed with AIP between 2005 and 2013. Diagnosis of definite/probable AIP was based on the revised HISORt criteria. When indicated, patients were treated with steroids and relapses were treated with azathioprine. All patients have been followed up to date. RESULTS: Twenty-two patients were diagnosed with AIP during this period. All patients had pancreatic protocol CT performed while some patients had either MR or EUS as part of the work up. Fourteen out of 22 (64%) had an elevated IgG4 level (mean: 10.9 g/L; range 3.4 - 31 g/L). Four (18%) patients underwent surgery. Extrapancreatic involvement was seen in 15 (68%) patients, with biliary involvement being the commonest. Nineteen (86%) were treated with steroids and five (23%) required further immunosuppression for treatment of relapses. The mean follow up period was 36.94 months (range 7 - 94). CONCLUSION: Autoimmune pancreatitis is being increasingly recognized in the British population. Extrapancreatic involvement, particularly extrahepatic biliary involvement seems to be a frequent feature. Diagnosis should be based on accepted criteria as this significantly reduces the chances of overlooking malignancy. Awareness of this relatively rare condition and a multi-disciplinary team approach will help us to diagnose and treat this condition more effectively thereby reducing unnecessary interventions.