Aim: Testing the feasibility of the determination to what extent the inability to repair DNA lesions in xeroderma pigmentosum (XP) patients, contributes to the alteration of immune responses, in the course of skin carcinogenesis.
Methods: Serum samples from 11 (five XP, six non-XP) bearing skin carcinomas and from three healthy donors, were available for the quantification of IL-2, IL-4, IL-10, IFN-γ and TNF-α cytokines concentrations. We used kits for ELISA test, by a non-competitive sandwich method. Statistical analysis of the results was performed, using non-parametric Mann-Whitney U test, with an accuracy of 5%.
Results: Our results showed that the majority of XP and non-XP cancer patients showed a significant increase in the secretion of TNF-α cytokine above healthy individuals (controls). TNF-α was also found to be significantly high in the serum of XP patients above that reported for the studied non-XP cancer patients. At the same time, TNF-α was not detected in the serum of non-XP and of healthy controls. This increase in the expression level of TNF-α was statistically significant between XP and non-XP patients, and between XP patients and controls. In contrast, there were no significant differences between XP patients and healthy controls, as well as between XP and non-XP patients, for the level of serum IL-2, IL-4 and IL-10 cytokines. On the other hand, we found no detectable levels of IFN-γ cytokine in the serum of all the studied subgroups.
Conclusions: In this study, we demonstrate a general tendency to secrete inflammatory cytokines, in the cancerous groups of patients (XP and non-XP), in comparison to healthy controls, while a significantly higher propensity to develop inflammation, in XP than in non-XP cancer patients.
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.
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.
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.
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.
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 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.
Aim: Assessing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunoglobulin G (IgG) antibodies among healthcare workers (HCWs) is crucial in understanding the durability of humoral immune response due to vaccination and the post-pandemic era. Therefore, this study aimed to evaluate IgG antibody seroprevalence, IgG levels, and long-term durability responses after the coronavirus disease 2019 (COVID-19) pandemic in HCWs.
Methods: The cross-sectional study recruited HCWs aged ≥ 18 years, vaccinated at least once, and without autoimmune diseases at Dr. Wahidin Sudirohusodo Hospital Makassar. Antibody titers against spike protein, nucleocapsid protein, and spike-nucleocapsid conjugate were quantified using dried blood spot (DBS) samples and multi-antigen profiling (xMAP) technology to measure seroprevalence.
Results: The results showed that there was a total of 103 participants with the majority being female (59.22%), ≤ 40-year-old (87.38%), nurses (56.31%), had no comorbidities (88.35%), and were infected with COVID-19 (70.87%). A significant proportion received three times vaccination (76.7%), while 102 of 103 (99.03%) showed seropositivity. IgG showed the highest mean antibody titers for spike protein [10,819.38 ± 2,554.23 mean fluorescence intensity (MFI)] in the first 6–12 months after the last vaccinations. Meanwhile, the IgG titer (MFI) showed a long duration over 30 months. Vaccine significantly influenced spike protein antibody levels, with the highest observed in the group receiving a combination of two inactivated vaccines followed by two messenger ribonucleic acid (mRNA) vaccines ( p < 0.05).
Conclusions: HCWs showed a sustained humoral immune response to SARS-CoV-2 for over 24 months post-vaccination. The type and combination of vaccines administered were significantly correlated with the IgG antibody levels, suggesting the long-term efficacy of the vaccination regimens. The application of DBS and xMAP technology in the study facilitated the assessment of SARS-CoV-2 IgG responses, offering valuable insights into the dynamics of immune persistence following vaccination.