Immune Alterations in Patients With Type 1 Autoimmune Hepatitis Persist Upon Standard Immunosuppressive Treatment

Amédée Renand (1, 2) , Sarah Habes (3, 1, 4) , Jean-François Mosnier (5, 2) , Hélène Aublé (6) , Jean-Paul Judor (1, 2) , Nicolas Vince (1, 7) , Philippe Hulin (8) , Steven Nedellec (8) , Sylvie Métairie (9) , Isabelle Archambeaud (4, 10) , Sophie Brouard (1, 2) , Jérôme Gournay (4) , Sophie Conchon (1, 2)

1 ITUN - Institut de transplantation urologie-néphrologie
2 Team 4 - U1064 Inserm - CRTI - Immunoregulation And Immunointervention in Transplantation and Autoimmunity
3 U1064 Inserm - CRTI - Centre de Recherche en Transplantation et Immunologie
4 Service d'hépato-gastro-entérologie, cancérologie digestive et assistance nutritionnelle [CHU de Nantes]
5 Service d’Anatomie et Cytologie Pathologiques [CHU Nantes]
6 Centre d'Investigation Clinique gastro-nutrition [CHU Nantes]
7 Team 5 - U1064 Inserm - CRTI - Translational ImmunoGenetic in AutoImmunity and Transplantation
8 SFR François Bonamy - Structure fédérative de recherche François Bonamy
9 Service Chirurgie Digestive et Endocrinienne [CHU Nantes]
10 Institut des Maladies de l'Appareil Digestif

Autoimmune hepatitis (AIH) is a rare disease characterized by an immune attack of the liver. This study consists of a comprehensive analysis of immune alterations related to AIH at diagnosis, and during remission phase under treatment. A total of 37 major lymphocyte populations were analyzed from the peripheral blood of new-onset AIH patients (AIHn; n = 14), AIH patients with controlled disease (n = 11), and healthy subjects (n = 14). Liver biopsy analyses were performed to complete the blood phenotypic analysis. Four blood lymphocyte populations were significantly altered in AIHn patients at diagnosis compared with healthy subjects. Levels of mucosal-associated invariant T cells (MAIT), Type 1/Type 17 helper (Th1/ Th17) cells, clusters of differentiation (CD4) T cells, and invariant natural killer T cells were decreased, whereas MAIT granzyme B+ (GrB) cells were increased. A trend toward an increase of CD8+CD161+GrB+ cells was also observed. These alterations were not restored with standard immunosuppressive treatments. In the liver of AIHn patients, CD4, forkhead box P3 (Foxp3), and MAIT cell markers were enriched in the portal tract, and CD8, CD161, and GrB markers were enriched in the hepatic lobule. During remission, the hepatic lobule was clear of infiltrating T cells, but residual CD4 and MAIT cells were found in the portal tract, where Foxp3 was decreased, as previously described. In vitro, MAIT cells were functionally altered in AIH patients. Ex vivo MAIT cell activity (GrB) was linked to severe fibrosis. Conclusion: Our work proposes a global view of the lymphocyte alterations from diagnosis to remission phase in AIH patients. The absence of blood immune homeostasis restoration and the persistence of a CD4 infiltrate in the liver under standard immunosuppres-sion could form the basis of the high risk of relapse observed in AIH.

Domaines: Médecine humaine et pathologie

Amédée Renand, Sarah Habes, Jean-François Mosnier, Hélène Aublé, Jean-Paul Judor, et al.. Immune Alterations in Patients With Type 1 Autoimmune Hepatitis Persist Upon Standard Immunosuppressive Treatment. International Hepatology Communications, 2018, 2 (8), pp.968-981. ⟨inserm-02157607⟩