The gastrointestinal tract is home to the largest microbial population in the human body. The gut microbiota plays significant roles in the development of the gut immune system and has a substantial impact on the maintenance of immune tolerance beginning in early life. These microbes interact with the immune system in a dynamic and interdependent manner. They generate immune signals by presenting a vast repertoire of antigenic determinants and microbial metabolites that influence the development, maturation and maintenance of immunological function and homeostasis. At the same time, both the innate and adaptive immune systems are involved in modulating a stable microbial ecosystem between the commensal and pathogenic microorganisms. Hence, the gut microbial population and the host immune system work together to maintain immune homeostasis synergistically. In susceptible hosts, disruption of such a harmonious state can greatly affect human health and lead to various auto-inflammatory and autoimmune disorders. In this review, we discuss our current understanding of the interactions between the gut microbiota and immunity with an emphasis on: a) important players of gut innate and adaptive immunity; b) the contribution of gut microbial metabolites; and c) the effect of disruption of innate and adaptive immunity as well as alteration of gut microbiome on the molecular mechanisms driving autoimmunity in various autoimmune diseases.

Connective tissue disease (CTD) related interstitial lung disease (CTD-ILD) is one of the leading causes of morbidity and mortality of CTD. Clinically, CTD-ILD is highly heterogenous and involves rheumatic immunity and multiple manifestations of respiratory complications affecting the airways, vessels, lung parenchyma, pleura, and respiratory muscles. The major pathological features of CTD are chronic inflammation of blood vessels and connective tissues, which can affect any organ leading to multi-system damage. The human lung is particularly vulnerable to such damage because anatomically it is abundant with collagen and blood vessels. The complex etiology of CTD-ILD includes genetic risks, epigenetic changes, and dysregulated immunity, which interact leading to disease under various ill-defined environmental triggers. CTD-ILD exhibits a broad spectra of clinical manifestations: from asymptomatic to severe dyspnea; from single-organ respiratory system involvement to multi-organ involvement. The disease course is also featured by remissions and relapses. It can range from stability or slow progression over several years to rapid deterioration. It can also present clinically as highly progressive from the initial onset of disease. Currently, the diagnosis of CTD-ILD is primarily based on distinct pathology subtype(s), imaging, as well as related CTD and autoantibodies profiles. Meticulous comprehensive clinical and laboratory assessment to improve the diagnostic process and management strategies are much needed. In this review, we focus on examining the pathogenesis of CTD-ILD with respect to genetics, environmental factors, and immunological factors. We also discuss the current state of knowledge and elaborate on the clinical characteristics of CTD-ILD, distinct pathohistological subtypes, imaging features, and related autoantibodies. Furthermore, we comment on the identification of high-risk patients and address how to stratify patients for precision medicine management approaches.

The anatomical architecture of the human liver and the diversity of its immune components endow the liver with its physiological function of immune competence. Adaptive immunity is a major arm of the immune system that is organized in a highly specialized and systematic manner, thus providing long-lasting protection with immunological memory. Adaptive immunity consists of humoral immunity and cellular immunity. Cellular immunity is known to have a crucial role in controlling infection, cancer and autoimmune disorders in the liver. In this article, we will focus on hepatic virus infections, hepatocellular carcinoma and autoimmune disorders as examples to illustrate the current understanding of the contribution of T cells to cellular immunity in these maladies. Cellular immune suppression is primarily responsible for chronic viral infections and cancer. However, an uncontrolled auto-reactive immune response accounts for autoimmunity. Consequently, these immune abnormalities are ascribed to the quantitative and functional changes in adaptive immune cells and their subsets, innate immunocytes, chemokines, cytokines and various surface receptors on immune cells. A greater understanding of the complex orchestration of the hepatic adaptive immune regulators during homeostasis and immune competence are much needed to identify relevant targets for clinical intervention to treat immunological disorders in the liver.

The identification of environmental factors that lead to loss of tolerance has been coined the holy grail of autoimmunity. Our work has focused on the reactivity of antimitochondrial autoantibodies (AMA) to chemical xenobiotics and has hypothesized that a modified peptide within PDC‐E2, the major mitochondrial autoantigen, will have been immunologically recognized at the time of loss of tolerance. Herein, we successfully applied intein technology to construct a PDC‐E2 protein fragment containing amino acid residues 177‐314 of PDC‐E2 by joining a recombinant peptide spanning residues 177‐252 (PDC‐228) with a 62‐residue synthetic peptide from 253 to 314 (PP), which encompasses PDC‐E2 inner lipoyl domain (ILD). We named this intein‐constructed fragment PPL. Importantly, PPL, as well as lipoic acid conjugated PPL (LA‐PPL) and xenobiotic 2‐octynoic acid conjugated PPL (2OA‐PPL), are recognized by AMA. Of great importance, AMA has specificity for the 2OA‐modified PDC‐E2 ILD peptide backbone distinct from antibodies that react with native lipoylated PDC‐E2 peptide. Interestingly, this unique AMA subfraction is of the immunoglobulin M isotype and more dominant in early‐stage primary biliary cholangitis (PBC), suggesting that exposure to 2OA‐PPL‐like compounds occurs early in the generation of AMA. To understand the structural basis of this differential recognition, we analyzed PPL, LA‐PPL, and 2OA‐PPL using electron paramagnetic resonance spectroscopy, with confirmations by enzyme‐linked immunosorbent assay, immunoblotting, and affinity antibody analysis. We demonstrate that the conformation of PDC‐E2 ILD is altered when conjugated with 2OA, compared to conjugation with lipoic acid. Conclusion: A molecular understanding of the conformation of xenobiotic‐modified PDC‐E2 is critical for understanding xenobiotic modification and loss of tolerance in PBC with widespread implications for a role of environmental chemicals in the induction of autoimmunity. (Hepatology 2017;65:1670‐1682).

IMPORTANCE: Digital health applications have been shown to be effective in the management of chronic diseases with simple treatment targets. The potential clinical value of digital health applications in rheumatoid arthritis (RA) has not been well studied.OBJECTIVE: To investigate whether assessing patient-reported outcomes using digital health applications could result in disease control for patients with RA.DESIGN, SETTING, AND PARTICIPANTS: This is a multicenter, open-label randomized clinical trial in 22 tertiary hospitals across China. Eligible participants were adult patients with RA. Participants were enrolled from November 1, 2018, to May 28, 2019, with a 12-month follow-up. The statisticians and rheumatologists who assessed disease activity were blinded. Investigators and participants were not blind to group assignment. Analysis was conducted from October 2020 to May 2022.INTERVENTIONS: Participants were randomly assigned at a 1:1 ratio (block size of 4) to a smart system of disease management group (SSDM) or a conventional care control group. Upon the completion of the 6-month parallel comparison, patients in the conventional care control group were instructed to use the SSDM application for an extension of 6 months.MAIN OUTCOMES AND MEASURES: The primary outcome was the rate of patients with disease activity score in 28 joints using the C-reactive protein (DAS28-CRP) of 3.2 or less at month 6.RESULTS: Of 3374 participants screened, 2204 were randomized, and 2197 patients with RA (mean [SD] age, 50.5 [12.4] years; 1812 [82.5%] female) were enrolled. The study included 1099 participants in the SSDM group and 1098 participants in the control group. At month 6, the rate of patients with DAS28-CRP of 3.2 or less was 71.0% (780 of 1099 patients) in the SSDM group vs 64.5% (708 of 1098 patients) in the control group (difference between groups, 6.6%; 95% CI, 2.7% to 10.4%; P = .001). At month 12, the rate of patients with DAS28-CRP of 3.2 or less in the control group increased to a level (77.7%) that was comparable with that (78,2%) in the SSDM group (difference between groups, −0.2%; 95% CI, −3.9% to 3.4%; P = .90).CONCLUSIONS AND RELEVANCE: In this randomized clinical trial of RA, the use of a digital health application with patient-reported outcomes was associated with an increase in disease control rate.TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03715595