SummaryBackgroundSevere acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), the causative pathogen of coronavirus disease 2019 (COVID‐19), became a global threat to human health. Liver impairment has been frequently reported as a common manifestation, although its clinical significance is still unclear, particularly in patients with underlying chronic liver disease (CLD).AimsTo summarise the changes in liver function tests during SARS‐CoV‐2 infection and the impact of COVID‐19 in patients with underlying CLD.MethodsA literature review using online database PubMed was done using the search terms “SARS‐CoV‐2”, “COVID‐19”, “liver”, “cirrhosis” and “liver transplantation”.ResultsCOVID‐19 is frequently associated with different degrees of abnormal liver function tests, most notably transaminases, which are usually transitory and of mild degree. Available evidence suggests that liver injury may result from direct pathogenic effect by the virus, systemic inflammation or toxicity from commonly used drugs in this subset of patients. SARS‐CoV‐2 infection in children is associated with minimal or no increase in liver enzymes, thus the presence of abnormal liver function tests should trigger evaluation for underlying liver diseases. Although it seems that patients with CLD are not at greater risk for acquiring the infection, those with cirrhosis, hepatocellular carcinoma, non‐alcoholic fatty liver disease, autoimmune liver diseases or liver transplant may have a greater risk for severe COVID‐19.ConclusionsAbnormal liver function tests during the course of COVID‐19 are common, though clinically significant liver injury is rare. Further research is needed focusing on the effect of existing liver‐related comorbidities on treatment and outcome of COVID‐19.

Regulatory T cells (Tregs) are central to the maintenance of self-tolerance and tissue homeostasis. Markers commonly used to define human Tregs in the research setting include high expression of CD25, FOXP3 positivity and low expression/negativity for CD127. Many other markers have been proposed, but none unequivocally identifies bona fide Tregs. Tregs are equipped with an array of mechanisms of suppression, including the modulation of antigen presenting cell maturation and function, the killing of target cells, the disruption of metabolic pathways and the production of anti-inflammatory cytokines. Treg impairment has been reported in a number of human autoimmune conditions and includes Treg numerical and functional defects and conversion into effector cells in response to inflammation. In addition to intrinsic Treg impairment, resistance of effector T cells to Treg control has been described. Discrepancies in the literature are common, reflecting differences in the choice of study participants and the technical challenges associated with investigating this cell population. Studies differ in terms of the methodology used to define and isolate putative regulatory cells and to assess their suppressive function. In this review we outline studies describing Treg frequency and suppressive function in systemic and organ specific autoimmune diseases, with a specific focus on the challenges faced when investigating Tregs in these conditions.

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Autoimmune hepatitis (AIH) is an important cause of severe liver disease and is associated with both quantitative and qualitative regulatory T-cell (Treg) impairments. Tregs express CD39, an ectonucleotidase responsible for extracellular nucleotide hydrolysis, culminating in the production of immunosuppressive adenosine. Here, we describe multiple CD39 pos Treg defects that potentially contribute to the impaired immunoregulation that is characteristic of AIH. We have examined the frequency and phenotype of CD39 pos Tregs by flow cytometry and measured their ectonucleotidase activity. The capacity of CD4 pos CD25 high , CD4 pos CD25 high CD39 pos , and CD4 pos CD25 high CD39 neg subsets to suppress both proliferation of effector T cells and interleukin (IL)-17 production was evaluated. In AIH, CD39 pos Tregs are decreased in frequency, exhibit limited adenosine triphosphate/adenosine diphosphate hydrolysis activity, and fail to suppress IL-17 production by effector CD4 T cells. Moreover, these CD39 pos Tregs display a more proinflammatory profile in AIH, which is characterized by elevated CD127 positivity, and a greater propensity to produce interferon-gamma or IL-17 upon challenge with proinflammatory stimuli. Conclusions: In AIH, CD39 pos Tregs are decreased in number, fail to adequately hydrolyze proinflammatory nucleotides and do not efficiently suppress IL-17 production by effector CD4 T cells. CD39 pos Tregs show plasticity and are unstable upon proinflammatory challenge, suggesting that defective immunoregulation in AIH might result not only from reduced Treg number and function, but also from increased conversion of Tregs into effector cells. (HEPATOLOGY 2014;59:1007-1015 See Editorial on Page 754A utoimmune hepatitis (AIH) is an inflammatory disease of the liver, characterized by female preponderance, interface hepatitis on histology, hypergammaglobulinemia, and serum autoantibody positivity. 1,2 Several lines of evidence indicate that in AIH, numerical and functional regulatory T-cell (Treg) defects are likely to play a permissive pathogenic role, allowing effector CD4 and CD8 T lymphocytes to initiate and perpetuate liver damage. [3][4][5] The reasons for Treg functional impairment in AIH are unclear. Previous studies in both mice and humans

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In autoimmune hepatitis (AIH), liver-damaging CD4 T cell responses are associated with defective CD4 pos CD25 pos regulatory T cells (T-regs). Galectin-9 (Gal9), a b-galactosidasebinding protein expressed by T-regs, is key to their function, inhibiting T helper 1 immune responses by binding T cell immunoglobulin and mucin domain 3 (Tim-3) on CD4 effector cells. We investigated whether impaired immunoregulation in AIH results from reduced expression of Gal9 in T-regs and/or Tim-3 on CD4 effector cells. Circulating Gal9 pos CD4 pos CD25 pos and Tim-3 pos CD4 pos CD25 neg T cell phenotype was assessed by flow cytometry in 75 AIH patients. To evaluate whether Tim-3 expression renders CD4 pos CD25 neg T cells amenable to T-reg control, purified CD4 pos CD25 neg Tim-3 pos (Tim-3 pos ) and CD4 pos CD25 neg Tim-3 neg (Tim-3 neg ) cells were cocultured with T-regs. To determine whether Gal9 expression is essential to function, T-regs were treated with small interfering RNA (siRNA) to repress Gal-9 translation; T-reg suppressor function was assessed by proliferation. In AIH, Tim-3 pos cells within CD4 pos CD25 neg cells and their T-bet pos and RORC pos subsets were fewer and contained higher numbers of interferon-c (IFNc) pos and interleukin (IL)-17 pos cells than healthy subjects (HS). In AIH and HS, Tim-3 pos cells proliferated less vigorously and were more susceptible to T-reg control than Tim-3 neg cells. In AIH, Gal9 pos T-regs were fewer and contained less FOXP3 pos , IL-10 pos , and transforming growth factor b pos and more IFNc pos and IL-17 pos cells than HS. siRNA treatment of Gal-9 pos T-regs drastically reduced T-reg ability to suppress CD4 pos CD25 neg and Tim-3 pos cell proliferation in AIH and HS. Tim-3 pos cell percentage correlated inversely with aminotransferase and CD25 neg T-bet pos cell values. Conclusion: Reduced levels of Tim-3 on CD4 pos CD25 neg effector cells and of Gal9 in T-regs contribute to impaired immunoregulation in AIH by rendering effector cells less prone to T-reg control and T-regs less capable of suppressing. (HEPATOLOGY 2012;56:677-686) A utoimmune hepatitis (AIH) is a progressive inflammatory liver disorder characterized by hypergammaglobulinemia, circulating autoantibodies, and histologically by a florid mononuclear cell infiltration referred to as interface hepatitis. 1,2 CD4 effector lymphocytes are the main orchestrators of liver damage in AIH, their proliferation and proinflammatory cytokine secretion (e.g., interferon-c [IFNc]) being correlated with the activity and severity of liver disease. 3 We have provided evidence that in AIH, the extent of autoreactive CD4 T cell effector immune responses is associated with a numerical and functional impairment of CD4 pos CD25 high regulatory T cells (T-regs), 4-6 a lymphocyte subset central to immunotolerance maintenance. 7,8 Because they are defective, T-regs in AIH are unable to control proliferation and effector cytokine production (i.e., IFNc, interleukin [IL]-17) by responder CD4 T cells stimulated in vitro with polyclonal or a...

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