Corrigendum to "Trends in decompensated cirrhosis and hepatocellular carcinoma among people with a hepatitis B notification in New South Wales" [JHEP Reports 4 (2022)].

[This corrects the article DOI: 10.1016/j.jhepr.2022.100552.].

Temporal change in aetiology and clinical characteristics of hepatocellular carcinoma in a large cohort of patients in New South Wales, Australia.

BACKGROUND: Viral hepatitis, alcohol-related liver disease (ARLD) and nonalcoholic fatty liver disease (NAFLD) are the main risk factors for hepatocellular carcinoma (HCC) in many countries. In Australia, given the access to hepatitis C virus (HCV) direct-acting antiviral (DAA) therapy since 2016, a temporal change in HCC aetiology was hypothesized. This study evaluated the temporal change in the aetiology and characteristics of HCC in New South Wales (NSW). METHODS: Patients diagnosed with HCC, admitted to three public hospitals in NSW between 2008 and 2021, were included in the analyses. We assessed the annual frequency of each HCC aetiology and the distribution of HCC characteristics in participants. RESULTS: Among 1370 patients, the most common HCC etiologies were HCV (n = 483, 35%), ARLD (n = 452, 33%), NAFLD (n = 347, 25%) and hepatitis B virus (n = 301, 22%). The proportion of HCV-related HCC was the highest in 2011-2016 (41%) and significantly declined to 30% in 2017-2021 (odds ratio [OR], 0.53 [95% confidence interval (CI), 0.35-0.79]; P = 0.002). The proportion of HCC diagnosed at an early stage (Barcelona Clinic Liver Cancer stage O/A) increased from 41% in 2008-2009 to 56% in 2020-2021 (OR per annum, 1.05 [95% CI, 1.02-1.08]; P = 0.002), and the proportion of patients receiving potentially curative HCC management increased from 29% in 2008-2009 to 41% in 2020-2021 (OR per annum, 1.06 [95% CI, 1.03-1.10]; P < 0.001). CONCLUSION: The contribution of HCV to HCC burden has been decreasing in the DAA era, suggesting the role of HCV elimination in decreasing HCC risk. Increasing frequency of less advanced HCC at diagnosis over time suggests improved HCC surveillance.

Viscoelastometry to Manage Bleeding in Liver Disease.

A state of "re-balanced haemostasis" describes complex coagulation changes that arise in patients with liver disease. Changes include alterations in procoagulant and anticoagulant proteins, platelets and von Willebrand factor, as well as the fibrinolytic system. Various circumstances including infection, trauma, or surgery may disrupt this balance and predispose an individual to bleeding or thrombosis. The prothrombin time, international normalised ratio, and activated partial thromboplastin time are conventional coagulation screening tests that are routinely employed by clinicians to investigate unexplained bleeding, monitor anticoagulation, and inform preoperative assessments of bleeding risk. These standard coagulation tests assess quantitative defects in procoagulant clotting factors and are insensitive to levels of natural anticoagulants, which together with procoagulant factors, are often perturbed in liver disease. Therefore, the prolongation of clotting times measured by these tests often does not reflect the multifaceted alterations of haemostasis in these patients. Viscoelastic testing (VET) provides a more encompassing assessment of clotting function by recording real-time viscoelastic changes in whole blood and includes parameters that provide information on coagulation factor function, platelet contribution to clot formation, as well as fibrinolysis. To date, VET has been employed to predict and inform transfusion support in obstetric, trauma, and cardiac surgical fields, and its use in patients undergoing liver transplantation is well established. The ability of VET to accurately predict bleeding risk and precisely guide transfusion algorithms for patients with liver disease undergoing other invasive procedures or experiencing bleeding complications has been the topic of research over the last decade. This review is a critical summary of this data and provides a detailed snapshot of the position of VET as a clinical tool in patients with liver disease.

Trends in decompensated cirrhosis and hepatocellular carcinoma among people with a hepatitis B notification in New South Wales.

Background & Aims: Population-level trends and factors associated with HBV-related decompensated cirrhosis (DC), hepatocellular carcinoma (HCC), and liver-related mortality are crucial to evaluate the impacts of therapeutic interventions. Methods: Trends in HBV-DC and -HCC diagnoses and liver-related mortality in New South Wales, Australia, were determined through linkage of HBV notifications (1993-2017) to hospital admissions (2001-2018), mortality (1993-2018), and cancer registry (1994-2014) databases. Late HBV notification was defined as notification at or within 2 years of a DC or HCC diagnosis. Cox proportional-hazards regression and multivariable logistic regression analyses were performed to evaluate associated factors. Results: Among 60,660 people with a HBV notification, 1,276 (2.0%) DC and 1,087 (1.8%) HCC diagnoses, and 1,219 (2.0%) liver-related deaths were documented. Since the early 2000s, the number of DC and HCC diagnoses increased; however, age-standardised incidence decreased from 2.64 and 1.95 in 2003 to 1.14 and 1.09 per 1,000 person-years in 2017, respectively. Similarly, age-standardised liver mortality decreased from 2.60 in 2003 to 1.14 per 1,000 person-years in 2017. Among people with DC and HCC diagnoses, late HBV notification declined from 41% and 40% between 2001-2009 to 29% and 25% in 2010-2018, respectively. Predictors of DC diagnosis included older age (birth <1944, adjusted hazard ratio [aHR] 2.06, 95% CI 1.57-2.69), alcohol use disorder (aHR 4.82, 95% CI 3.96-5.87) and HCV co-infection (aHR 1.88, 95% CI 1.53-2.31). Predictors of HCC diagnosis included older age (birth <1944, aHR 3.94, 95% CI 2.91-5.32) and male sex (aHR 3.79, 95% CI 3.05-4.71). Conclusion: In an era of improved antiviral therapies, the risk of HBV-related liver morbidity and mortality has declined. HCV co-infection and alcohol use disorder are key modifiable risk factors associated with the burden of HBV. Lay summary: Rising hepatitis B-related morbidity and mortality is a major public health concern. However, the development of highly effective medicines against hepatitis B virus (HBV) has brought renewed optimism for its elimination by 2030. This study shows a steady decline in HBV-related liver morbidity and mortality in New South Wales, Australia. Moreover, late hepatitis notification has also declined, allowing individuals with HBV to have access to timely antiviral treatment. Despite this, hepatitis C co-infection and alcohol use disorder are key modifiable risk factors associated with HBV disease burden. To attain the desired benefits from highly effective antiviral treatment, managing comorbidities, including hepatitis C and high alcohol use, must improve among individuals with hepatitis B.

Selective internal radiation therapy for hepatocellular carcinoma: A 15-year multicenter Australian cohort study.

BACKGROUND AND AIM: The exact place for selective internal radiation therapy (SIRT) in the therapeutic algorithm for hepatocellular carcinoma (HCC) is debated. There are limited data on its indications, efficacy, and safety in Australia. METHODS: We performed a multicenter retrospective cohort study of patients undergoing SIRT for HCC in all Sydney hospitals between 2005 and 2019. The primary outcome was overall survival. Secondary outcomes were progression-free survival and adverse events. RESULTS: During the study period, 156 patients underwent SIRT across 10 institutions (mean age 67 years, 81% male). SIRT use progressively increased from 2005 (n = 2), peaking in 2017 (n = 42) before declining (2019: n = 21). Barcelona Clinic Liver Cancer stages at treatment were A (13%), B (33%), C (52%), and D (2%). Forty-four (28%) patients had tumor thrombus. After a median follow-up of 13.9 months, there were 117 deaths. Median overall survival was 15 months (95% confidence interval 11-19). Independent predictors of mortality on multivariable analysis were extent of liver involvement, Barcelona Clinic Liver Cancer stage, baseline ascites, alpha fetoprotein, and model for end-stage liver disease score. Median progression-free survival was 6.0 months (95% confidence interval 5.1-6.9 months). Following SIRT, 11% of patients were downstaged to curative therapy. SIRT-related complications occurred in 17%: radioembolization-induced liver disease (11%), pneumonitis (3%), gastrointestinal ulceration, and cholecystitis (1% each). Baseline ascites predicted for radioembolization-induced liver disease. CONCLUSION: We present the largest Australian SIRT cohort for HCC. We have identified several factors associated with a poor outcome following SIRT. Patients with early-stage disease had the best survival with some being downstaged to curative therapy.

HCC incidence after hepatitis C cure among patients with advanced fibrosis or cirrhosis: A meta-analysis.

BACKGROUND AND AIMS: HCV cure reduces but does not eliminate the risk of HCC. HCC surveillance is recommended in populations where the incidence exceeds 1.5% per year. In cirrhosis, HCC surveillance should continue after HCV cure, although it is uncertain if this should be indefinite. For patients with advanced fibrosis (F3), guidelines are inconsistent in their recommendations. We evaluated the incidence of HCC after HCV cure among patients with F3 fibrosis or cirrhosis. APPROACH AND RESULTS: This systematic review and meta-analysis identified 44 studies (107,548 person-years of follow-up) assessing the incidence of HCC after HCV cure among patients with F3 fibrosis or cirrhosis. The incidence of HCC was 2.1 per 100 person-years (95% CI, 1.9-2.4) among patients with cirrhosis and 0.5 per 100 person-years (95% CI, 0.3-0.7) among patients with F3 fibrosis. In a meta-regression analysis among patients with cirrhosis, older age (adjusted rate ratio [aRR] per 10-year increase in mean/median age, 1.32; 95% CI, 1.00-1.73) and prior decompensation (aRR per 10% increase in the proportion of patients with prior decompensation, 1.06; 95% CI, 1.01-1.12) were associated with an increased incidence of HCC. Longer follow-up after HCV cure was associated with a decreased incidence of HCC (aRR per year increase in mean/median follow-up, 0.87; 95% CI, 0.79-0.96). CONCLUSIONS: Among patients with cirrhosis, the incidence of HCC decreases over time after HCV cure and is lowest in patients with younger age and compensated cirrhosis. The substantially lower incidence in F3 fibrosis is below the recommended threshold for cost-effective screening. The results should encourage the development of validated predictive models that better identify at-risk individuals, especially among patients with F3 fibrosis.

Pharmacotherapeutic strategies for hepatitis B and hepatitis C coinfection.

INTRODUCTION: Hepatitis B (HBV) and Hepatitis C (HCV) infection place a significant burden on the global health system, with chronic carriage leading to cirrhosis and hepatocellular carcinoma. HBV/HCV coinfection can be seen in highly endemic areas and present a heterogenous group given varying virologic profiles. Coinfected patients have a greater risk of advanced liver disease; hence, diagnosis and early antiviral therapy (AVT) should be a priority. Optimal treatment regimens for coinfected patients remain unknown with differing recommendations, particularly relating to the risk of HBV reactivation whilst on AVT for HCV. AREAS COVERED: This article summarizes the available data on HBV/HCV coinfection with regards to epidemiology, virologic interactions, and risk of HBV reactivation. The authors also provide a framework for the assessment and treatment of coinfected patients. EXPERT OPINION: There is a moderate risk of HBV reactivation in hepatitis B surface antigen (HBsAg) positive patients undergoing HCV direct-acting antiviral (DAA) treatment; however, clinically significant events are rare. The risk of HBV reactivation in HBsAg negative patients undergoing HCV DAA treatment is negligible. Thus, prophylactic HBV treatment in both groups is not required. The authors recommend close monitoring with HBV treatment if there is evidence of HBV reactivation or elevated alanine aminotransferase levels.

All-cause hepatocellular carcinoma survival in the era of direct-acting antiviral therapy.

BACKGROUND AND AIM: Hepatitis C virus (HCV) cure with direct-acting antiviral (DAA) therapy improves survival in patients with HCV-related hepatocellular carcinoma (HCC). We hypothesized that HCV-HCC survival has increased in the DAA era, more than other aetiologies of HCC. We aimed to evaluate survival following HCC diagnosis in the pre-DAA and DAA eras, across each aetiology of HCC. METHODS: Patients with HCC at three tertiary referral hospitals were included retrospectively (January 2008 to December 2019). Patients were categorized as HCV-HCC, hepatitis B virus (HBV)-HCC, or non-viral HCC. For each aetiology, the risk of death following incident HCC among patients diagnosed in the DAA era (2015-2019) was compared with patients diagnosed in the pre-DAA era (2008-2014). RESULTS: Among 1161 patients, there were 422 (36%) patients with HCV-HCC, 227 (20%) with HBV-HCC, and 512 (44%) with non-viral HCC. In adjusted analysis, the risk of death was lower in patients with HCV-HCC diagnosed in 2015-2019, compared with patients diagnosed in 2008-2014 (adjusted hazard ratio [aHR]: 0.68; 95% confidence interval [CI]: 0.52-0.89; P = 0.005). In contrast, there was no difference in the risk of death between time periods for patients with HBV-HCC (HR: 0.91; 95% CI: 0.64-1.29; P = 0.602) or non-viral HCC on adjusted analysis (aHR: 0.92; 95% CI: 0.74-1.15; P = 0.476). Although patients with HBV-HCC had better survival compared with patients with HCV-HCC in 2008-2014 (aHR: 0.74; 95% CI: 0.55-0.98; P = 0.037), this difference disappeared in 2015-2019 (aHR: 1.26; 95% CI: 0.90-1.77; P = 0.175). CONCLUSIONS: Hepatitis C virus-related HCC survival has increased in the DAA era, whereas adjusted survival remained stable for HBV-HCC and non-viral HCC.

Systematic review with meta-analysis: The effects of non-steroidal anti-inflammatory drugs and anti-platelet therapy on the incidence and recurrence of hepatocellular carcinoma.

BACKGROUND: Chemoprevention with NSAIDs, including aspirin, and anti-platelet therapy (APT), has been suggested to reduce the incidence and recurrence of hepatocellular carcinoma (HCC). AIM: To determine by meta-analysis whether NSAIDs and APT use affected HCC incidence, HCC recurrence and liver-related mortality in at-risk populations with chronic liver disease. METHOD: Electronic databases including Pubmed, Scopus, Medline, Embase and Cochrane Library were searched (from inception to 31 May 2021) for eligible studies evaluating the impacts of NSAID or APT use on HCC incidence, recurrence and mortality. Data on HCC incidence, recurrence, liver-related mortality or bleeding complications had to be available. Studies were included if they evaluated adults with hepatitis B virus (HBV), hepatitis C virus (HCV), alcohol-related liver disease (ALD) or nonalcoholic steatohepatitis that were administered at least one NSAID or APT for a defined period of time and were followed for at least 6 months. The primary outcome was HCC incidence. Secondary outcomes included: HCC recurrence, liver-related mortality and bleeding complications. Data were pooled using a random effects model with hazard ratios (HRs) or odds ratio (OR), and 95% confidence intervals (CIs) presented. RESULTS: Of 3773 articles screened, 19 studies were included, with a total of 147 283 participants. Aspirin use reduced the risk of HCC incidence (HR: 0.51, 95% CI: 0.36-0.72); and improved liver-related mortality (OR: 0.32, 95% CI: 0.15-0.70), with a small increased risk of gastrointestinal bleeding events (OR: 1.32, 95% CI: 1.08-1.94). With respect to HCC recurrence following treatment, analysis of all aspirin and NSAID treatment (including; aspirin only; non-aspirin NSAIDs only; and combination NSAIDs groups) was associated with a decreased risk of HCC recurrence (HR: 0.80, 95% CI: 0.75-0.86). By stratified analysis, only the non-aspirin NSAID group showed significant risk reduction (HR: 0.73, 95% CI: 0.63-0.84). CONCLUSION: The study supports the use of aspirin in at-risk individuals to reduce the incidence of HCC and liver-related mortality. HCC recurrence following treatment was lower with NSAID treatment.

Preservation of Gastrointestinal Mucosal Barrier Function and Microbiome in Patients With Controlled HIV Infection.

Background: Despite successful ART in people living with HIV infection (PLHIV) they experience increased morbidity and mortality compared with HIV-negative controls. A dominant paradigm is that gut-associated lymphatic tissue (GALT) destruction at the time of primary HIV infection leads to loss of gut integrity, pathological microbial translocation across the compromised gastrointestinal barrier and, consequently, systemic inflammation. We aimed to identify and measure specific changes in the gastrointestinal barrier that might allow bacterial translocation, and their persistence despite initiation of antiretroviral therapy (ART). Method: We conducted a cross-sectional study of the gastrointestinal (GIT) barrier in PLHIV and HIV-uninfected controls (HUC). The GIT barrier was assessed as follows: in vivo mucosal imaging using confocal endomicroscopy (CEM); the immunophenotype of GIT and circulating lymphocytes; the gut microbiome; and plasma inflammation markers Tumour Necrosis Factor-α (TNF-α) and Interleukin-6 (IL-6); and the microbial translocation marker sCD14. Results: A cohort of PLHIV who initiated ART early, during primary HIV infection (PHI), n=5), and late (chronic HIV infection (CHI), n=7) infection were evaluated for the differential effects of the stage of ART initiation on the GIT barrier compared with HUC (n=6). We observed a significant decrease in the CD4 T-cell count of CHI patients in the left colon (p=0.03) and a trend to a decrease in the terminal ileum (p=0.13). We did not find evidence of increased epithelial permeability by CEM. No significant differences were found in microbial translocation or inflammatory markers in plasma. In gut biopsies, CD8 T-cells, including resident intraepithelial CD103+ cells, did not show any significant elevation of activation in PLHIV, compared to HUC. The majority of residual circulating activated CD38+HLA-DR+ CD8 T-cells did not exhibit gut-homing integrins α4ß7, suggesting that they did not originate in GALT. A significant reduction in the evenness of species distribution in the microbiome of CHI subjects (p=0.016) was observed, with significantly higher relative abundance of the genus Spirochaeta in PHI subjects (p=0.042). Conclusion: These data suggest that substantial, non-specific increases in epithelial permeability may not be the most important mechanism of HIV-associated immune activation in well-controlled HIV-positive patients on antiretroviral therapy. Changes in gut microbiota warrant further study.

Hepatitis C virus cure before hepatocellular carcinoma diagnosis is associated with improved survival.

The impact of hepatitis C virus (HCV) cure on survival in patients with HCV-related hepatocellular carcinoma (HCC) has been examined, although many studies have been subject to survivor treatment selection bias. We assessed the impact of HCV cure before HCC diagnosis on overall survival. Patients with HCV-related HCC at three referral hospitals in Australia were included retrospectively (January 2008 to December 2019). The risk of death following HCC diagnosis among patients who achieved HCV cure before HCC diagnosis was compared to patients who were viraemic at diagnosis. Among 422 patients with HCV-related HCC, 101 (24%) achieved HCV cure before HCC diagnosis, 37 with interferon (IFN) and 64 with direct-acting antiviral (DAA) therapy. Patients with HCV cure were more likely to have no cirrhosis or Child-Pugh A liver disease (83% vs. 66%, p = .002), surveillance detection (71% vs. 48%, p < .001), HCC stage O or A (64% vs. 45%, p < .001) and receive curative initial HCC management (51% vs. 28%, p < .001), compared with patients who were viraemic at diagnosis. The 5-year overall survival was 51% in the HCV cure group and 22% in the viraemic group. In adjusted analysis, risk of death was lower in patients with HCV cure before HCC diagnosis compared with patients who were viraemic at diagnosis (adjusted hazard ratio: 0.63; 95% CI: 0.44-0.91; p = .013). Patients with HCV-related HCC who have achieved HCV cure before HCC diagnosis have improved overall survival compared with patients who were viraemic at diagnosis.

The Role of Diet in the Pathogenesis and Management of Inflammatory Bowel Disease: A Review.

Inflammatory bowel diseases, which include ulcerative colitis and Crohn's disease, are chronic relapsing and remitting inflammatory diseases of the gastrointestinal tract that are increasing in prevalence and incidence globally. They are associated with significant morbidity, reduced quality of life to individual sufferers and are an increasing burden on society through direct and indirect costs. Current treatment strategies rely on immunosuppression, which, while effective, is associated with adverse events. Epidemiological evidence suggests that diet impacts the risk of developing IBD and modulates disease activity. Using diet as a therapeutic option is attractive to patients and clinicians alike due to its availability, low cost and few side effects. Diet may influence IBD risk and disease behaviour through several mechanisms. Firstly, some components of the diet influence microbiota structure and function with downstream effects on immune activity. Secondly, dietary components act to alter the structure and permeability of the mucosal barrier, and lastly dietary elements may have direct interactions with components of the immune response. This review will summarise the mechanisms of diet-microbial-immune system interaction, outline key studies examining associations between diet and IBD and evidence demonstrating the impact of diet on disease control. Finally, this review will outline current prescribed dietary therapies for active CD.

Systematic review with meta-analysis: effectiveness of direct-acting antiviral treatment for hepatitis C in patients with hepatocellular carcinoma.

BACKGROUND: Direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) infection is highly curative and tolerable. Among patients with hepatocellular carcinoma (HCC), optimal timing of DAA therapy remains unclear. Data on efficacy of DAA therapy in patients with HCC would inform this decision-making. AIM: To evaluate response to DAA therapy among patients diagnosed with HCV infection and HCC. METHODS: Bibliographic databases and conference abstracts were searched. Meta-analysis was conducted to pool sustained virologic response (SVR) estimates. RESULTS: Fifty-six studies with 5522 patients with HCV and HCC were included. Overall SVR was 88.3% (95% CI 86.1-90.4). Twenty-seven studies included patients with prior or present HCC (n = 3126) and patients without HCC (n = 49 138), in which SVR was 88.2% (95% CI 85.0-91.4) and 92.4% (95% CI 91.1-93.7) among patients with and without HCC, respectively (odds ratio: 0.54, 95% CI 0.43-0.68, P < .001). In the subgroup analyses, higher SVR was seen in patients who received curative HCC management (SVR 90.4%, 95% CI 88.3-92.4), or treated with sofosbuvir + NS5A inhibitor DAAs (SVR 96.9%, 95% CI 94.3-99.4), or in patients with HCV genotype 1 infection (SVR 92.0%, 95% CI 88.1-95.6). CONCLUSION: Response to DAA therapy was lower in patients with HCC compared to those without HCC, regardless of cirrhosis status. Among HCC patients, there was an impact of proportion with curative HCC management on DAA therapy response.

Cancer screening in Australia: future directions in melanoma, Lynch syndrome, and liver, lung and prostate cancers.

While Australia now has well-established national screening programs for breast, bowel and cervical cancers, research continues into the feasibility of developing systematic screening programs for a number of other cancers. In this paper, experts in their fields provide perspectives on the current state of play and future directions for screening and surveillance for melanoma, Lynch syndrome, and liver, lung and prostate cancers in Australia. Although the evidence does not support population screening, there may be opportunities to prevent thousands of deaths through systematic approaches to the early detection of lung cancer and melanoma, testing for Lynch syndrome, and organised surveillance for hepatocellular carcinoma among individuals at high risk - guided by targeted research. The paper also looks at what impact new prostate specific antigen testing guidelines are having on screening for prostate cancer.

Possible clearance of transfusion-acquired nef/LTR-deleted attenuated HIV-1 infection by an elite controller with CCR5 Δ32 heterozygous and HLA-B57 genotype.

BACKGROUND: Subject C135 is one of the members of the Sydney Blood Bank Cohort, infected in 1981 through transfusion with attenuated nef/3' long terminal repeat (LTR)-deleted HIV-1, and has maintained undetectable plasma viral load and steady CD4 cell count, in the absence of therapy. Uniquely, C135 combines five factors separately associated with control of viraemia: nef/LTR-deleted HIV-1, HLA-B57, HLA-DR13, heterozygous CCR5 Δ32 genotype and vigorous p24-stimulated peripheral blood mononuclear cell (PBMC) proliferation. Therefore, we studied in detail viral burden and immunological responses in this individual. METHODS: PBMC and gut and lymph node biopsy samples were analysed for proviral HIV-1 DNA by real-time and nested PCRs, and nef/LTR alleles by nested PCR. HIV-specific antibodies were studied by Western blotting, and CD4+ and CD8+ T lymphocyte responses were measured by proliferation and cytokine production in vitro. RESULTS: PBMC samples from 1996, but not since, showed amplification of nef alleles with gross deletions. Infectious HIV-1 was never recovered. Proviral HIV-1 DNA was not detected in recent PBMC or gut or lymph node biopsy samples. C135 has a consistently weak antibody response and a substantial CD4+ T cell proliferative response to a previously described HLA-DR13-restricted epitope of HIV-1 p24 in vitro, which augmented a CD8+ T cell response to an immunodominant HLA-B57-restricted epitope of p24, while his T cells show reduced levels of CCR5. CONCLUSIONS: Subject C135's early PCR and weak antibody results are consistent with limited infection with a poorly replicating nef/LTR-deleted strain of HIV-1. With his HLA-B57-restricted gag-specific CD8 and helper HLA-DR13-restricted CD4 T cell proliferative responses, C135 appears to have cleared his HIV-1 infection 37 years after transfusion.

CCR9 Expressing T Helper and T Follicular Helper Cells Exhibit Site-Specific Identities During Inflammatory Disease.

CD4+ T helper (Th) cells that express the gut homing chemokine receptor CCR9 are increased in the peripheral blood of patients with inflammatory bowel disease and Sjögren's syndrome and in the inflamed lesions of autoimmune diseases that affect the accessory organs of the digestive system. However, despite the important role of the GIT in both immunity and autoimmunity, the nature of CCR9-expressing cells in GIT lymphoid organs and their role in chronic inflammatory diseases remains unknown. In this study, we analyzed the characteristics of CCR9+ Th and T follicular helper (Tfh) cells in GIT associated lymphoid tissues in health, chronic inflammation and autoimmunity. Our findings reveal an association between the transcriptome and phenotype of CCR9+ Th in the pancreas and CCR9+ Tfh cells from GIT-associated lymphoid tissues. GIT CCR9+ Tfh cells exhibited characteristics, including a Th17-like transcriptome and production of effector cytokines, which indicated a microenvironment-specific signature. Both CCR9+ Tfh cells and CCR9+ Th cells from GIT-associated lymphoid tissues migrated to the pancreas. The expression of CCR9 was important for migration of both subsets to the pancreas, but Tfh cells that accumulated in the pancreas had downmodulated expression of CXCR5. Taken together, the findings provide evidence that CCR9+ Tfh cells and Th cells from the GIT exhibit plasticity and can accumulate in distal accessory organs of the digestive system where they may participate in autoimmunity.