Therapeutic potential of TAM receptors in autoimmune diseases: insights from original studies

In recent years, it has been reported that there is an increased incidence of accelerated atherosclerosis among young women with systemic lupus erythematosus (SLE). Accelerated atherosclerosis has also been observed in other autoimmune diseases such as rheumatoid arthritis and systemic sclerosis. The end-organ damage most commonly observed in SLE patients is kidney failure. Recent advances in the treatment of kidney dysfunction, has led to the observation that many SLE patients also suffer from coronary heart disease and other endpoint cardiac events. As a result, studies have been designed and performed to better understand the basis for the accelerated disease progression in patients with autoimmune disease. The development of atherosclerosis is driven, to a large extent, by inflammation. Initiation of atherosclerotic lesions can occur as a result of damage to the endothelium by a number of factors including oxidized low density lipoprotein (oxLDL), inflammatory cytokines, and immune complexes. The lesion progression involves inflammatory cell interactions with the endothelium and extravasation into the subendothelial space. Inflammation resulting from both atherosclerosis and autoimmunity is an essential, yet not well understood, factor in the initiation and progression of atherosclerosis associated with autoimmune diseases. Currently, one of the most widely studied areas among the genetic causes of SLE is decreased clearance of apoptotic bodies, which is thought to propagate the progression of the disease. There are numerous in vivo studies that support this hypothesis. For example, it has been shown that a long-term autoimmune response does not occur when there is efficient apoptotic body clearance. In cases where the machinery that is responsible for the clearance is disrupted in genetic mouse models, it has been shown that apoptotic bodies accumulate, resulting in lupus-like autoimmune diseases. This is evidenced by the variety of mouse models that develop autoimmunity in the absence of genes involved in apoptotic cell clearance. Apoptotic cell clearance also plays a role in atherosclerotic lesion development depending on the stage of the lesion. Our lab generated the first mouse model to study the interactions between SLE and atherosclerosis and subsequently, many new mouse models have been generated in order to further elucidate the mechanism by which the synergy between the two disease processes occurs. The focus of this chapter will be to discuss the recognition and phagocytosis of an apoptotic cell, the machinery involved in apoptotic cell clearance, and the effects of alterations to various steps of this process. This will be demonstrated by including evidence of relevant

Atherosclerosis is an inflammatory disease and the major cause of cardiovascular disease (CVD) in general. Atherosclerotic plaques are characterized by the presence of activated immune competent cells, but antigens and underlying mechanisms causing this immune activation are not well defined. During recent years and with improved treatment of acute disease manifestations, it has become clear that the risk of CVD is very high in a prototypic autoimmune disease, systemic lupus erythematosus (SLE). SLE-related CVD and atherosclerosis are important clinical problems but may in addition also shed light on how immune reactions are related to premature atherosclerosis and atherothrombosis. A combination of traditional and nontraditional risk factors, including dyslipidaemia (and to a varying degree hypertension, diabetes and smoking), inflammation, antiphospholipid antibodies (aPL) and lipid oxidation are related to CVD in SLE. Premature atherosclerosis in some form leading to atherothrombosis is likely to be a major underlying mechanism, though distinctive features if any, of SLE-related atherosclerosis when compared with 'normal' atherosclerosis are not clear. One interesting possibility is that factors such as inflammation or aPL make atherosclerotic lesions in autoimmune disease more prone to rupture than in 'normal' atherosclerosis. Whether premature atherosclerosis is a general feature of SLE or only affects a subgroup of patients remains to be demonstrated. Treatment of SLE patients should also include a close monitoring of traditional risk factors for CVD. In addition, attention should also be paid to nontraditional risk factors such as inflammation and SLE-related factors such as aPL. Hopefully novel therapeutic principles will be developed that target the causes of the inflammation and immune reactions present in atherosclerotic lesions.

Autoimmune diseases are complex multifactorial disorders, and a mixture of genetic and environmental factors play a role in their onset. In recent years, the microbiota has gained attention as it helps to maintain host health and immune homeostasis and is a relevant player in the interaction between our body and the outside world. Alterations (dysbiosis) in its composition or function have been linked to different pathologies, including autoimmune diseases. Among the different microbiota functions, there is the activation/modulation of immune cells that can protect against infections. However, if dysbiosis occurs, it can compromise the host’s ability to protect against pathogens, contributing to the development and progression of autoimmune diseases. In some cases, infections can trigger autoimmune diseases by several mechanisms, including the alteration of gut permeability and the activation of innate immune cells to produce pro-inflammatory cytokines that recruit autoreactive T and B cells. In this complex scenario, we cannot neglect critical hormones’ roles in regulating immune responses. Different hormones, especially estrogens, have been shown to influence the development and progression of autoimmune diseases by modulating the activity and function of the immune system in different ways. In this review, we summarized the main mechanisms of connection between infections, microbiota, immunity, and hormones in autoimmune diseases’ onset and progression given the influence of some infections and hormone levels on their pathogenesis. In detail, we focused on rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus.

TYRO3, AXL, and MERTK (TAM) receptors are a family of receptor tyrosine kinases that maintain homeostasis through the clearance of apoptotic cells, and when defective, contribute to chronic inflammatory and autoimmune diseases such as atherosclerosis, multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, and Crohn's disease. In addition, certain enveloped viruses utilize TAM receptors for immune evasion and entry into host cells, with several viruses preferentially hijacking MERTK for these purposes. Despite the biological importance of TAM receptors, little is understood of their recent evolution and its impact on their function. Using evolutionary analysis of primate TAM receptor sequences, we identified strong, recent positive selection in MERTK's signal peptide and transmembrane domain that was absent from TYRO3 and AXL. Reconstruction of hominid and primate ancestral MERTK sequences revealed three nonsynonymous single nucleotide polymorphisms in the human MERTK signal peptide, with a G14C mutation resulting in a predicted non-B DNA cruciform motif, producing a significant decrease in MERTK expression with no significant effect on MERTK trafficking or half-life. Reconstruction of MERTK's transmembrane domain identified three amino acid substitutions and four amino acid insertions in humans, which led to significantly higher levels of self-clustering through the creation of a new interaction motif. This clustering counteracted the effect of the signal peptide mutations through enhancing MERTK avidity, whereas the lower MERTK expression led to reduced binding of Ebola virus-like particles. The decreased MERTK expression counterbalanced by increased avidity is consistent with antagonistic coevolution to evade viral hijacking of MERTK.

In Search of Magic Bullets: The Golden Age of Immunotherapeutics

Advances in autoimmune rheumatic diseases

To describe the frequency of polyautoimmunity and multiple autoimmune syndrome in patients with rheumatoid arthritis (RA) and patients with systemic lupus erythematosus (SLE). This was a cross-sectional observational study of patients with RA, SLE, and controls without autoimmune rheumatic disease. Cases were those with RA according to the 2010 American College of Rheumatology/European League Against Rheumatism criteria and SLE according to the 2019 American College of Rheumatology/European League Against Rheumatism criteria, consecutively recruited in a rheumatology clinic. Controls were subjects with no rheumatic autoimmune disease (AIDs) recruited in the same area. Patients filled out a questionnaire on polyautoimmunity. Variables of interest were polyautoimmunity (RA or SLE with other AIDs), whereas secondary variables were rheumatic, skin, endocrine, digestive, and neurological AIDs. Multiple autoimmune syndrome is defined as the presence of 3 or more AIDs and a family history of AIDs. Statistical analyses performed were descriptive, bivariate, and multivariate (dependent variable: polyautoimmunity). The study population comprised 109 patients with RA, 105 patients with SLE, and 88 controls. Polyautoimmunity was recorded in 15 patients with RA (13.8%), 43 with SLE (41%), and 2 controls (2.2%). The most frequent AID in RA was Sjögren syndrome (53.3%), followed by Hashimoto thyroiditis and psoriasis; the most frequent AIDs in SLE were Sjögren syndrome (55.8%) and antiphospholipid syndrome (30.2%), followed by Hashimoto thyroiditis. Obesity was associated with polyautoimmunity in RA (odds ratio [OR], 3.362; p = 0.034). In SLE, joint damage (OR, 2.282; p = 0.038) and anti-RNP antibodies (OR, 5.095; p = 0.028) were risk factors for polyautoimmunity, and hydroxychloroquine was a protective factor (OR, 0.190; p = 0.004). Polyautoimmunity is frequent in RA and even more frequent in SLE. It was associated with obesity in RA and with joint damage and anti-RNP in SLE. Hydroxychloroquine was a protector.

IntroductionMer and Tyro3 are receptor tyrosine kinases important for the phagocytosis of apoptotic cells. Together with Axl, they constitute the TAM receptor family. These receptors can be shed from the cell membrane and their soluble extracellular regions can be found in plasma. The objective of this study was to elucidate whether the plasma levels of soluble Mer (sMer) and Tyro3 (sTyro3) were increased in systemic lupus erythematosis (SLE), rheumatoid arthritis (RA), or critical limb ischemia (CLI).MethodsELISA kits were used to test plasma concentrations in controls and in patients with SLE, RA or CLI.ResultsIncreased levels of, in particular, sMer and, to some extent, sTyro3, were found in patients with SLE or RA, but not in patients with CLI. Patients with SLE demonstrated the highest sMer levels and there was a strong correlation to higher SLE disease activity score (SLEDAI). In contrast, in patients with RA, the sMer levels did not correlate with the disease activity score (DAS). In SLE, sMer levels were particularly high in those with lupus nephritis, patients who also had decreased C1q levels and increased titers of anti-DNA antibodies. After therapy, the plasma concentrations of sMer decreased in parallel to the decrease in SLEDAI score.ConclusionsThe plasma concentrations of sMer and sTyro3 were significantly increased in patients with active SLE and RA, suggesting the TAM receptor shedding was affected by these autoimmune diseases. In particular, sMer was increased in SLE, the plasma levels of sMer reflecting disease activity.

Calcification of the thoracic aorta is often associated with valvular and coronary calcification, reflecting an underlying atherosclerotic process.1,2 It has been found to be associated with an increased rate of mortality and cardiovascular disease.1 Porcelain aorta (PA) is extensive calcification of the ascending aorta or aortic arch that can be completely or near completely circumferential.3–5 This entity is rare in the general population, but it has an increasing incidence in older patients and in patients with coronary artery disease (CAD) or aortic stenosis (AS).6,7 The clinical relevance is based on the fact that it can complicate surgical aortic valve replacement (SAVR) for the treatment of severe AS by preventing safe access via the ascending aorta. PA is associated with increased morbidity and mortality, especially as a result of increased perioperative stroke risk.8,9 Recently, transcatheter aortic valve replacement (TAVR) has emerged as a less invasive and feasible treatment option in patients at high risk for conventional SAVR.10 In some series, ≈20% (5%–33%) of patients undergoing TAVR were diagnosed with PA.11 Inconsistencies in the definition and the use of different diagnostic modalities contribute to this wide range of PA prevalence. We reviewed the available published data to seek a consistent, clinically relevant definition based on contemporary imaging, a firm understanding of the pathogenesis and associations, and the clinical implications of this disease entity. PA has been used to address extensive circumferential or nearly circumferential calcification of the thoracic aorta such that it precludes safe cross-clamping or entry to the ascending aorta. However, there is no clear description or definition used; thus, cardiac surgeons and cardiologists use this term inconsistently. In the 1980s, Coselli and Crawford12 initially described 2 …

Immunological Consequences of Apoptotic Cell Phagocytosis

The term autoimmune rheumatic diseases (ARDs) encompasses a heterogeneous group of conditions characterized by joint involvement along with a wide spectrum of systemic manifestations. The most common ARDs are rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Nevertheless, all these conditions share similar pathophysiological mechanisms [1, 2] and a common risk of developing a process of accelerated atherosclerosis [3]. In this regard, in this special issue J. Amaya-Amaya and colleagues discussed the mechanisms associated with the increased risk of cardiovascular disease (CVD) in patients with autoimmune diseases. These authors emphasize the relevance of the CVD in rheumatic conditions and its connection with inflammation and autoimmunity. They also highlight the need of a more aggressive management of these conditions, both of disease activity and classic cardiovascular risk factors. A good example of accelerated atherosclerosis in the setting of an ARD is SLE, in which endothelial dysfunction, an early step in the atherogenesis process, is observed before cardiovascular events can occur. With respect to this, A. Mak and N. Y. Kow performed a comprehensive review of the mechanisms that are involved in endothelial damage.These authors focused on the factors involved in endothelial damage and repair and, therefore, in the development of CVD in patients with SLE. They discussed the relevant role of factors such as type 1 interferon, proinflammatory cytokines, inflammatory cells, immune complexes, costimulatory molecules, neutrophils extracellular traps, lupus-related autoantibodies, oxidative stress, and dyslipidemia that along with the aberrant function of the endothelial progenitor cells lead to endothelial dysfunction and increased susceptibility to develop CVD in patients with SLE. Based on these lines of evidence, the authors’ claim is in favor of early intervention at the preclinical stage of atherogenesis in these patients.

Objective To study the probability of other autoimmune diseases in primary biliary cirrhosis (PBC), autoimmune hepatitis (AIH) and primary sclerosing cholangitis (PSC) and explore its effects on the prognosis. Methods From January 1994 to March 2014, the data of 232 patients with autoimmune liver diseases (AILD) were collected. The type and case number of coexisting with other autoimmune diseases of patients with PBC, AIH and PSC were analyzed and compared. Cox regression model was performed to analyze the effects of coexisting with autoimmune diseases on the prognosis of AILD. Results Among 135 PBC patients, there were 64 cases that coexisted with Sjogren's syndrome (SS), seven cases with systemic lupus erythematosus (SLE), seven cases with rheumatoid arthritis (RA), nine cases with systemic sclerosis (SSc), three cases with polymyositis and/or dermatomyositis (PM/DM) and one case with Crohn's disease. Among 55 AIH patients, threre were 19 cases that coexisted with SS, 10 cases with SLE, one case with RA, two cases with SSc and two cases with PM/DM. Among 24 PSC patients, there were seven cases combined with ulceric colitis, one case with Crohn's disease and one case with RA. Among 18 patients with PBC-AIH overlap syndrome, there were five cases with SS and one case with RA. Compared with PBC patients, the risk of pulmonary interstitial fibrosis increased in PBC patiento coexisting with SS (OR=34.0, 95%CI 8.9 to 130.1). After gender, age, disease course and medicine intervention were adjusted, the prognosis of AILD which included death, liver transplantation and liver cirrhosis complications was not affected by the coexistence with other autoimmune diseases. Conclusions AILD patients coexisting with other autoimmune diseases is common, most of which are SS, SLE, SSc and RA. PBC patients coexisting with SS is the risk factor of pulmonary interstitial fibrosis, and coexisting with other autoimmune disease does not independently affect the prognosis of AILD. Key words: Hepatitis, autoimmune; Comorbidity; Autoimmune diseases; Prognosis

Peroxynitrite-modified histone as a pathophysiological biomarker in autoimmune diseases

Autoimmune diseases (AIDs) are multifaceted, chronic illnesses characterized by immune dysregulation and systemic inflammation. Newer evidence has pointed a finger at the human gut microbiota, a trillion-fold population of microorganisms that inhabits the human GI tract, as a major influential modulator of immune reactivity and a significant contributor to autoimmune pathogenesis. This systematic review will seek to address how the literature correlates with systematic changes in the gut microbiota in AIDs as well as explore mechanistic associations with biological processes like intestinal permeability and modulation of the immune system, coupled with determining the effectiveness of microbiota-directed interventions.An extensive literature search was conducted in PubMed, Embase, Cochrane Central, and Web of Science, involving the availability of studies until May 2025. The eligible studies included observational studies, randomized controlled trials, and relevant mechanistic research regarding autoimmune diseases and alterations of the gut microbiome or administered interventions. Data extraction and risk of bias (ROB) assessments were performed by two independent reviewers, and a narrative synthesis with an illustrative meta-analysis was applied.Inclusion criteria were met by 10 studies, encompassing various autoimmune diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), type 1 diabetes mellitus (T1DM), autoimmune thyroid diseases (AITDs), and psoriasis. Familiar patterns of microbiome dysbiosis were identified, such as a reduction in microbial diversity, increased intestinal permeability, and the expansion of pro-inflammatory species like Ruminococcus gnavus. Dietary interventions, fecal microbiota transplantation, and probiotics demonstrated positive effects on clinical outcomes and immune measures across multiple studies.The meta-analysis revealed that microbiota-directed interventions significantly improved disease activity and immune response markers in AIDs, indicating a robust link between gut microbiota composition and autoimmune pathology. In autoimmune disorders, gut microbiota is a key factor in immunopathology. Gut biology as an adjunct interventional strategy provides potential in managing these diseases. Additional studies are required to help standardize methods and identify microbial targets specific to diseases that can then be addressed through therapeutic interventions.

Thanks to advances in research, it may soon be easier to diagnose autoimmune diseases earlier, but therapy remains a tricky problem