David N Assis1, Hiroki Takahashi2, Lin Leng3, Mikio Zeniya2,4, James L Boyer3, Richard Bucala3. 1. Section of Digestive Diseases, Yale University School of Medicine, 333 Cedar St, 1080 LMP, New Haven, CT, 06510, USA. david.assis@yale.edu. 2. The Jikei University School of Medicine, Tokyo, Japan. 3. Section of Digestive Diseases, Yale University School of Medicine, 333 Cedar St, 1080 LMP, New Haven, CT, 06510, USA. 4. Clinical Research Center, Sanno Hospital, International University of Health and Welfare, Tokyo, Japan.
Abstract
BACKGROUND: The pathogenesis of autoimmune hepatitis (AIH) is incompletely understood. Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine implicated in the pathophysiology of multiple autoimmune diseases. We recently reported that MIF expression was increased in a US AIH cohort. MIF expression in non-Western AIH patients is unknown. A MIF-173 GC single nucleotide polymorphism in the MIF promoter (rs755622) is clinically associated with steroid resistance in several inflammatory disorders but has not been evaluated in AIH. AIM: To compare MIF polymorphisms and their relationship to clinical parameters in AIH patients from the USA and Japan. METHODS: DNA and matched sera from AIH patients and healthy controls from Japan (N = 52) were compared to the US group. Serum concentrations of MIF and its circulating receptor CD74 were measured by ELISA. MIF-173 GC (rs755622) and MIF-794 CATT5-8 (rs5844572) polymorphisms were analyzed by standard methods. MIF genotypes were correlated with serum ALT and steroid requirements. RESULTS: Serum MIF was increased in Japanese AIH patients versus local controls, in agreement with the US AIH patients. Within both AIH groups, ALT was higher in CC/GC versus GG patients. Further, the steroid requirement was higher in AIH patients with GC/CC genotypes from both groups. In the Japanese patient group, the GC/CC genotype also was associated with acute symptomatic presentation. CONCLUSIONS: The MIF-173 CC/GC genotypes may be associated with both higher ALT and maintenance steroid requirements in AIH patients from the USA and Japan. This polymorphism could be a marker of disease severity in AIH patients.
BACKGROUND: The pathogenesis of autoimmune hepatitis (AIH) is incompletely understood. Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine implicated in the pathophysiology of multiple autoimmune diseases. We recently reported that MIF expression was increased in a US AIH cohort. MIF expression in non-Western AIH patients is unknown. A MIF-173 GC single nucleotide polymorphism in the MIF promoter (rs755622) is clinically associated with steroid resistance in several inflammatory disorders but has not been evaluated in AIH. AIM: To compare MIF polymorphisms and their relationship to clinical parameters in AIH patients from the USA and Japan. METHODS: DNA and matched sera from AIH patients and healthy controls from Japan (N = 52) were compared to the US group. Serum concentrations of MIF and its circulating receptor CD74 were measured by ELISA. MIF-173 GC (rs755622) and MIF-794 CATT5-8 (rs5844572) polymorphisms were analyzed by standard methods. MIF genotypes were correlated with serum ALT and steroid requirements. RESULTS: Serum MIF was increased in Japanese AIH patients versus local controls, in agreement with the US AIH patients. Within both AIH groups, ALT was higher in CC/GC versus GG patients. Further, the steroid requirement was higher in AIH patients with GC/CC genotypes from both groups. In the Japanese patient group, the GC/CC genotype also was associated with acute symptomatic presentation. CONCLUSIONS: The MIF-173 CC/GC genotypes may be associated with both higher ALT and maintenance steroid requirements in AIH patients from the USA and Japan. This polymorphism could be a marker of disease severity in AIH patients.
Authors: Ynto S de Boer; Nicole M F van Gerven; Antonie Zwiers; Bart J Verwer; Bart van Hoek; Karel J van Erpecum; Ulrich Beuers; Henk R van Buuren; Joost P H Drenth; Jannie W den Ouden; Robert C Verdonk; Ger H Koek; Johannes T Brouwer; Maureen M J Guichelaar; Jan M Vrolijk; Georg Kraal; Chris J J Mulder; Carin M J van Nieuwkerk; Janett Fischer; Thomas Berg; Felix Stickel; Christoph Sarrazin; Christoph Schramm; Ansgar W Lohse; Christina Weiler-Normann; Markus M Lerch; Matthias Nauck; Henry Völzke; Georg Homuth; Elisabeth Bloemena; Hein W Verspaget; Vinod Kumar; Alexandra Zhernakova; Cisca Wijmenga; Lude Franke; Gerd Bouma Journal: Gastroenterology Date: 2014-04-23 Impact factor: 22.682
Authors: Nicole M F van Gerven; Bart J Verwer; Birgit I Witte; Bart van Hoek; Minneke J Coenraad; Karel J van Erpecum; Ulrich Beuers; Henk R van Buuren; Rob A de Man; Joost P H Drenth; Jannie W den Ouden; Robert C Verdonk; Ger H Koek; Johannes T Brouwer; Maureen M J Guichelaar; Chris J J Mulder; Karin M J van Nieuwkerk; Gerd Bouma Journal: J Hepatol Date: 2012-09-16 Impact factor: 25.083
Authors: F Alvarez; P A Berg; F B Bianchi; L Bianchi; A K Burroughs; E L Cancado; R W Chapman; W G Cooksley; A J Czaja; V J Desmet; P T Donaldson; A L Eddleston; L Fainboim; J Heathcote; J C Homberg; J H Hoofnagle; S Kakumu; E L Krawitt; I R Mackay; R N MacSween; W C Maddrey; M P Manns; I G McFarlane; K H Meyer zum Büschenfelde; M Zeniya Journal: J Hepatol Date: 1999-11 Impact factor: 25.083
Authors: M Bacher; C N Metz; T Calandra; K Mayer; J Chesney; M Lohoff; D Gemsa; T Donnelly; R Bucala Journal: Proc Natl Acad Sci U S A Date: 1996-07-23 Impact factor: 11.205
Authors: M A Llamas-Covarrubias; Y Valle; R Bucala; R E Navarro-Hernández; C A Palafox-Sánchez; J R Padilla-Gutiérrez; I Parra-Rojas; A G Bernard-Medina; Z Reyes-Castillo; J F Muñoz-Valle Journal: Cytokine Date: 2013-02-09 Impact factor: 3.861
Authors: Marina Vivarelli; Leila Emma D'Urbano; Gilda Stringini; Gian Marco Ghiggeri; Gianluca Caridi; Rachelle Donn; Alberto Tozzi; Francesco Emma; Fabrizio De Benedetti Journal: Pediatr Nephrol Date: 2008-01-29 Impact factor: 3.714
Authors: T Calandra; J Bernhagen; C N Metz; L A Spiegel; M Bacher; T Donnelly; A Cerami; R Bucala Journal: Nature Date: 1995-09-07 Impact factor: 49.962
Authors: Fang-Fang Wang; Xin-Fang Huang; Nan Shen; Lin Leng; Richard Bucala; Shun-Le Chen; Liang-Jing Lu Journal: Arthritis Res Ther Date: 2013 Impact factor: 5.156
Authors: C Zhang; C Ramsey; A Berical; L Yu; L Leng; K A McGinnis; Y Song; H Michael; M C McCormack; H Allore; A Morris; K Crothers; R Bucala; P J Lee; M Sauler Journal: Am J Physiol Lung Cell Mol Physiol Date: 2018-12-06 Impact factor: 5.464
Authors: Gil Benedek; Mahmoud Abed El Latif; Keren Miller; Mila Rivkin; Ally Ahmed Ramadhan Lasu; Lul P Riek; Richard Lako; Shimon Edvardson; Sagit Arbel-Alon; Eithan Galun; Mia Levite Journal: PLoS Negl Trop Dis Date: 2021-10-18