Hepatitis C Virus (HCV)-Specific Immune Responses of Long‐Term Injection Drug Users Frequently Exposed to HCV

BACKGROUND: Injection drug users (IDUs) who successfully clear hepatitis C virus (HCV) have a reduced risk of developing chronic reinfection, despite their continuing exposure to the virus. To identify immunological correlates for this apparent protection, we studied HCV-specific immune responses in long-term IDUs (duration, >10 years). METHODS: HCV-specific T cell responses were assessed in proliferation, enzyme-linked immunospot (ELISPOT), interferon (IFN)–γ secretion, and cytotoxicity assays, whereas HCV-specific antibodies were assessed in enzyme immunoassays (EIAs), chemiluminescent assays, and in vitro neutralization assays. RESULTS: HCV-specific T cell proliferation and IFN-γ production were more common in nonviremic EIA-positive IDUs (16 [94%] of 17 IDUs) than in viremic EIA-positive IDUs (9 [45%] of 20 IDUs) (P = .003). They were also noted in 16 (62%) of 26 nonviremic EIA-negative IDUs. In contrast, 19 (90%) of 21 viremic IDUs displayed neutralizing antibodies (nAbs), compared with 9 (56%) of 16 nonviremic EIA-positive IDUs (P = .04) and 0 of 24 nonviremic EIA-negative IDUs. Nonviremic IDUs with nAbs were older (P = .0115) than those without nAbs, but these groups did not differ in terms of either injection drug use duration or HCV-specific T cell responses. CONCLUSION: The reduced risk of HCV persistence in IDUs previously recovered from HCV infection correlated with T cell responses, and prolonged antigenic stimulation appears to be required to maintain humoral responses

Key Terms and Definitions in Acute Porphyrias: Results of an International Delphi Consensus Led by the European Porphyria Network

Background: Acute porphyrias are a group of rare inherited disorders causing acute neurovisceral attacks. Many terms used frequently in the literature and in clinical practice are ambiguous, which can lead to confusion in the way patients are managed, studied, and reported in clinical studies. Agreed definitions are a necessary first step in developing management guidelines and will facilitate communication of results of future clinical research. Methods: The Delphi method was used to generate consensus on key terms and definitions in acute porphyria. The process started with a brainstorming phase offered to all members of the European Porphyria Network followed by 2 Delphi rounds among international experts in the field of porphyria (the Acute Porphyria Expert Panel). A consensus of 75% or more was defined as the agreement threshold. Results: 63 respondents from 26 countries participated in the brainstorming phase, leading to the choice of 9 terms and definitions. 34 experts were invited to take part in the Delphi rounds. 7 of the initial 9 terms and definitions which entered the first Delphi round achieved the threshold for agreement. Following a second Delphi round, all 9 definitions achieved agreement. Conclusion: Agreement on the definitions for 9 important terms describing acute porphyrias represents a significant step forward for the porphyria community. It will facilitate more accurate comparison of outcomes among porphyria centres and in clinical trials and provide a strong framework for developing evidence based clinical guidelines.Background: Acute porphyrias are a group of rare inherited disorders causing acute neurovisceral attacks. Many terms used frequently in the literature and in clinical practice are ambiguous, which can lead to confusion in the way patients are managed, studied, and reported in clinical studies. Agreed definitions are a necessary first step in developing management guidelines and will facilitate communication of results of future clinical research. Methods: The Delphi method was used to generate consensus on key terms and definitions in acute porphyria. The process started with a brainstorming phase offered to all members of the European Porphyria Network followed by 2 Delphi rounds among international experts in the field of porphyria (the Acute Porphyria Expert Panel). A consensus of 75% or more was defined as the agreement threshold. Results: 63 respondents from 26 countries participated in the brainstorming phase, leading to the choice of 9 terms and definitions. 34 experts were invited to take part in the Delphi rounds. 7 of the initial 9 terms and definitions which entered the first Delphi round achieved the threshold for agreement. Following a second Delphi round, all 9 definitions achieved agreement. Conclusion: Agreement on the definitions for 9 important terms describing acute porphyrias represents a significant step forward for the porphyria community. It will facilitate more accurate comparison of outcomes among porphyria centres and in clinical trials and provide a strong framework for developing evidence based clinical guidelines

Functional Contribution of Elevated Circulating and Hepatic Non-Classical CD14+CD16+ Monocytes to Inflammation and Human Liver Fibrosis

BACKGROUND: Monocyte-derived macrophages critically perpetuate inflammatory responses after liver injury as a prerequisite for organ fibrosis. Experimental murine models identified an essential role for the CCR2-dependent infiltration of classical Gr1/Ly6C(+) monocytes in hepatic fibrosis. Moreover, the monocyte-related chemokine receptors CCR1 and CCR5 were recently recognized as important fibrosis modulators in mice. In humans, monocytes consist of classical CD14(+)CD16(-) and non-classical CD14(+)CD16(+) cells. We aimed at investigating the relevance of monocyte subpopulations for human liver fibrosis, and hypothesized that 'non-classical' monocytes critically exert inflammatory as well as profibrogenic functions in patients during liver disease progression. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed circulating monocyte subsets from freshly drawn blood samples of 226 patients with chronic liver disease (CLD) and 184 healthy controls by FACS analysis. Circulating monocytes were significantly expanded in CLD-patients compared to controls with a marked increase of the non-classical CD14(+)CD16(+) subset that showed an activated phenotype in patients and correlated with proinflammatory cytokines and clinical progression. Correspondingly, CD14(+)CD16(+) macrophages massively accumulated in fibrotic/cirrhotic livers, as evidenced by immunofluorescence and FACS. Ligands of monocyte-related chemokine receptors CCR2, CCR1 and CCR5 were expressed at higher levels in fibrotic and cirrhotic livers, while CCL3 and CCL4 were also systemically elevated in CLD-patients. Isolated monocyte/macrophage subpopulations were functionally characterized regarding cytokine/chemokine expression and interactions with primary human hepatic stellate cells (HSC) in vitro. CD14(+)CD16(+) monocytes released abundant proinflammatory cytokines. Furthermore, CD14(+)CD16(+), but not CD14(+)CD16(-) monocytes could directly activate collagen-producing HSC. CONCLUSIONS/SIGNIFICANCE: Our data demonstrate the expansion of CD14(+)CD16(+) monocytes in the circulation and liver of CLD-patients upon disease progression and suggest their functional contribution to the perpetuation of intrahepatic inflammation and profibrogenic HSC activation in liver cirrhosis. The modulation of monocyte-subset recruitment into the liver via chemokines/chemokine receptors and their subsequent differentiation may represent promising approaches for therapeutic interventions in human liver fibrosis

Fragile x syndrome and autism: from disease model to therapeutic targets

Autism is an umbrella diagnosis with several different etiologies. Fragile X syndrome (FXS), one of the first identified and leading causes of autism, has been modeled in mice using molecular genetic manipulation. These Fmr1 knockout mice have recently been used to identify a new putative therapeutic target, the metabotropic glutamate receptor 5 (mGluR5), for the treatment of FXS. Moreover, mGluR5 signaling cascades interact with a number of synaptic proteins, many of which have been implicated in autism, raising the possibility that therapeutic targets identified for FXS may have efficacy in treating multiple other causes of autism

Risk factors and outcomes associated with recurrent autoimmune hepatitis following liver transplantation

Background & Aims: Autoimmune hepatitis can recur after liver transplantation (LT), though the impact of recurrence on patient and graft survival has not been well characterized. We evaluated a large, international, multicenter cohort to identify the probability and risk factors associated with recurrent AIH and the association between recurrent disease and patient and graft survival.Methods: We included 736 patients (77% female, mean age 42 +/- 1 years) with AIH who underwent LT from January 1987 through June 2020, among 33 centers in North America, South America, Europe and Asia. Clinical data before and after LT, biochemical data within the first 12 months after LT, and immunosuppression after LT were analyzed to identify patients at higher risk of AIH recurrence based on histological diagnosis.Results: AIH recurred in 20% of patients after 5 years and 31% after 10 years. Age at LT <= 42 years (hazard ratio [HR] 3.15; 95% CI 1.22-8.16; p = 0.02), use of mycophenolate mofetil post-LT (HR 3.06; 95% CI 1.39-6.73; p = 0.005), donor and recipient sex mismatch (HR 2.57; 95% CI 1.39-4.76; p = 0.003) and high IgG pre-LT (HR 1.04; 95% CI 1.01-1.06; p = 0.004) were associated with higher risk of AIH recurrence after adjusting for other confounders. In multivariate Cox regression, recurrent AIH (as a time-dependent covariate) was significantly associated with graft loss (HR 10.79, 95% CI 5.37-21.66, p <0.001) and death (HR 2.53, 95% CI 1.48-4.33, p = 0.001).Conclusion: Recurrence of AIH following transplant is frequent and is associated with younger age at LT, use of mycophenolate mofetil post-LT, sex mismatch and high IgG pre-LT. We demonstrate an association between disease recurrence and impaired graft and overall survival in patients with AIH, highlighting the importance of ongoing efforts to better characterize, prevent and treat recurrent AIH.Lay summary: Recurrent autoimmune hepatitis following liver transplant is frequent and is associated with some recipient features and the type of immunosuppressive medications use. Recurrent autoimmune hepatitis negatively affects outcomes after liver transplantation. Thus, improved measures are required to prevent and treat this condition. (C) 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Permanent immunosuppression in SLA/LP-positive autoimmune hepatitis is required although overall response and survival are similar

Background and aims: Antibodies against soluble liver antigen/liver pancreas (anti-SLA/LP) are highly specific for autoimmune hepatitis (AIH) and have been linked with a more severe clinical course of the disease, frequent relapses after treatment withdrawal and worse outcome. To address definitely the clinical significance of anti-SLA/LP, we investigated a large number of anti-SLA/LP-positive and -negative patients followed in three referral centres. Methods: Prospectively collected data from 89 anti-SLA/LP-positive AIH patients (29 from Hamburg-Germany, 20 from Bologna-Italy and 40 from Larissa-Greece) were analysed retrospectively. Age- and sex-matched anti-SLA/LP-negative patients served as disease controls (n&nbsp;=&nbsp;230; 1:2.5 ratio). Results: In respect to baseline characteristics, anti-SLA/LP-positive patients were more frequently asymptomatic compared to anti-SLA/LP-negative (P&nbsp;&lt;.05). However, anti-SLA/LP-positive patients did not differ from anti-SLA/LP-negative in terms of the overall response to treatment, disease progression and survival even though, they were less likely to achieve corticosteroid withdrawal (P&nbsp;&lt;.05), needed longer treatment duration to achieve first complete response (P&nbsp;&lt;.001) and relapsed more frequently after treatment withdrawal compared to anti-SLA/LP-negative patients (P&nbsp;=&nbsp;&lt;.001). Conclusions: We showed that anti-SLA/LP antibodies do not characterize a group of AIH patients with distinct features and cannot identify patients with a more severe form of the disease or worse survival. Most importantly, however, anti-SLA/LP-positive patients appear to require lifelong immunosuppression as they are less likely to achieve the cessation of corticosteroids and present higher relapse rates after treatment withdrawal. Therefore, close long-term monitoring should be advised in all anti-SLA/LP-positive patients after withdrawal of immunosuppressive treatment

Autoantibodies to intracellular “rods and rings” structures in two patients with autoimmune hepatitis treated with azathioprine

In vitro, inhibition of the synthesis of guanosine monophosphate (GMP) by various drugs such as ribavirin, acyclovir, azathioprine, and mycophenolic acid leads to the formation of subcellular structures in cultured cells. Autoantibodies targeting these cellular structures can be detected as “rods and rings” (RR) patterns by immunofluorescence. In vivo, autoantibodies to RR have been almost exclusively associated with hepatitis C virus patients treated with pegylated interferon-α and ribavirin. However, longitudinal data for other patient groups are scarce. Here, we reviewed 276 sequential immunofluorescence results from 127 patients with autoimmune hepatitis for the presence of RR patterns. Of 102 patients exposed to drugs known to induce RR in vitro, two patients under long-term azathioprine therapy were positive for this pattern. This is the first report of anti-RR in patients with autoimmune hepatitis and in patients treated with azathioprine