Female preponderance of primary biliary cholangitis is all about our understanding of its autoimmune nature

Are Gender Differences Important for Autoimmune Liver Diseases?

“…Furthermore, a recent systematic review of population-based studies reported the highest incidence in Northern Europe (Finland, 1.58, and Norway, 1.3, per 100,000 subjects, respectively) and Minnesota (1.47), with the lowest rate observed in the Mediterranean area (Italy, 0.1) [86]. Using the database from the Italian Epidemiological Rare Disease Registry, the crude annual incidence of PSC in females increased from 0.05 per 100,000 in 2012 to 0.09 per 100,000 in 2014, reaching a rate similar to that of males [67].…”

“…Mechanistically, the knockout of interferon type I signaling prevents this female-prevalent autoimmune cholangitis phenotype [66]. Although an effect directly exerted by estrogens on IFN-γ expression has not yet been demonstrated, it is well known that sexual hormones can modify the expression of pattern of recognition receptors, such as Toll-like receptors (TLR) [67]. Therefore, this modulation can have an impact on the levels of type 1 IFN, indirectly.…”

“…Female BALB/C mice develop a more severe drug-induced AIH Tregs confer protection against drug-induced autoimmune hepatitis [13,14] Estrogens Estrogens promote DC maturation, leading to an increase in Th1 cells activity, increased production of proinflammatory ILs, Estrogens upregulate the expression of checkpoint inhibitors, e.g., PD-L1 [20][21][22][23][24] Androgens Androgens may influence the pathogenesis of AIH by shifting the Th-1 to the Th-2 phenotype, reducing hepatic Th-17 and increasing IL-10 secretion, which drives Treg differentiation [25][26][27][28] Pregnancy Pregnancy increases risk of fetal and maternal complications and flares in AIH activity after delivery [15][16][17] HLA-DR3 Increased expression of HLA-DR3 (DRB1*0301) in male AIH patients [31] HLA-DR4 Increased HLA-DR4 (DRB1*0401) in female AIH patients [32] PBC Estrogens ERα and Erβ modulate cholangiocyte response to damage, activating intracellular cascades involving ERK1/2 and PI3-kinase/AKT Estrogens stimulate the secretion of different growth factors in proliferating cholangiopathies and shift Th cells from Th1 to the Th2 phenotype Sexual hormone regulation of TLRs affect type 1 IFN that may impact on PBC progression Estrogens exert a homeostatic positive effect on cholangiocytes [3,[62][63][64]67]…”

Reasons why women are more likely to develop primary biliary cholangitis

“…Sex hormones affect the function of immune cells by binding to their receptors. In general, estrogens are thought to enhance humoral immunity, whereas androgens and progestins suppress it [ 17 ]. The ERS1 and ERS2 genes encode the nuclear estrogen receptors ERα and ERβ, respectively, which are differentially expressed in different tissues and cells, mainly ERα in T cells and ERβ in B cells, and can modulate the immune response through binding effects with ERα or ERβ [ 15 , 18 ].Binding of estrogen to ERα stimulates proliferation of Th17 cells, which affects a number of autoimmune diseases [ 19 ]; increased estrogen levels during pregnancy lead to decreased production of B lymphocytes through interaction with ERα or ERβ; In contrast, serum immunoglobulin levels were elevated in nonpregnant women following estrogen therapy; low doses of estrogen also induce production of pro-inflammatory cytokines by mononuclear macrophages [ 20 ].ERβ expression in T cells was significantly lower in patients with systemic lupus erythematosus (SLE) than in controls, as also observed in inflammatory bowel disease species [ 21 , 22 ].ERα was found to exhibit strong pro-inflammatory properties in which ERβ was found to inhibit immunoreactivity in SLE mice by SLE mouse model [ 23 ].…”