Primary biliary cholangitis (PBC) is a rare immune-mediated disease, commonly affecting women in their 40s, and ultimately progressing to liver failure. The incidence and prevalence of the disease are increasing worldwide, possibly due to better diagnostic tools. This review will focus on its epidemiology, pathophysiology, diagnosis, prognosis, and new developments in therapy.

The impaired function of regulatory T (Treg) cells and the imbalance of Treg/Th17 cells play a central role in developing autoimmune diseases such as systemic lupus erythematosus (SLE). Treg cells are crucial for maintaining immune homeostasis and tolerance to self-antigens. One of the most important transcription factors that regulate the differentiation and function of Treg cells is the FOXP3 protein. Aberrant epigenetic modifications affecting FOXP3 gene expression and consequently dysregulated function of Treg cells have been implicated in the pathogenesis of SLE. Therefore, understanding the intricate interplay between FOXP3 expression pattern in Treg cells and epigenetic regulatory mechanisms (e.g., DNA methylation, histone modifications and non-coding RNAs such as microRNAs and long non-coding RNAs) is crucial for unravelling the underlying mechanisms of SLE. Moreover, targeting these epigenetic pathways may offer novel therapeutic strategies for restoring immune balance and ameliorating autoimmune pathology. This review report aimed to provide an update on the epigenetic controlling of FOXP3 gene expression in SLE disease.

Primary biliary cholangitis (PBC) is a chronic cholestatic progressive liver disease associated with cholangiopathies. The detection of antimitochondrial autoantibodies (AMAs) plays an important role in the diagnosis of classical PBC. AMAs are formed against the antigenic component associated with the dihydrolipoyl transacetylase of pyruvate dehydrogenase complex (E2 PDC) localized on the inner membrane of mitochondria. The loss of immune tolerance of E2 PDC in PBC is thought to be the cause of the mechanism of AMA formation and immune-mediated destruction of biliary epithelial cells (BECs) of the small- and medium-sized intrahepatic bile ducts. E2 PDC is not only present in BECs, but is also abundant in the mitochondria of all nucleated cells. The question remains as to why E2 PDC of only small BECs is the target of autoimmune attack. There is no evidence that AMAs have a deleterious effect on BECs. New scientific data has emerged that explains the damage to BECs in PBC by the defect of the biliary bicarbonate (HCO₃^–) “umbrella” that protects BECs from the detergent action of bile acids under physiological conditions. Disruption of HCO₃^– production by BECs in PBC leads to changes in the pH of hepatic bile, accompanied by accumulation of bile acids in the small BECs. The detergent action of bile acids leads to damage of membrane structures of BECs and their apoptosis, development of ductulopenia, and intrahepatic cholestasis. For the first time, it has been suggested that under the influence of bile acids, the E2 PDC antigen may undergo conformational changes that alter its immunological properties. E2 PDC becomes a neoantigen that is recognized by the normal (“healthy”) immune system as a foreign antigen, leading to the production of AMAs. For the first time, the authors of this review provide an explanation for why only small BECs are damaged in PBC.

Autoimmune diseases result from the immune system’s response to autoantigen components, leading to damage to one’s own tissues and organs. The correlation between long noncoding RNAs (lncRNAs) and autoimmune diseases remains inconclusive. However, recent studies have revealed that the lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) plays a vital role in the development of various autoimmune diseases. Here, this review briefly summarizes the progress in understanding NEAT1 expression variations and related mechanisms in different autoimmune diseases, and discusses its potential use for future therapeutic applications.

Complement is both evolutionary and scientifically old. It predates the adaptive immunity by some 600 million years and was first described in 1905 by Jules Bordet and Paul Ehrlich. For the most of its, the existence complement system has been ignored by most scientists and clinicians due to the perception of it being complicated and its relevance for the pathogenesis of human disease being unclear. With the recent US Food and Drug Administration (FDA) approvals of pegcetacoplan for both paroxysmal nocturnal haemoglobinuria (PNH) and geographic atrophy (GA), avacincaptad pegol for GA and iptacopan and danicopan for PNH, we are at a crucial juncture for complement-targeting therapies. A number of companies and academic institutions are developing next-generation complement therapies, which is resulting in an increasingly competitive landscape. If one looks at the serum complement cascade, all 3 pathways now have biotechnology or pharmaceutical industry players with 1 or multiple clinical-stage inhibitors that are expected to be FDA approved within the next few years. Furthermore, with the limited number of clinically validated targets in complement-mediated disease, the competition in this space is set to further intensify in the coming years. In this review, we will discuss the timeline of the academic discoveries that led to the development of the current crop of FDA-approved complement therapeutics. We follow with a discussion of an increasingly crowded complement therapy space and of the scientific advances that have emerged in recent two decades underpinning future innovation, including advances in our understanding of complement biology, such as local and intracellular complement, emerging complement targets, combinational approaches of complement and non-complement therapeutics to unlock new disease indications and new technologies such as gene therapy. We will also give a comprehensive overview of the gene therapy landscape and how it can be utilized to target complement dysregulation.

Type I diabetes susceptibility is caused by both environmental and genetic factors, the latter comprising approximately half of the total risk as evidenced by the fact that identical twins have approximately 50% concordance, suggesting 50% of the disease risk is environmental. The human leukocyte antigen (HLA) genes account for approximately half of the genetic risk, as demonstrated by the concordance between HLA identical siblings. Because environmental and genetic differences vary between racial groups, the incidence of type 1 diabetes (TID) differs across the world, being highest in Caucasians. Recent GWAS (genome-wide association studies) studies have suggested there may be up to 50 genomic regions contributing to the non-major histocompatibility complex (MHC) genetic risk contribution. This review presents and discusses the latest research on the MHC and non-MHC genes. Only the non-MHC regions, which have been confirmed in multiple studies and which are considered definite regions of genetic susceptibility, are included in the review.