Loss Of Immune Tolerance Research Articles

Activation in Autoimmunity: Mechanisms and Clinical Implications

Autoimmunity arises when the immune system mistakenly targets the body’s own tissues, leading to chronic inflammatory diseases that can affect multiple organs. The central event in autoimmunity is the inappropriate activation of immune cells, which normally tolerate self-antigens. This review examines the mechanisms underlying immune activation in autoimmunity, focusing on the loss of immune tolerance, molecular mimicry, bystander activation, and epitope spreading. Genetic predispositions and environmental triggers, such as infections, play key roles in this process, contributing to the dysregulation of immune responses. Specific immune cells, including autoreactive T cells, B cells producing autoantibodies, and dendritic cells presenting self-antigens, drive disease pathogenesis by perpetuating inflammation and tissue damage. Dysfunctions in regulatory T cells (Tregs) further exacerbate immune activation by failing to suppress autoreactive lymphocytes. Clinically, understanding these activation mechanisms is crucial for developing diagnostic biomarkers and targeted therapies. Current treatments focus on modulating immune responses through biologic agents that block pro-inflammatory cytokines (e.g., TNF-α, IL-6), deplete B cells (e.g., rituximab), or restore immune regulation (e.g., Treg therapies). Emerging therapies aim to restore immune tolerance, offering hope for more effective and personalized interventions. This review highlights the critical role of immune activation in autoimmunity and discusses therapeutic strategies to prevent or reverse this process. The ongoing exploration of these mechanisms is key to improving outcomes for patients with autoimmune diseases. Keywords: Autoimmunity, immune tolerance, molecular mimicry, T cells, autoantibodies, targeted therapy

Mechanism of formation and significance of antimitochondrial autoantibodies in the pathogenesis of primary biliary cholangitis

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.

Immunotherapeutic potential of collagen V oral administration in mBSA/CFA-induced arthritis.

We hypothesized that after synovial injury, collagen V (Col V) expose occult antigens, and Col V autoantibodies develop, indicating the loss of immune tolerance against this molecule, thus leading to damage to mesenchymal-derived cells as well as the extracellular matrix in experimental arthritis. Thus, the present study investigated the effects of oral administration of Col V on the synovium after the development of inflammation in mBSA/CFA-induced arthritis. After fourteen days of intraarticular administration of mBSA, 10 male Lewis rats were orally administered Col V (500 μg/300 μL) diluted in 0.01 N acetic acid (IA-Col V group). The arthritic group (IA group, n = 10) received only intraarticular mBSA. An intra-articular saline injection (20 μL) was given to the control group (CT-Col V, n = 5). IA group presented damaged synovia, the expansion of the extracellular matrix by cellular infiltrate, which was characterized by T and B lymphocytes, and fibroblastic infiltration. In contrast, after Col V oral immunotherapy IA-Col V group showed a significant reduction in synovial inflammation and intense expression of IL-10+ and FoxP3+ cells, in addition to a reduction in Col V and an increase in Col I in the synovia compared to those in the IA group. Furthermore, an increase in IL-10 production was detected after IA-Col V group spleen cell stimulation with Col V in vitro. PET imaging did not differ between the groups. The evaluation of oral treatment with Col V, after mBSA/CFA-induced arthritis in rats, protects against inflammation and reduces synovial tissue damage, through modulation of the synovial matrix, showing an immunotherapeutic potential in inhibiting synovitis.

Causal effects of plasma metabolites on autoimmune hepatitis (AIH): a bidirectional two-sample mendelian randomization study

Autoimmune hepatitis(AIH) is a chronic progressive inflammatory liver disease induced by loss of immune tolerance. The role of circulating metabolites in disease pathogenesis is unclear. This study aimed to investigate potential causal links between plasma metabolites and AIH risk by employing a two-sample Mendelian randomization approach. A comprehensive bidirectional two-sample Mendelian randomization analysis was conducted using genome-wide significant variant-metabolite and variant-AIH associations in European ancestry individuals. Various methods assessed causal relationships among 1400 metabolites and AIH, incorporating sensitivity analyses to evaluate pleiotropy and heterogeneity. Fifty-eight metabolites displayed possible associations, including increased AIH risk with genetically predicted higher kynurenine (p = 2.79 × 10− 5, OR: 1.64, 95% CI 1.30–2.07) and a protective effect for the dopamine sulfate ratio (p = 1.06 × 10− 5,OR: 0.62, 95% CI 0.49–0.79). Reciprocal analysis revealed a causal effect of AIH on kynurenine( p = 2.79 × 10− 5, OR: 1.64, 95% CI 1.30–2.07), but not on the dopamine sulfate ratio(p = 0.691, OR: 1.05, 95% CI 0.67–1.64). Our genetics-based approach provides evidence supporting a causal role for specific metabolite levels in AIH risk. The results deliver evidence supporting a causal effect of a specific metabolite ratio(dopamine 4-sulfate/dopamine 3-O-sulfate) on AIH risk. Experimental validation and mechanistic examinations are warranted to confirm findings.

Lichen striatus: a review.

Lichen striatus (LS) is an acquired blaschkitis, with typical linear and unilateral distribution. It occurs mainly in children and is self-resolving, yet its etiopathogenesis remains widely unknown. A review of the literature on LS cases was performed using the keyword "lichen striatus" to retrieve all relevant articles through PubMed and Google Scholar. A total of 27 articles describing 440 LS patients were included in the present review. Mean age of patients was 3.8 years; male: female: ratio was 1:1.9. The present review confirms LS as a primarily pediatric condition, mainly affecting females. Dysregulation of the immune system might be involved in its pathogenesis, with cytotoxic T-cells attacking mosaic keratinocytes after loss of immune tolerance. The review confirms LS is mainly diagnosed clinically (80%) based on its clinical characteristics: erythematous (70%) or hypopigmented (24%) papules, distributed along the lines of Blashko. The benignity of this clinical entity is suggested by the rather short duration of disease (9.5 months on average) and by the uncommonness of therapy, adopted in only 20% of cases, and when needed, administered topically. This review examines the complexities of LS but acknowledges limitations in data sources and calls for further research.

The Contribution of the Skin Microbiome to Psoriasis Pathogenesis and Its Implications for Therapeutic Strategies.

Psoriasis is a common chronic inflammatory skin disease, associated with significant morbidity and a considerable negative impact on the patients' quality of life. The complex pathogenesis of psoriasis is still incompletely understood. Genetic predisposition, environmental factors like smoking, alcohol consumption, psychological stress, consumption of certain drugs, and mechanical trauma, as well as specific immune dysfunctions, contribute to the onset of the disease. Mounting evidence indicate that skin dysbiosis plays a significant role in the development and exacerbation of psoriasis through loss of immune tolerance to commensal skin flora, an altered balance between Tregs and effector cells, and an excessive Th1 and Th17 polarization. While the implications of skin dysbiosis in psoriasis pathogenesis are only starting to be revealed, the progress in the characterization of the skin microbiome changes in psoriasis patients has opened a whole new avenue of research focusing on the modulation of the skin microbiome as an adjuvant treatment for psoriasis and as part of a long-term plan to prevent disease flares. The skin microbiome may also represent a valuable predictive marker of treatment response and may aid in the selection of the optimal personalized treatment. We present the current knowledge on the skin microbiome changes in psoriasis and the results of the studies that investigated the efficacy of the different skin microbiome modulation strategies in the management of psoriasis, and discuss the complex interaction between the host and skin commensal flora.

Diagnosis and Treatment of Membranous Nephropathy in Integrative Medicine

Membranous nephropathy (MN) is a common glomerular disease. The related pathological changes are primarily characterized by the deposition of immune complexes beneath the epithelial cells of the glomerular basement membrane, accompanied by diffuse thickening of the basement membrane. Its etiology and pathogenesis are not fully understood yet; however, they are associated with genetics, infections, tumors, drugs, heavy metals poisoning, environmental pollution, and the loss of immune tolerance. Over 10 target antigens, including the phospholipase A2 receptor (PLA2R) and thrombospondin type 1 domain containing 7A (THSD7A), associated with MN have been identified, each having different clinical implications. Clinical manifestations of MN patients mainly include proteinuria and nephrotic syndrome, with a propensity to form thrombi. Its diagnostic accuracy can be enhanced by combining clinical manifestations, serum antibody testing, and renal biopsy. Proteinuria, estimated glomerular filtration rate (eGFR), and PLA2R antibody levels are vital for the prognostic risk stratification of MN. Low-risk patients primarily undergo non-immunosuppressive treatment (angiotensin-converting enzyme inhibitor [ACEI]/angiotensin II receptor blocker [ARB], sodium-glucose cotransporter 2 inhibitor [SGLT2i], anticoagulants, and traditional Chinese medicine [TCM] treatments), while high-risk patients need to consider using steroids and immunosuppressants, such as cyclophosphamide (CTX), calcineurin inhibitors (CNIs), and anti-cluster of differentiation 20 (anti-CD20) monoclonal antibodies. TCM holds that MN is the imbalance of Fei (lung), Pi (spleen), and Shen (kidney) function, leading to the generation of Neixie such as Shi, Re, Du, and Yu. This disease is difficult to heal because of Shire and Yu. The treatment is based on the use of Jianpi Bushen, simultaneously emphasizing the use of drugs for Qingre Qushi Huoxue. Dialectical use of TCM can obviously improve the clinical response rate and alleviate symptoms such as edema and fatigue by increasing the serum albumin level more rapidly while introducing fewer adverse reactions. Combined with Western medicine, TCM can also reduce toxicity and increase efficiency. This article systematically reviews the etiology, podocyte antigens, clinical manifestations, diagnostic approaches, risk assessment, and integrative medicine therapeutic strategies for MN, aiming to deepen the understanding of MN and guide clinical practice.

Abstract P180: Female mice with systemic lupus erythematosus produce antibodies to mitochondrial antigens and have impaired renal mitochondrial function

Patients with autoimmune disorders like systemic lupus erythematosus (SLE) are at significant risk for renal and cardiovascular mortality. The pathology of SLE is driven by a loss of immune tolerance with the subsequent production of autoantibodies (IgG), and our laboratory previously demonstrated a mechanistic role for autoantibodies in autoimmune mediated hypertension. While anti-double stranded DNA (dsDNA) antibodies are pathognomonic for SLE, a breadth of autoantibodies may contribute to disease pathology. The goal of this study is to identify autoantibodies that may contribute to the renal and cardiovascular consequences associated with SLE. To accomplish this goal, an antigen array was performed (University of Texas Southwestern Genomics & Microarray Core Facility) using plasma samples collected from an established experimental mouse model of SLE (30 week old female NZBWF1, n=8) and healthy controls (30 week old female NZWLacJ, n=7). As anticipated, autoantibodies raised to nuclear antigens were prominently represented in the array and were significantly increased relative to control mice. This includes antibodies to dsDNA, ssRNA, chromatin, and histones (total) (p<0.02). In addition, SLE mice produce antibodies to mitochondrial antigens including cardiolipin and cytochrome C (p<0.02 vs control mice), critical components of the inner mitochondrial membrane and respiratory chain, respectively. In a separate study, renal mitochondrial function was tested using high resolution respirometry (Oroboros Instruments) in whole kidney homogenates from 30 week old female SLE (n=6) and control mice (n=5). Results show that coupled respiration, an estimation of oxidative phosphorylation, is significantly impaired at Complex I in kidneys from SLE mice compared to healthy controls (62±9 vs. 90±7 pmol/s/mg tissue, p<0.05). Uncoupled respiration, an estimation of maximal electron transport, is also reduced in the kidneys of female SLE mice compared to controls (157±23 vs. 212±14 pmol/s/mg tissue, p=0.07). These data provide insight for new mechanistic pathways to pursue in understanding the underlying mechanisms promoting cardiovascular risk factors like hypertension during SLE.

Amplification of autoimmune organ damage by NKp46-activated ILC1s.

In systemic lupus erythematosus, loss of immune tolerance, autoantibody production and immune complex deposition are required but not sufficient for organ damage1. How inflammatory signals are initiated and amplified in the setting of autoimmunity remains elusive. Here we set out to dissect layers and hierarchies of autoimmune kidney inflammation to identify tissue-specific cellular hubs that amplify autoinflammatory responses. Using high-resolution single-cell profiling of kidney immune and parenchymal cells, in combination with antibody blockade and genetic deficiency, we show that tissue-resident NKp46+ innate lymphoid cells (ILCs) are crucial signal amplifiers of disease-associated macrophage expansion and epithelial cell injury in lupus nephritis, downstream of autoantibody production. NKp46 signalling in a distinct subset of group 1 ILCs (ILC1s) instructed an unconventional immune-regulatory transcriptional program, which included the expression of the myeloid cell growth factor CSF2. CSF2 production by NKp46+ ILCs promoted the population expansion of monocyte-derived macrophages. Blockade of the NKp46 receptor (using the antibody clonemNCR1.15; ref.2) or genetic deficiency of NKp46 abrogated epithelial cell injury. The same cellular and molecular patterns were operative in human lupus nephritis. Our data provide support for the idea that NKp46+ ILC1s promote parenchymal cell injury by granting monocyte-derived macrophages access to epithelial cell niches. NKp46 activation in ILC1s therefore constitutes a previously unrecognized, crucial tissue rheostat that amplifies organ damage in autoimmune hosts, with broad implications for inflammatory pathologies and therapies.

Gut microbiota and rheumatic diseases: new insights into pathogenesis

Background: Rheumatic diseases are a group of disorders characterised by a loss of immune tolerance, which leads to chronic inflammation, degeneration or metabolic abnormalities in various organs or tissues. Despite the lack of clarity surrounding the causes of these diseases, both environmental and genetic factors play an important role. Recent research indicates that alterations in the composition of the gut microbiota, known as gut dysbiosis, may contribute to the development of a number of rheumatic diseases, including rheumatoid arthritis, systemic lupus, ankylosing spondylitis, systemic scleroderma and Sjögren's syndrome. The gut microbiota influences the balance between pro- and anti-inflammatory immune responses, which may have important implications for the pathogenesis of these diseases. Furthermore, studies have indicated that the composition of the gut microbiota may be associated with the response to therapies used to treat rheumatic diseases, thus opening up new avenues for the development of microbiota-targeted treatments for these conditions. Aim of the study: The objective of this review is to investigate the impact of the gut microbiota on the pathogenesis of rheumatic diseases and to evaluate potential therapies targeting the manipulation of the gut microbiota. Material and methods: The present study is based on literature available in scientific databases from 2019-2024, such as PubMed, Corchane Library and Google Scholar.Results and conclusions: A growing body of evidence suggests a potential link between the gut microbiota and rheumatic diseases. Patients often exhibit a reduced ratio of Firmicutes to Bacteroidetes and abnormal numbers of Bacteroides. Molecular mimicry and a potential association with short-chain fatty acids have also been observed. Further human studies are needed to more fully understand the role of the gut microbiota and potential therapeutic interventions.

Reduced Tolerogenic Program Death-Ligand 1-Expressing Conventional Type 1 Dendritic Cells Are Associated with Rapid Decline in Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is characterized, at least in part, by autoimmunity through amplified T helper 1 and 17 (Th1 and Th17) immune responses. The loss of immune tolerance controlled by programmed death-ligand 1 (PD-L1) may contribute to this. We studied the tolerogenic role of PD-L1+ dendritic cells (DCs) and their subtypes in relation to specific T cell immunity and the clinical phenotypes of COPD. We used flow cytometry to analyze PD-L1 expression by the DCs and their subtypes in the peripheral blood mononuclear cells (PBMCs) from normal participants and those with COPD. T cell proliferation and the signature cytokines of T cell subtypes stimulated with elastin as autoantigens were measured using flow cytometry and enzyme-linked immunosorbent assays (ELISA), respectively. A total of 83 participants were enrolled (normal, n = 29; COPD, n = 54). A reduced PD-L1+ conventional dendritic cell 1 (cDC1) ratio in the PBMCs of the patients with COPD was shown (13.7 ± 13.7%, p = 0.03). The decrease in the PD-L1+ cDC1 ratio was associated with a rapid decline in COPD (p = 0.02) and correlated with the CD4+ T cells (r = -0.33, p = 0.02). This is supported by the NCBI GEO database accession number GSE56766, the researchers of which found that the gene expressions of PD-L1 and CD4, but not CD8 were negatively correlated from PBMC in COPD patients (r = -0.43, p = 0.002). Functionally, the PD-L1 blockade enhanced CD4+ T cell proliferation stimulated by CD3/elastin (31.2 ± 22.3%, p = 0.04) and interleukin (IL)-17A production stimulated by both CD3 (156.3 ± 54.7, p = 0.03) and CD3/elastin (148 ± 64.9, p = 0.03) from the normal PBMCs. The PD-L1 blockade failed to increase IL-17A production in the cDC1-depleted PBMCs. By contrast, there was no significant change in interferon (IFN)-γ, IL-4, or IL-10 after the PD-L1 blockade. Again, these findings were supported by the NCBI GEO database accession number GSE56766, the researchers of which found that only the expression of RORC, a master transcription factor driving the Th17 cells, was significantly negatively correlated to PD-L1 (r = -0.33, p = 0.02). Circulating PD-L1+ cDC1 was reduced in the patients with COPD, and the tolerogenic role was suppressed with susceptibility to self-antigens and linked to rapid decline caused by Th17-skewed chronic inflammation.

Daucosterol regulates JAK2-STAT3 signaling pathway to promote megakaryocyte differentiation

Immune thrombocytopenia (ITP) is an autoimmune disease caused by the loss of immune tolerance to platelet autoantigens, resulting in reduced platelet production and increased platelet destruction. Impaired megakaryocyte differentiation and maturation is a key factor in the pathogenesis and treatment of ITP. Sarcandra glabra, a plant of the Chloranthaceae family, is commonly used in clinical practice to treat ITP, and daucosterol (Dau) is one of its active ingredients. However, whether Dau can treat ITP and the key mechanism of its effect are still unclear. In this study, we found that Dau could effectively promote the differentiation and maturation of megakaryocytes and the formation of polyploidy in the megakaryocyte differentiation disorder model constructed by co-culturing Dami and HS-5 cells. In vivo experiments showed that Dau could not only increase the number of polyploidized megakaryocytes in the ITP rat model, but also promote the recovery of platelet count. In addition, through network pharmacology analysis, we speculated that the JAK2-STAT3 signaling pathway might be involved in the process of Dau promoting megakaryocyte differentiation. Western blot results showed that Dau inhibited the expression of P-JAK2 and P-STAT3. In summary, these results provide a basis for further studying the pharmacological mechanism of Dau in treating ITP.

OA24 Age-associated T-bet+ B cells in healthy and autoimmune pregnancy

Abstract Background/Aims Inflammatory rheumatic diseases (IRD), including systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), affect females of reproductive age and are characterised by loss of immune tolerance and an increased burden of adverse pregnancy outcomes (APO). Mechanisms by which IRD may affect immune adaptations of healthy pregnancy to maintain host and fetal defence whilst tolerating male fetal antigens are poorly characterised. This study aimed to investigate B cell subpopulations in healthy and IRD in pregnancy, with a focus on IgD-CD27- (double negative, DN) T-bet+ B cells, considered pathogenic in IRD. Given disparate relationships between disease activity and risk of APO in SLE and RA pregnancy, the objective of this pilot study was to determine if pregnancy alters the frequency and/or the phenotype of DN T-bet+ B cells in IRD compared with healthy control pregnancies. Methods Peripheral blood mononuclear cells were obtained from IRD pregnancy (SLE n = 5; RA n = 8), IRD non-pregnancy (SLE n = 12; RA n = 10), and healthy pregnant (n = 8) people at University College London Hospital by informed consent. Cells were analysed by flow cytometry to identify B cell subpopulations and their expression of multiple markers including T-bet, IFN-γR, TLR7, TLR9, Ki67, CD38 and CD19 was assessed. Results There were no significant differences in B cell subpopulations, categorised based on the expression of IgD and CD27, between the cohorts. In healthy pregnancy, the median frequency (%) of CD19+T-bet+, IgD-CD27+T-bet+, DNT-bet+ cells was 5, 1.3 and 2, respectively. In contrast, the median frequency of CD19+T-bet+ cells was significantly elevated in SLE pregnancy at 13% compared with 5% (p < 0.05) in healthy pregnancy[GI3] [RV4] . Similarly, the median frequency of DNT-bet+ B cells was elevated in SLE pregnancy at 6% compared with 2% (p = 0.009) in healthy pregnancy. RA pregnancy, but not SLE pregnancy, had significantly lower frequency of Ki67+ DN T-bet+ cells compared to non-pregnant RA (p=0.04) and SLE (p=0.07). ROC analysis demonstrated that for both RA (p = 0.016, AUC = 0.84, 95% CI [0.65, 1.00]) and SLE (p = 0.015, AUC=0.88) the frequency of DN T-bet+ Ki67+ B cells can discriminate between pregnancy and non-pregnancy samples. In pooled analysis (n = 43), but not in single cohorts, DN T-bet+ cells had significantly high TLR7 and TLR9 expression. High frequencies of CD19hi DN T-bet+ cells were found but were unaffected by pregnancy. Clustering revealed canonical DN T-bet+ clusters and CD38hi T-bet+ clusters enriched in SLE and pregnancy-altered. Conclusion We have immunophenotyped B cell populations in healthy pregnancy and identified different patterns of alteration in frequency and proliferation of DNTbet+ cells in IRD compared with healthy pregnancy that are disease specific. This pilot study reveals previously unrecognized immunological changes in disease pregnancy warranting further larger studies of their mechanistic basis and clinical relevance. Disclosure S. Benton: None. C. Raine: None. K. Shah: None. S. Luong: None. A. Venkatkrishnan: None. M. Leandro: None. M. Castelino: None. D. Sen: None. D.A. Isenberg: None. A. Akbar: None. I. Giles: Grants/research support; IG has received an unrestricted research grant, travel and speaker fees from UCB Pharma. V.R. Reddy: None.

Immune Ataxias: The Continuum of Latent Ataxia, Primary Ataxia and Clinical Ataxia.

The clinical category of immune-mediated cerebellar ataxias (IMCAs) is now recognized after 3 decades of clinical and experimental research. The cerebellum gathers about 60% of neurons in the brain, is enriched in numerous plasticity mechanisms, and presents a large variety of antigens at the neuroglial level: ion channels and related proteins, synaptic adhesion/organizing proteins, transmitter receptors, and glial cells. Cerebellar circuitry is especially vulnerable to immune attacks. After the loss of immune tolerance, IMCAs present in an acute or subacute manner with various combinations of a vestibulocerebellar syndrome (VCS), a cerebellar motor syndrome (CMS), and a cerebellar cognitive affective syndrome/Schmahmann's syndrome (CCAS/SS). IMCAs include gluten ataxia (GA), post-infectious cerebellitis (PIC), Miller Fisher syndrome (MFS), paraneoplastic cerebellar degeneration (PCD), opsoclonus myoclonus syndrome (OMS), anti-glutamic acid decarboxylase (anti-GAD) ataxia, and glial fibrillary acidic protein (GFAP) astrocytopathy (GFAP-A). In addition, multiple sclerosis (MS), acute disseminated encephalomyelitis (ADEM), Behçet disease, and collagen-vascular disorders may also present with cerebellar symptoms when lesions involve cerebellar afferences/efferences. Patients whose clinical profiles do not fit with IMCAs are now gathered in the group of primary autoimmune cerebellar ataxias (PACAs). Latent auto-immune cerebellar ataxia (LACA) refers to a clinical stage with a slow progressive course and a lack of obvious auto-immune background. At a pre-symptomatic stage, patients remain asymptomatic, whereas at the prodromal stage aspecific symptoms occur, announcing the symptomatic neuronal loss. LACA corresponds to a time-window where an intervention could lead to preservation of plasticity mechanisms. Patients may evolve from LACA to PACA and typical IMCAs, highlighting a continuum. Immune ataxias represent a model to elucidate the sequence of events leading to destruction of cerebellar neuronal reserve and develop novel strategies aiming to restore plasticity mechanisms.

Tolerogenic dendritic cell-mediated regulatory T cell differentiation by Chinese herbal formulation attenuates colitis progression

IntroductionUlcerative colitis (UC) is a chronic inflammatory disease characterized by loss of immune tolerance to luminal antigens and progressive intestinal tissue injury. Thus, the re-establishment of immune tolerance is crucial for suppressing aberrant immune responses and UC progression. ObjectivesThis study aimed to investigate the mechanisms underlying the action of CDD-2103 and its bioactive compounds in mediating immune regulation in mouse models of colitis. MethodsTwo experimental colitis models, chronic 2,4,6-trinitrobenzene sulfonic acid (TNBS)- and T-cell transfer-induced Rag1-/- mice, were used to determine the effects of CDD-2103 on colitis progression. Single-cell transcriptome analysis was used to profile the immune landscape and its interactions after CDD-2103 treatment. Liquid chromatography-mass spectrometry (LC-MS) was used to analyze the major components interacting with lymphoid cells. A primary cell co-culture system was used to confirm the effects of bioactive component. ResultsCDD-2103 dose-dependently suppresses the progression of colitis induced by chemicals or T cell transplantation in Rag1-/- mice. The effect of CDD-2103 is primarily attributable to an increase in the de novo generation of regulatory T cells (Tregs) in the lamina propria (LP). Single-cell transcriptomic analysis revealed that CDD-2103 treatment increased the number of tolerogenic dendritic cells (DCs). Mechanistically, CDD-2103 promoted tolerogenic DCs accumulation and function by upregulating several genes in the electron transport chain related to oxidative phosphorylation, leading to increased differentiation of Tregs. Further LC-MS analysis identified several compounds in CDD-2103, particularly those distributed within the mesenteric lymph nodes of mice. Subsequent studies revealed that palmatine and berberine promoted tolerogenic bone marrow-derived dendritic cells (BMDC)-mediated Treg differentiation. ConclusionOverall, our study demonstrated that the clinically beneficial effect of CDD-2103 in the treatment of UC is based on the induction of immune tolerance. In addition, this study supports berberine and palmatine as potential chemical entities in CDD-2103 that modulate immune tolerance.

Main circulating CD8<sup>+</sup> T cell subsets in patients with systemic lupus erythematosus

Relevance. Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by loss of immune tolerance and sustained production of autoantibodies.The aim of the study – to compare composition of peripheral blood cytotoxic CD8+ T lymphocytes (Tc) subsets and assess the clinical significance of them in systemic lupus erythematosus. Materials and methods. A total of 35 SLE patients and 49 healthy volunteers were included in the study. Phenotyping of peripheral blood T cell subpopulations was carried out by means of flow cytometry. T lymphocytes were determined using CD3+, CD4+, CD8+ antibodies. Tc were identified by using CD45RA and CD62L antibodies. Also the expression of chemokine receptors (CCR4, CCR6, CXCR3 and CXCR5) on Tc cells was assessed and the main Tc subpopulations were determined: Type 1 (Tc1), type 2 (Tc2), type 17 (Tc17), type 17/1 (Tc17.1), type 17/22 (Tc17.22) cytotoxic cells and T follicular cytotoxic cells (Tfc).Results. The absolute and relative number of Tc was significantly higher in the group of patients with SLE compared with the control group. Additionally, there was a significant decrease in the relative number of Tc1, Tc 17.1 and Tfc1 and a significant increase in the relative number of Tc2, Tfc 17 and Tfc17.1 within the SLE group when compared to the control group. There were significant positive correlationfor Tc1 and levels of C3 and C4 complement components (r=0.404, p<0.05).Conclusions. The absolute and relative number of peripheral blood Tc subsets is altered in SLE patients compared with the control group. It was found that patients with SLE contained increased number of Tc2 cells, which seems to be associated with markers of disease activity. These results demonstrate a prominent pathological role of Tc2 in SLE. While Tc1, Tc17, Tc17.1, Tfc subsets probably have regulatory functions

Macrophage extracellular traps require peptidylarginine deiminase 2 and 4 and are a source of citrullinated antigens bound by rheumatoid arthritis autoantibodies.

Anti-citrullinated protein antibodies (ACPAs) are a hallmark of rheumatoid arthritis, but the sources of citrullinated antigens as well as which peptidylarginine deiminases (PADs) are required for their production remain incompletely defined. Here, we investigated if macrophage extracellular traps (METs) could be a source of citrullinated proteins bound by APCAs, and if their formation requires PAD2 or PAD4. Thioglycolate-induced peritoneal macrophages from wild-type, PAD2-/-, and PAD4-/- mice or human peripheral blood-derived M1 macrophages were activated with a variety of stimulants, then fixed and stained with DAPI and either anti-citrullinated histone H4 (citH4) antibody or sera from ACPA+ or ACPA- rheumatoid arthritis subjects. METs were visualized by immunofluorescence, confirmed to be extracellular using DNase, and quantified. We found that ionomycin and monosodium urate crystals reliably induced murine citH4+ METs, which were reduced in the absence of PAD2 and lost in the absence of PAD4. Also, IgG from ACPA+, but not ACPA-, rheumatoid arthritis sera bound to murine METs, and in the absence of PAD2 or PAD4, ACPA-bound METs were lost. Finally, ionomycin induced human METs that are citH4+ and ACPA-bound. Thus, METs may contribute to the pool of citrullinated antigens bound by ACPAs in a PAD2- and PAD4-dependent manner, providing new insights into the targets of immune tolerance loss in rheumatoid arthritis.

The susceptibility of single nucleotide polymorphisms located within co-stimulatory pathways to systemic lupus erythematosus.

Autoimmune diseases result from the loss of immune tolerance, and they exhibit complex pathogenic mechanisms that remain challenging to effectively treat. It has been reported that the altered expression levels of co-stimulatory/inhibitory molecules will affect the level of T/B cell activation and lead to the loss of immune tolerance. In this study, we evaluated the gene polymorphisms of the ligand genes corresponding co-stimulatory system that were expressed on antigen-presenting cells (CD80, CD86, ICOSLG, and PDL1) from 60 systemic lupus erythematosus (SLE) patients and 60 healthy controls. The results showed that rs16829984 and rs57271503 of the CD80 gene and rs4143815 of the PDL1 gene were associated with SLE, in which the G-allele of rs16829984 (p=0.022), the A-allele of rs57271503 (p=0.029), and the GG and GC genotype of rs4143815 (p=0.039) may be risk polymorphisms for SLE. These SNPs are in the promoter and 3'UTR of the genes, so they may affect the transcription and translation activity of the genes, thereby regulating immune function and contributing to the development of SLE.

Recent advances in prevention and treatment of chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

Chronic graft-versus-host disease (cGVHD) negatively impacts long-term survival and quality of life (QOL) after allogeneic hematopoietic cell transplantation. Corticosteroids are the first-line treatment for cGVHD, but approximately 30% to 70% of patients develop steroid-refractory cGVHD (SR-cGVHD), which has an extremely poor prognosis. The pathophysiology of cGVHD is more complicated than acute GVHD, but recent advances using murine models in conjunction with human studies indicate three major phases: 1) acute inflammation, 2) chronic inflammation with loss of immune tolerance, and 3) disrupted target organ homeostasis and fibrosis. Strategies that help prevent cGVHD include optimal donor selection and choice of conditioning regimen as well as pharmacologic and graft manipulation strategies. The key cellular mediators of SR-cGVHD are T cells, B cells, antigen-presenting cells, and fibroblasts. T cells and B cells are now targetable with the inhibitors ibrutinib and ruxolitinib, respectively. Recently, promising results have been obtained by modulating pathologic T cell responses with Rock2 inhibitors and targeting fibrosis with CSF-1R inhibitors. To optimize the use of these medications, a better understanding of the biological and target organ-specific mechanisms of cGVHD is needed. Here we review recent advances in cGVHD pathogenesis and discuss how best to implement recently approved biology-driven treatments for cGVHD.

The Role and Mechanism of Autoantibodies in Dysimmunity Related Neurological Diseases

Autoantibodies are antibodies produced by B cells capable of attacking their own tissues or organs after loss of immune tolerance. A large body of literature shows that autoantibodies play an important role in neurological diseases associated with immune abnormalities. Nowadays, neurological disorders are an important cause of disability and death in populations around the world, so it is important to study the role and mechanisms of autoantibodies in neurological disorders associated with immune abnormalities. The blood-brain barrier is biologically important for maintaining the normal physiological state of the central nervous system, and we have previously found that monoclonal autoantibodies of SLE origin can inhibit the expression of tight junction proteins in the blood-brain barrier. Our findings provide clues for the study of the role of autoantibodies in neurological disorders and greatly attract us to conduct a more in-depth and systematic review and synthesis. In this paper, we summarize the functions of autoantibodies in autoimmune and non-autoimmune diseases and focus on the roles and mechanisms of autoantibodies in immune-associated neurological disorders by taking central and peripheral neurological diseases as the entry points, which can provide new molecular targets and new theoretical basis for the specific diagnosis and targeted therapy of neurological diseases.