Polyclonal T-cell responses to cytochrome P450IID6 are associated with disease activity in autoimmune hepatitis type 2.
OBJECTIVE
Autoimmune hepatitis type 2 (AIH-2), a severe juvenile liver disorder of unknown etiology and pathogenesis, is characterized by liver-kidney microsomal antibody type 1 targeting cytochrome P450IID6 (CYP2D6) and is associated to HLA DRB1*07. Although CYP2D6 B-cell reactivity has been extensively characterized, little is known about CYP2D6-specific T-cell responses. The aim of the present study was to characterize anti-CYP2D6 cellular immune responses and their possible pathogenic role in patients with AIH-2.


METHODS
We investigated T-cell reactivity against 61 overlapping peptides spanning the full CYP2D6 protein using ex vivo cultures obtained at diagnosis, remission, and relapse. Moreover, CYP2D6-specific T-cell reactivity was investigated in the context of HLA restriction, peptide-binding affinity to HLA DRB1*07, cytokine profile, disease specificity, and clinical course.


RESULTS
Proliferative responses to CYP2D6 cluster to 7 antigenic regions in DRB1*07 and to 4 regions in non-DRB1*07 patients. Whereas distinct peptides induce production of interferon gamma, interleukin-4, or interleukin-10, peptides inducing interferon-gamma and proliferation overlap. There is also an overlap between sequences inducing T- and B-cell responses. The breadth (number of epitopes) and intensity (quantity of cytokine produced) of the T-cell response are directly correlated to disease activity (biochemical and histologic markers).


CONCLUSIONS
These data imply that the T-cell response to CYP2D6 in AIH-2 is polyclonal, involves multiple effector types targeting different epitopes, and is associated with hepatocyte damage, knowledge that should form the basis for a more refined therapeutic approach.
Ma
Yun
Y
Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, Denmark Hill, London, United Kingdom.
Bogdanos
Dimitrios P
DP
Hussain
Munther J
MJ
Underhill
James
J
Bansal
Sanjay
S
Longhi
Maria Serena
MS
Cheeseman
Paul
P
Mieli-Vergani
Giorgina
G
Vergani
Diego
D
D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D019389:Cytochrome P-450 CYP2D6 / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D018604:Epitope Mapping; D018984:Epitopes, T-Lymphocyte; D005260:Female; D006684:HLA-DR Antigens / Q000276:immunology; D059811:HLA-DRB1 Chains; D019693:Hepatitis, Autoimmune / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation; D008297:Male; D008969:Molecular Sequence Data
D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C456920:HLA-DRB1*07 antigen; D019389:Cytochrome P-450 CYP2D6