The role of androgens in autoimmune liver diseases

The autoimmune liver diseases autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) exhibit some of the highest female predominance among all autoimmune diseases. The underlying reasons remain unknown but there is evidence that androgens play an important role in mediating sex differences in immunity. To analyse the effects of androgens on immune cells, we recruited different human cohorts: transgender people before and during gender-affirming hormone therapy (GAHT) and age-matched cis women with PBC, AIH and healthy controls and performed detailed analyses of immune cells. We found that testosterone affects CD4+ T cell function by inhibiting Th1 and Th17 differentiation and by supporting the differentiation into regulatory T (Treg) cells. We noted decreased testosterone serum levels in women with PBC compared to age-matched controls, supporting a potential role of androgens for T cell dysfunction in this disease. In a trans man with AIH/primary sclerosing cholangitis variant syndrome we observed a markedly improved clinical disease course and profound changes in T cell state using single-cell RNA sequencing during GAHT.

We hypothesise that androgens affect T cells directly and that androgen signalling shapes the interaction between T cells and parenchymal cells in the liver.

We aim to dissect the cell-specific role of androgens in liver inflammation using conditional knockout models lacking the androgen receptor AR or/and the membrane-bound androgen receptor ZIP9 in T cells and liver parenchymal cells such as cholangiocytes. To investigate the sex-related immune cell state and the interaction between immune cells and hepatic parenchymal cells, we will analyse a large single-nucleus sequencing dataset derived from human liver samples we obtained from different liver diseases. We will functionally validate findings using established 3-D cholangiocyte organoid models. Overall, the elucidation of the role of androgen signalling in the liver may reveal novel treatment targets for autoimmune liver diseases.

Liwinski T, Auer MK, Schröder J, Pieknik I, Casar C, Schwinge D, Henze L, Stalla GK, Lang UE, von Klitzing A, Briken P, Hildebrandt T, Desbuleux JC, Biedermann SV, Holterhus PM, Bang C, Schramm C*, Fuss J*. (2024)
Gender-affirming hormonal therapy induces a gender-concordant fecal metagenome transition in transgender individuals.
BMC Med I 22:346

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Poch T*, Bahn J*, Casar C, Krause J, Evangelakos I, Gilladi H, Kunzmann LK, Laschtowitz A, Iuso N, Schäfer AM, Liebig LA, Steinmann S, Sebode M, Folseraas T, Engesæter LK, Karlsen TH, Franke A, Hubner N, Schlein C, Galun E, Huber S, Lohse AW, Gagliani N, Schwinge D*, Schramm C*. (2024)
Intergenic risk variant rs56258221 skews the fate of naive CD4+ T cells via miR4464-BACH2 interplay in primary sclerosing cholangitis.
Cell Rep Med I 5:101620

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Zecher BF, Ellinghaus D, Schloer S, Niehrs A, Padoan B, Baumdick ME, Yuki Y, Martin MP, Glow D, Schroder-Schwarz J, Niersch J, Brias S, Muller LM, Habermann R, Kretschmer P, Fruh T, Danekas J, Wehmeyer MH, Poch T, Sebode M, International PSCSG, Ellinghaus E, Degenhardt F, Korner C, Hoelzemer A, Fehse B, Oldhafer KJ, Schumacher U, Sauter G, Carrington M, Franke A, Bunders MJ, Schramm C, Altfeld M. (2024)
HLA-DPA1*02:01~B1*01:01 is a risk haplotype for primary sclerosing cholangitis mediating activation of NKp44+ NK cells.
Gut I 73:325-337

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Laschtowitz A, de Veer RC, Van der Meer AJ, Schramm C. (2020)
Diagnosis and treatment of primary biliary cholangitis.
United European Gastroenterol J I 8:667-674

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Sebode M, Kloppenburg A, Aigner A, Lohse AW, Schramm C, Linder R. (2020)
Population-based study of autoimmune hepatitis and primary biliary cholangitis in Germany: rising prevalences based on ICD codes, yet deficits in medical treatment.
Z Gastroenterol I 58:431-438

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Liwinski T, Zenouzi R, John C, Ehlken H, Ruhlemann MC, Bang C, Groth S, Lieb W, Kantowski M, Andersen N, Schachschal G, Karlsen TH, Hov JR, Rosch T, Lohse AW, Heeren J, Franke A, Schramm C. (2020)
Alterations of the bile microbiome in primary sclerosing cholangitis.
Gut I 69:665-672

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Poch T*, Krause J*, Casar C, Liwinski T, Glau L, Kaufmann M, Ahrenstorf AE, Hess LU, Ziegler AE, Martrus G, Lunemann S, Sebode M, Li J, Schwinge D, Krebs CF, Franke A, Friese MA, Oldhafer KJ, Fischer L, Altfeld M, Lohse AW, Huber S, Tolosa E*, Gagliani N*, Schramm C*. 2021.
Single-cell atlas of hepatic T cells reveals expansion of liver-resident naive-like CD4(+) T cells in primary sclerosing cholangitis.
J Hepatol I 75:414-423

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Kunzmann LK*, Schoknecht T*, Poch T, Henze L, Stein S, Kriz M, Grewe I, Preti M, Hartl J, Pannicke N, Peiseler M, Sebode M, Zenouzi R, Horvatits T, Bottcher M, Petersen BS, Weiler-Normann C, Hess LU, Ahrenstorf AE, Lunemann S, Martrus G, Fischer L, Li J, Carambia A, Kluwe J, Huber S, Lohse AW, Franke A, Herkel J, Schramm C, Schwinge D. (2020)
Monocytes as potential mediators of pathogen-induced Th17 differentiation in patients with primary sclerosing cholangitis (PSC).
Hepatology I 72:1310-1326

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Glaser F*, John C*, Engel B*, Höh B, Weidemann S, Dieckhoff J, Stein S, Becker N, Casar C, Amrei Schuran F, Wieschendorf B, Preti M, Jessen F, Franke A, Carambia A, Lohse AW, Ittrich H, Herkel J, Heeren J, Schramm C*, and Schwinge D*. (2019)
Liver infiltrating T cells regulate bile acid metabolism in experimental cholangitis.
J Hepatol I 71:783-792

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Schwinge D*, von Haxthausen F*, Quaas A, Carambia A, Otto B, Glaser F, Hoh B, Thiele N, Schoknecht T, Huber S, Steffens N, Lohse AW, Herkel J, Schramm C. (2017)
Dysfunction of hepatic regulatory T cells in experimental sclerosing cholangitis is related with IL-12 signaling.
J Hepatol I 66: 798-805

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* equally contributing authors