The roles and control of CD4+ effector and regulatory T cells in biliary autoimmunity

Autoimmunity represents a misdirection of the adaptive immune response against the self. The pre- valence of human autoimmunity is increasing, including an increasing prevalence of autoimmune liver disease. Novel therapeutic options are required and failure of the regulation of CD4+ T cells has been implicated in pathogenesis. OX40, ligated by OX40L, is a secondary co-stimulatory molecule which promotes activation and survival of CD4+ T cells and has been proposed as a therapeutic target in autoimmunity and regulatory failure. Complete deficiency in FOXP3-positive regulatory T cells results in a lymphocytic hepatitis associated with autoantibodies and loss of effector CD4+ T cell control. This thesis confirms this finding and demonstrates similar pathology in mice deficient in the regulatory molecule CTLA4 and in Roquin sanroque mutant mice. Each of these mouse models is shown to hyperexpress OX40 on liver-infiltrating CD4+ T cells. In FOXP3 deficiency, blockade of OX40-OX40L interactions abrogates hepatitis; whereas in CTLA4 deficiency and the Roquin sanroque mutant mouse, OX40-OX40L blockade is ineffective. Complementary to these findings, increased expression of OX40 is demonstrated in human autoim- mune liver disease, and a negative regulatory mechanism on the expression of OX40L by T cells by the action of gamma-chain cytokines including interleukin-2 is described

The epidemiology of UK autoimmune liver disease varies with geographic latitude

BACKGROUND & AIMS: The epidemiology of autoimmune liver disease (AILD) is challenging to study because of the diseases’ rarity and because of cohort selection bias. Increased incidence farther from the Equator has been reported for multiple sclerosis, another autoimmune disease. We assessed the incidence of primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and autoimmune hepatitis (AIH) in relation to latitude. METHODS: We performed a retrospective cohort study using anonymized UK primary care records from January 1, 2002, to May 10, 2016. All adults without a baseline diagnosis of AILD were included and followed up until the first occurrence of an AILD diagnosis, death, or they left the database. Latitude was measured as registered general practice rounded down to whole degrees. RESULTS: The cohort included 8,590,421 records with 53.3 × 10(7) years of follow-up evaluation from 694 practices. There were 1314 incident cases of PBC, 396 of PSC, and 1034 of AIH. Crude incidences were as follows: PBC, 2.47 (95% CI, 2.34–2.60); PSC, 0.74 (95% CI, 0.67–0.82); and AIH, 1.94 (95% CI, 1.83–2.06) per 100,000 per year. PBC incidence correlated with female sex, smoking, and deprivation; PSC incidence correlated with male sex and non-smoking; AIH incidence correlated with female sex and deprivation. A more northerly latitude was associated strongly with incidence of PBC: 2.16 (95% CI, 1.79–2.60) to 4.86 (95% CI, 3.93–6.00) from 50°N to 57°N (P = .002) and incidence of AIH: 2.00 (95% CI, 1.65–2.43) to 3.28 (95% CI, 2.53–4.24) (P = .003), but not incidence of PSC: 0.82 (95% CI, 0.60–1.11) to 1.02 (95% CI, 0.64–1.61) (P = .473). Incidence after adjustment for age, sex, smoking, and deprivation status showed similar positive correlations for PBC and AIH with latitude, but not PSC. Incident AIH cases were younger at more northerly latitude. CONCLUSIONS: We describe an association in the United Kingdom between more northerly latitude and the incidence of PBC and AIH that requires both confirmation and explanation

COVID-19 and liver transplantation: the jury is still out – Authors' reply

We thank Oliver Tavabie and colleagues for their interest in our work and their comments. We also thank them for contributing patient data from their institution to our registries

Broad external validation of a multivariable risk prediction model for gastrointestinal malignancy in iron deficiency anaemia.

BACKGROUND: Using two large datasets from Dorset, we previously reported an internally validated multivariable risk model for predicting the risk of GI malignancy in IDA-the IDIOM score. The aim of this retrospective observational study was to validate the IDIOM model using two independent external datasets. METHODS: The external validation datasets were collected, in a secondary care setting, by different investigators from cohorts in Oxford and Sheffield derived under different circumstances, comprising 1117 and 474 patients with confirmed IDA respectively. The data were anonymised prior to analysis. The predictive performance of the original model was evaluated by estimating measures of calibration, discrimination and clinical utility using the validation datasets. RESULTS: The discrimination of the original model using the external validation data was 70% (95% CI 65, 75) for the Oxford dataset and 70% (95% CI 61, 79) for the Sheffield dataset. The analysis of mean, weak, flexible and across the risk groups' calibration showed no tendency for under or over-estimated risks in the combined validation data. Decision curve analysis demonstrated the clinical value of the IDIOM model with a net benefit that is higher than 'investigate all' and 'investigate no-one' strategies up to a threshold of 18% in the combined validation data, using a risk cut-off of around 1.2% to categorise patients into the very low risk group showed that none of the patients stratified in this risk group proved to have GI cancer on investigation in the validation datasets. CONCLUSION: This external validation exercise has shown promising results for the IDIOM model in predicting the risk of underlying GI malignancy in independent IDA datasets collected in different clinical settings

Broad external validation of a multivariable risk prediction model for gastrointestinal malignancy in iron deficiency anaemia.

BACKGROUND: Using two large datasets from Dorset, we previously reported an internally validated multivariable risk model for predicting the risk of GI malignancy in IDA-the IDIOM score. The aim of this retrospective observational study was to validate the IDIOM model using two independent external datasets. METHODS: The external validation datasets were collected, in a secondary care setting, by different investigators from cohorts in Oxford and Sheffield derived under different circumstances, comprising 1117 and 474 patients with confirmed IDA respectively. The data were anonymised prior to analysis. The predictive performance of the original model was evaluated by estimating measures of calibration, discrimination and clinical utility using the validation datasets. RESULTS: The discrimination of the original model using the external validation data was 70% (95% CI 65, 75) for the Oxford dataset and 70% (95% CI 61, 79) for the Sheffield dataset. The analysis of mean, weak, flexible and across the risk groups' calibration showed no tendency for under or over-estimated risks in the combined validation data. Decision curve analysis demonstrated the clinical value of the IDIOM model with a net benefit that is higher than 'investigate all' and 'investigate no-one' strategies up to a threshold of 18% in the combined validation data, using a risk cut-off of around 1.2% to categorise patients into the very low risk group showed that none of the patients stratified in this risk group proved to have GI cancer on investigation in the validation datasets. CONCLUSION: This external validation exercise has shown promising results for the IDIOM model in predicting the risk of underlying GI malignancy in independent IDA datasets collected in different clinical settings

SARS-CoV-2 Infections Among Patients With Liver Disease and Liver Transplantation Who Received COVID-19 Vaccination.

Many safe and effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccinations dramatically reduce risks of coronavirus disease 2019 (COVID-19) complications and deaths. We aimed to describe cases of SARS-CoV-2 infection among patients with chronic liver disease (CLD) and liver transplant (LT) recipients with at least one prior COVID-19 vaccine dose. The SECURE-Liver and COVID-Hep international reporting registries were used to identify laboratory-confirmed COVID-19 in CLD and LT patients who received a COVID-19 vaccination. Of the 342 cases of lab-confirmed SARS-CoV-2 infections in the era after vaccine licensing, 40 patients (21 with CLD and 19 with LT) had at least one prior COVID-19 vaccination, including 12 who were fully vaccinated (≥2 weeks after second dose). Of the 21 patients with CLD (90% with cirrhosis), 7 (33%) were hospitalized, 1 (5%) was admitted to the intensive care unit (ICU), and 0 died. In the LT cohort (n = 19), there were 6 hospitalizations (32%), including 3 (16%) resulting in mechanical ventilation and 2 (11%) resulting in death. All three cases of severe COVID-19 occurred in patients who had a single vaccine dose within the last 1-2 weeks. In contemporary patients with CLD, rates of symptomatic infection, hospitalization, ICU admission, invasive ventilation, and death were numerically higher in unvaccinated individuals. Conclusion: This case series demonstrates the potential for COVID-19 infections among patients with CLD and LT recipients who had received the COVID-19 vaccination. Vaccination against SARS-CoV-2 appears to result in favorable outcomes as attested by the absence of mechanical ventilation, ICU, or death among fully vaccinated patients

Single-gene association between GATA-2 and autoimmune hepatitis:a novel genetic insight highlighting immunologic pathways to disease

AbstractBackground & AimsAutoimmune hepatitis (AIH), an immune-mediated liver disease, originates as a consequence of interacting genetic and environmental risk factors. Treatment remains non-specific and prone to side effects. Deficiencies in regulatory T cell (Treg) function are hypothesized to contribute to the pathogenesis of AIH.MethodsWe describe an adult patient who presented with AIH in the context of monocytopenia. The patient was characterized by GATA2 gene sequencing, flow cytometry of peripheral blood for leucocyte subsets, ELISA for serum Flt-3 ligand, and immunohistochemistry of liver biopsy tissue.ResultsSequencing confirmed a GATA2 mutation. Peripheral Treg were absent in the context of a preserved total T cell count. Immunostaining for the Treg transcription factor FOXP3 was reduced in liver tissue as compared to a control AIH specimen. There were marked deficiencies in multiple antigen-presenting cell subsets and Flt-3 ligand was elevated. These findings are consistent with previous reports of GATA2 dysfunction.ConclusionsThe association of a GATA2 mutation with AIH is previously unrecognized. GATA2 encodes a hematopoietic cell transcription factor, and mutations may manifest as monocytopenia, dendritic and B cell deficiencies, myelodysplasia, and immunodeficiency. Tregs may be depleted as in this case. Our findings provide support for the role of Tregs in AIH, complement reports of other deficiencies in T cell regulation causing AIH-like syndromes, and support the rationale of attempting to modulate the Treg axis for the therapeutic benefit of AIH patients