Autoimmune Inflammatory Response Research Articles

High-intensity interval training improves bone remodeling, lipid profile, and physical function in multiple sclerosis patients

Multiple sclerosis (MS) is a demyelinating and neurodegenerative disease due to an autoimmune chronic inflammatory response, yet the etiology is currently not completely understood. It is already known that physical activity plays an essential role in improving quality of life, especially in neuropathological conditions. The study was aimed to investigate the possible benefits of high-intensity interval training (HIIT) in bone and lipid metabolism markers, and neuromotor abilities in MS patients. 130 participants were recruited; 16 subjects with MS met the inclusion criteria and were included in the data analysis. The patients were randomly assigned to two groups: a Control group (CG) (34.88 ± 4.45 yrs) that didn’t perform any physical activity and the Exercise group (EG) (36.20 ± 7.80 yrs) that performed HIIT protocol. The training program was conducted remotely by a kinesiologist. It was performed three times a week for 8 weeks. At the beginning (T0) and the end of the study (T1) physical function tests, bone remodelling markers, and lipid markers analyses were performed. After 8 weeks of training the wall squat (s) (T0 = 27.18 ± 4.21; T1 = 41.68 ± 5.38, p ≤ 0.01) and Time Up and Go test (s) (T0 = 7.65 ± 0.43; T1 = 6.34 ± 0.38 p ≤ 0.01) performances improved; lipid markers analysis showed a decrease in Total (mg/dl) (T0 = 187.22 ± 15.73; T1 = 173.44 ± 13.03, p ≤ 0.05) and LDL (mg/dl) (T0 = 108 ± 21.08; T1 = 95.02 ± 17.99, p < 0.05) cholesterol levels. Additionally, the levels of osteocalcin (µg/L), a marker of bone formation increased (T0 = 20.88 ± 4.22; T1 = 23.66 ± 6.24, p < 0.05), 25-OH Vitamin D (µg/L) improved after 8 weeks (T0 = 21.11 ± 7.11; T1 = 27.66 ± 7.59, p < 0.05). HIIT had an effect on lower limb strength and gait control, improved bone formation, and lipid management, in MS patients.

Acacetin alleviates autoimmune myocarditis by regulating CD4+ T cell mitochondrial respiration

BackgroundMyocarditis refers to an autoimmune inflammatory response of the myocardium with characterization of self-reactive CD4+ T cell activation, which lacks effective treatment and has a poor prognosis. Acacetin is a natural flavonoid product that has been reported to have anti-inflammatory effects. However, acacetin has not been investigated in myocarditis.MethodsOral acacetin treatment was administered in an experimental autoimmune myocarditis model established with myosin heavy chain-alpha peptide. Echocardiography, pathological staining, and RT-qPCR were used to detect cardiac function, myocardial injury, and inflammation levels. Flow cytometry was utilized to detect the effect of acacetin on CD4+ T cell function. RNA-seq, molecular docking, and microscale thermophoresis (MST) were employed to investigate potential mechanisms. Seahorse analysis, mitoSOX, JC-1, and mitotracker were utilized to detect the effect of acacetin on mitochondrial function.ResultsAcacetin attenuated cardiac injury and fibrosis as well as heart dysfunction, and reduced cardiac inflammatory cytokines and ratio of effector CD4+ T and Th17 cells. Acacetin inhibited CD4+ T cell activation, proliferation, and Th17 cell differentiation. Mechanistically, the effects of acacetin were related to reducing mitochondrial complex II activity thereby inhibiting mitochondrial respiration and mitochondrial reactive oxygen species in CD4+ T cells.ConclusionAcacetin may be a valuable therapeutic drug in treating CD4+ T cell-mediated myocarditis.Graphical

SkQ1 improves immune status and normalises the activity of antioxidant and nadph-generating enzymes in adjuvant-induced rheumatoid arthritis in rats

Rheumatoid arthritis (RA) is a severe systemic autoimmune inflammatory disease. Oxidative stress and excessive formation of mitochondrial reactive oxygen species (ROS) are now considered to be the central pathogenetic mechanisms of connective tissue component destruction and the factors responsible for a highly active inflammatory process and autoimmune response. The aim of the present work was to evaluate the effect of mitochondrial-directed antioxidant 10-(6′-plastoquinonyl)decyltriphenylphosphonium (SkQ1) on immune status, intensity of free radical-induced oxidation and functioning of antioxidant system (AOS) and NADPH-generating enzymes in rats with adjuvant-induced RA. Laboratory animals were divided into 4 groups: a control group; a group of animals with RA; animals injected intraperitoneally with SkQ1 at a dose of 1250 nmol/kg every 24 hours during the next 8 days from day 7 of RA development, and animals given SkQ1 at a dose of 625 nmol/kg according to the above scheme. Material for the study was taken on day 15 after the start of the experiment. The rate of erythrocyte sedimentation, the level of circulating immune complexes, and the concentration of immunoglobulins A, M and G were determined in rats by enzyme immunoassay. The intensity of free radical-induced oxidation was assessed by iron-induced biochemiluminescence, diene conjugate content and aconitate hydratase activity. Enzyme activity and metabolite content in animal tissues were analysed spectrophotometrically. The results of the work showed that the development of RA was associated with an increase in the indicators of immune response and intensity of free radical-induced oxidation. The development of an imbalance in AOS functioning and an increase in the activity of NADPH-generating enzymes was also observed. The administration of SkQ1 resulted in a dose-dependent change in the oxidative status indicators towards the control, which was accompanied by the normalization of the immune status parameters. It seems that the tested compound decreased the level of mitochondrial ROS, resulting in an inhibition of the inflammatory response. The consequence of these changes could be inhibition of free radical generation by immunocompetent cells and subsequent mitigation of the severity of oxidative stress in the tissues.

Abstract B038: Targeting a Treg-specific deubiquitinase module for antitumor immune therapy

Abstract Checkpoint immunotherapies have transformed the treatment landscape for multiple human malignancies, but still with very limited success in treatment of many human cancers. A major hurdle is mediated by regulatory T (Treg) cells, which suppress the function of antitumor effector T cells. However, current approaches in targeting Treg to activate antitumor immune responses have shown only transient efficacy and are highly unspecific. Importantly, our recent studies, through unbiased CRISPR screening, identified the death from cancer cell signature gene USP22 required for optimal FoxP3 expression. USP22 genetic inhibition resulted in an approximately 15-25% reduction of FoxP3 expression in Tregs and partially diminishes Treg suppressive functions, which consequently results in elevated antitumor immunity against a broad spectrum of cancer types in mice. Therefore, a 20% reduction in FoxP3 protein expression, in this case, by USP22 inhibition, creates an ideal therapeutic window to boost antitumor immunity without triggering extensive autoimmune inflammatory responses (Nature, 2020). More recently, we further demonstrated that tumor microenvironment factors, including TGF-β, hypoxia, and tumor metabolites, induce Treg fitness/adaptation through selectively upregulating a deubiquitinase module, including USP21 and USP22 (Science Advances, 2022). Our ongoing study has identified USP22-specific small molecule inhibitors that largely diminish Treg fitness and dramatically inhibit tumor growth at a clinically relevant setting. In addition, our recent unpublished single-cell RNA-seq characterization revealed a novel function of the Treg-specific deubiquitination module in Treg terminal differentiation into a unique immune suppressive subpopulation, specifically in the tumor microenvironment. Collectively, our study defines a novel Treg deubiquitination module in tumor immunosurveillance and provides a rationale for the first Treg-specific targeting in antitumor immune therapy. Citation Format: Deyu Fang. Targeting a Treg-specific deubiquitinase module for antitumor immune therapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr B038.

Interferon-γ controls aquaporin 4-specific Th17 and B cells in neuromyelitis optica spectrum disorder.

Neuromyelitis optica spectrum disorder (NMOSD) is a CNS autoimmune inflammatory disease mediated by T helper 17 (Th17) and antibody responses to the water channel protein, aquaporin 4 (AQP4), and associated with astrocytopathy, demyelination and axonal loss. Knowledge about disease pathogenesis is limited and the search for new therapies impeded by the absence of a reliable animal model. In our work, we determined that NMOSD is characterized by decreased IFN-γ receptor signalling and that IFN-γ depletion in AQP4201-220-immunized C57BL/6 mice results in severe clinical disease resembling human NMOSD. Pathologically, the disease causes autoimmune astrocytic and CNS injury secondary to cellular and humoral inflammation. Immunologically, the absence of IFN-γ allows for increased expression of IL-6 in B cells and activation of Th17 cells, and generation of a robust autoimmune inflammatory response. Consistent with NMOSD, the experimental disease is exacerbated by administration of IFN-β, whereas repletion of IFN-γ, as well as therapeutic targeting of IL-17A, IL-6R and B cells, ameliorates it. We also demonstrate that immune tolerization with AQP4201-220-coupled poly(lactic-co-glycolic acid) nanoparticles could both prevent and effectively treat the disease. Our findings enhance the understanding of NMOSD pathogenesis and provide a platform for the development of immune tolerance-based therapies, avoiding the limitations of the current immunosuppressive therapies.

Striatal Hyperintensity in Non-Ketotic Hyperglycemia Induced Hemichorea-Hemiballismus Syndrome: Case Report

Introduction: Hemichorea-Hemiballismus (HC-HB) is usually associated with lesions in the contralateral basal ganglia of the central nervous system and can be caused by infection, neurodegeneration, oncological cases, stroke, and metabolic disorders. HC-HB disorders associated with non-ketotic hyperglycemia are rare and are characterized by involuntary and arrhythmic unilateral movements. This occurrence is more common in cases of women, the elderly and poor control of blood sugar levels. Case Report: A female patient 46 years old, came with complaints of uncontrolled movements in the right half of the body since July 2021. Then it spread to the legs also 1 month later. Prior to this complaint, it was triggered by a stressor. History of non-routine use of drugs. On general physical examination and vital signs within normal limits. Neurological examination found right hemichorea with arrhythmic characteristics, 1-5 Hz, medium-large amplitude, stereotypy, right arm and leg, suppressibility (+), worsens when stressed. A CT-Scan of the head without contrast showed no abnormalities, but an MRI revealed a non-ketotic hyperglycemic image. The patient then received haloperidol 0.75 mg orally every 12 hours and clobazam 5 mg every 12 hours orally and insulin therapy. Discussion: In this case report, it was found that female patients was poor in control her blood glucose and causing complications. This condition also known as diabetic striatopathy (DS). Several mechanisms to explain the pathogenesis of DS include metabolic disorders, ischemic injury resulting in ion deposition, hemorrhagic injury, dopaminergic and estrogenic imbalances, autoimmune inflammatory responses, and neurodegeneration. This is supported by MRI imaging that supports the presence of hyperintense on T1. Keywords: Hyperglycemia, Involuntary Movement, Striatopathy

SkQ1 Improves Immune Status and Normalizes Activity of NADPH-Generating and Antioxidant Enzymes in Rats with Adjuvant-Induced Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a severe systemic autoimmune inflammatory disease. Oxidative stress and excessive formation of reactive oxygen species (ROS) by the mitochondria are considered as the central pathogenetic mechanisms of connective tissue destruction and factors responsible for a highly active inflammatory process and autoimmune response. The aim of this work was to evaluate the effect of mitochondria-targeted antioxidant 10-(6'-plastoquinonyl)decyltriphenylphosphonium (SkQ1) on the immune status, intensity of free radical-induced oxidation, and functioning of the antioxidant system (AOS) and NADPH-generating enzymes in rats with the adjuvant-induced RA. Laboratory animals were divided into 4 groups: control group; animals with RA; animals injected intraperitoneally with SkQ1 at the doses of 1250 and 625 nmol/kg, respectively, every 24 h for 8 days starting from day 7 of RA development. Tissue samples for analysis were collected on day 15 of the experiment. Erythrocyte sedimentation rate, the content of circulating immune complexes, and the concentration of class A, M, and G immunoglobulins were determined by enzyme immunoassay. The intensity of free radical-induced oxidation was evaluated based on the assessment of the iron-induced biochemiluminescence, diene conjugate content, and activity of aconitate hydratase. Enzymatic activity and metabolite content in the tissue samples were analyzed spectrophotometrically. It was shown that the development of RA was associated with an increase in the manifestation of immune response markers and intensity of free radical-induced oxidation, as well as with disruption of the AOS functioning and activation of NADPH-generating enzymes. SkQ1 administration resulted in a dose-dependent changes in the oxidative status indicators towards the control values and normalization of the immune status parameters. SkQ1 decreased the level of mitochondrial ROS, resulting in the suppression of the inflammatory response, which might cause inhibition of free radical generation by immunocompetent cells and subsequent mitigation of the oxidative stress severity in the tissues.

Implementation of Family Nursing Care for Clients with Rheumatoid Arthritis to Physical Mobility Disorders with Active and Passive Movement Exercises

Background: Rheumatoid Arthritis (RA) is a disease characterized by a chronic autoimmune inflammatory disorder or autoimmune response that causes weakening of the joints and synovial lining, especially in the hands, feet, and knees. Patients with RA often experience impaired physical mobility, a condition where a person cannot move freely due to conditions that hinder movement (activity). One of the interventions that can be given to RA patients is Range of motion (ROM) exercises, which are exercises performed to maintain or improve the perfection of the ability to move joints normally and completely to increase muscle mass and muscle tone. research to assess the effectiveness of implementing family nursing care with active and passive movement exercises against impaired physical mobility in Rheumatoid Arthritis sufferers in the work area of Taba Health Center, Lubuklinggau City, in 2022. Methods: This study uses a qualitative design with a case study approach to describe information descriptively. In-depth and explores nursing problems for families with rheumatoid arthritis with impaired physical mobility due to joint stiffness. Results: After implementation by giving active and passive motion exercises to both subjects (Mr. S and Mrs. E) for five consecutive days with a time of 10-15 minutes, both subjects said that stiffness in the extremities was reduced and the value of muscle strength increased to 5 and 4. Conclusion: Implementing nursing care with active and passive motion exercises can increase joint strength in clients with rheumatoid arthritis.

The Implementation of Range of Motion Exercises in Overcoming Impaired Physical Mobility in Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a disease characterized by an autoimmune chronic inflammatory disorder or autoimmune response that causes weakening of the joints and lining of the synovial organs, especially in the hands, feet, and knees. This study aims to determine the implementation of nursing care with active and passive motion exercises for impaired physical mobility in patients with rheumatoid arthritis in the work area at Taba Health Center, Lubuklinggau City, in 2022. The method used is descriptive in the form of a case study with two clients experiencing rheumatoid disease as subjects. arthritis with impaired physical mobility problems that experience joint stiffness. The results showed that after being given active and passive motion training therapy, muscle strength increased. Implementation of nursing care with active and passive motion exercises can increase muscle strength in clients with rheumatoid arthritis. Because this motion exercise does not require costs and each movement can be done independently at home.

Ginseng polysaccharide reduces autoimmune hepatitis inflammatory response by inhibiting PI3K/AKT and TLRs/NF-κB signaling pathways

BackgroundGinseng polysaccharides (GP) have been found to exhibit significant immune regulatory effects, making them a promising candidate for treating immune-related diseases. However, their mechanism of action in immune liver injury is not yet clear. The innovation of this study lies in exploring the mechanism of action of ginseng polysaccharides (GP) in immune liver injury. While GP has been previously identified for its immune regulatory effects, this study aims to provide a clearer understanding of its therapeutic potential for immune-related liver diseases. PurposeThe purpose of this study is to characterize low molecular weight gingeng polysaccharides (LGP), investigate their effect on ConA-induced autoimmune hepatitis (AIH), and identify their potential molecular mechanisms. MethodsLGP was extracted and purified using water-alcohol precipitation, DEAE-52 cellulose column, and Sephadex G200. And its structure was analyzed. It was then evaluated for anti-inflammatory and hepatoprotective effects in ConA-induced cells and mice, assessing cellular viability and inflammation with Cell Counting Kit-8 (CCK-8), Reverse Transcription-polymerase Chain Reaction (RT-PCR), and Western Blot, and hepatic injury, inflammation, and apoptosis with various biochemical and staining methods. ResultsLGP is a polysaccharide composed of glucose (Glu), galactose (Gal), and arabinose (Ara), with a molar ratio of 12.9:1.6:1.0. LGP has a low crystallinity amorphous powder structure and is free from impurities. LGP enhances cell viability and reduces inflammatory factors in ConA-induced RAW264.7 cells and inhibits inflammation and hepatocyte apoptosis in ConA-induced mice. LGP inhibits Phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) and Toll-like receptors/Nuclear factor kappa B (TLRs/NF-κB) signaling pathways in vitro and in vivo to treat AIH. ConclusionsLGP was successfully extracted and purified, exhibiting potential as a treatment for ConA-induced autoimmune hepatitis due to its ability to inhibit the PI3K/AKT and TLRs/NF-κB signaling pathways and protect liver cells from damage.

Phenotypic Evaluation of TREX1 Null Mice as a Model for Lupus-Like Autoimmune Disease

Abstract TREX1 (DNase III) is the major mammalian 3’-5’ DNA exonuclease and thought to play a major role in cell death and genomic DNA degradation. Dysfunction of Trex1 has been suggested to activate immune response by self DNA, as TREX1 null mice develop inflammatory myocarditis similar to autoimmune cardiomyopathy and produce type 1 IFN. TREX1 D18N causes a monogenic cutaneous form of lupus called familial chilblain lupus and exhibits dysfunctioned dsDNA-degrading activity, providing a link between dsDNA degradation and nucleic acid-mediated autoimmune diseases. Using CRISPR-Cas9, we generated a Trex1 −/−mouse by knocking out exon 2 and performed comprehensive phenotypic analyses to evaluate the loss of function of TREX1 and its potential application in SLE research. Both female and male TREX1 null mice showed dramatically increased post-wean morbidity and significantly increased serum ALT, AST and LDH levels, compared to wildtype and heterozygotes from 6 to 24 weeks of age, indicating liver and heart injuries. Pathohistological analysis showed inflammatory immune cell infiltration in liver, heart, spleen, kidney, lung and skin among TREX1 null mice. Serum anti-dsDNA antibody levels were significantly increased and remained high from 7 to 25 weeks of age, consistent with Trex1’s being the major DNA exonuclease. Urine protein to creatinine ratio was dramatically increased at 28 weeks of age among TREX1 null mice. In conclusion, the Trex1 −/−mice we generated in this work showed lupus-like inflammatory autoimmune responses in multiple organs, providing an urgently needed tool to study Trex1-mediated autoimmunity and to evaluate potential therapeutic treatments for lupus.

Nsun2 coupling with RoRγt shapes the fate of Th17 cells and promotes colitis

T helper 17 (Th17) cells are a subset of CD4+ T helper cells involved in the inflammatory response in autoimmunity. Th17 cells secrete Th17 specific cytokines, such as IL-17A and IL17-F, which are governed by the master transcription factor RoRγt. However, the epigenetic mechanism regulating Th17 cell function is still not fully understood. Here, we reveal that deletion of RNA 5-methylcytosine (m5C) methyltransferase Nsun2 in mouse CD4+ T cells specifically inhibits Th17 cell differentiation and alleviates Th17 cell-induced colitis pathogenesis. Mechanistically, RoRγt can recruit Nsun2 to chromatin regions of their targets, including Il17a and Il17f, leading to the transcription-coupled m5C formation and consequently enhanced mRNA stability. Our study demonstrates a m5C mediated cell intrinsic function in Th17 cells and suggests Nsun2 as a potential therapeutic target for autoimmune disease.

Teprotumumab for the treatment of thyroid eye disease

ABSTRACT Introduction Thyroid eye disease (TED) is an autoimmune disease characterized by inflammation of orbital and extraocular muscles. It induces proptosis and diplopia, leading to a worsening of quality of life (QoL) because of its impact on physical appearance, and visual function. The natural history involves an ‘active TED,’ which is an autoimmune inflammatory response targeting orbital soft tissues, and ‘inactive TED,’ where there is tissue expansion remodeling. To date, glucocorticoids represent the main medical therapy, even if often ineffective and associated with side effects. Areas covered In TED, the autoimmune process leads to production of TSH-R and IGF-1 R autoantibodies. This induces inflammatory changes in the orbital tissue, and activation of fibroblasts with accumulation of glycosaminoglycans, leading to consequent proptosis, and diplopia. In two previous randomized, double-masked, placebo-controlled, parallel-group, multicenter trials, teprotumumab has been shown to be effective in improving proptosis, inflammation, diplopia, and QoL. More recently, it has been shown that teprotumumab is also effective in chronic-inactive TED. Teprotumumab was approved by the FDA on 21 January 2020 for the treatment of TED. Expert opinion For the above-mentioned reasons teprotumumab represents a potential first line therapy for TED that could replace the use of steroids in the next future.

Neurological complications of COVID-19 and SARS-CoV-2 vaccination: an update

The respiratory infectious disease COVID-19, which emerged in 2019, has affected the world population over a brief period. In 2020, the disease was declared a pandemic by the World Health Organization. Although most COVID-19 patients primarily develop respiratory symptoms, neurological symptoms have been observed. Neurological symptoms are usually mild and non-specific. However, some patients could experience life-threatening neurological symptoms. With the increase in the incidence of COVID-19, the disease spectrum of patients with central and peripheral nervous system involvement has expanded significantly compared to the previous period. Lack of awareness has caused delays in diagnosis and treatment; therefore, updating the disease spectrum of neurological complications of COVID-19 is necessary. After COVID-19 claimed millions of lives, researchers found that some vaccines may induce autoimmune inflammatory responses in the nervous system via molecular mimicry, leading to SARS-CoV-2 vaccine-related neurological deficits. These neurological complications are often ignored by clinicians, delaying diagnosis and treatment; it is essential to study cases of vaccine-associated neurological complications. Therefore, we summarize the neurological complications of COVID-19 and nervous system adverse reactions caused by SARS-CoV-2 vaccines to help clinicians and public health service personnel understand these rare complications. Avoiding delays in diagnosis and treatment would ensure the safety of COVID-19 patients and SARS-CoV-2 vaccine recipients.

PSUN300 The sex-specific correlation of IL7, high HbA1c and liver damage markers in African Americans

Abstract Background Type 2 Diabetes (T2D) has been considered an inflammatory disease that correlates with elevated responses cytokines. The increasing prevalence of T2D worldwide, is accompanied by the higher incidence of T2D globally and nationally. African Americans (AA) compared to other ethnic groups, have a higher prevalence of obesity (49.6%) and 1.4-2.3-fold higher in T2D. IL-7 is resident to the liver and been previously reported to drive inflammation in several chronic (rheumatic) inflammatory autoimmune responses. Obese patients with high levels of HbA1c are at higher risk of inflammatory diseases compared with non- obese individuals. This suggests that high blood sugar levels and subsequent inflammation may impact the prevalence of circulating cholesterol levels of LDL and or HDL. PCSK9 regulates the LDL-receptor and could potentially be a link between inflammation and active PCSK9. Preliminary data in our lab show elevated levels of IL-7 (&amp;gt;8 pg/mL) significantly correlate with various serum biomarkers of lipid metabolism, inflammation, and liver damage Methods A total of 239 serum samples were collected from AA: 172 women and 67 men. All participants had an BMI &amp;gt; 30. This group consists of 68 normal HbA1c and 171 high HbA1c participants. Clinical metabolic parameters were determined using standard commercial kits. Cytokines were measured using Luminex X-MAP® technology. Cytokine levels were compared using unpaired t-test, followed by Pearson's correlation coefficient (r) to determine the correlation between cytokine expression and clinical metabolic parameters. Results We found that men with high HbA1c significantly correlate with BMI (P= 0.0052) and increased levels of IL-7, which was not seen in women. Women with both normal and high HbA1c levels significantly correlate with IL-7 and liver damage markers AST; normal HbA1c (P= 0.0036), high HbA1c (P= 0.0194) and ALT; high HbA1c (P=0.0174). These correlations are not seen in men supporting the possible influence of blood sugar levels on liver function in women. When normal HbA1c and high HbA1c participants are combined, all women IL-7 levels significantly correlate with active PCSK9 (P= 0.02). This suggests high circulating LDL contribute to active PCSK9, which is not present in men. Conclusion Our findings suggest increased circulating levels of IL-7 based on individuals HbA1c significantly correlate with markers of inflammation, lipid metabolism and liver damage of obese individuals with T2D, while identifying a definitive difference between men and women. These findings establish IL-7 as playing a role in inflammatory responses in obese AA with T2D and potentially being a mediator of obesity-associated inflammation. IL-7 is an indicator of sex being a variable that influences innate and adaptive immune responses, resulting in sex-specific outcomes from multiple diseases including T2D. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Volatile organic compounds: A proinflammatory activator in autoimmune diseases.

The etiopathogenesis of inflammatory and autoimmune diseases, including pulmonary disease, atherosclerosis, and rheumatoid arthritis, has been linked to human exposure to volatile organic compounds (VOC) present in the environment. Chronic inflammation due to immune breakdown and malfunctioning of the immune system has been projected to play a major role in the initiation and progression of autoimmune disorders. Macrophages, major phagocytes involved in the regulation of chronic inflammation, are a major target of VOC. Excessive and prolonged activation of immune cells (T and B lymphocytes) and overexpression of the master pro-inflammatory constituents [cytokine and tumor necrosis factor-alpha, together with other mediators (interleukin-6, interleukin-1, and interferon-gamma)] have been shown to play a central role in the pathogenesis of autoimmune inflammatory responses. The function and efficiency of the immune system resulting in immunostimulation and immunosuppression are a result of exogenous and endogenous factors. An autoimmune disorder is a by-product of the overproduction of these inflammatory mediators. Additionally, an excess of these toxicants helps in promoting autoimmunity through alterations in DNA methylation in CD4 T cells. The purpose of this review is to shed light on the possible role of VOC exposure in the onset and progression of autoimmune diseases.

Role of altered IL-33/ST2 immune axis in the immunobiology of Guillain-Barré syndrome.

The IL-33/ST2 immune axis plays crucial roles in infection and immunity. A dysregulated IL-33/ST2 axis can induce autoimmune reaction and inflammatory responses. Guillain-Barré syndrome (GBS) is an acute peripheral neuropathy, mostly caused by post-infection autoimmunity. The role of IL-33/ST2 axis is not known in GBS. This study aimed to explore the role of IL-33/ST2 axis in GBS. Three single nucleotide polymorphisms (SNPs) of Il33 gene (rs16924159, rs7044343, rs1342336) and three SNPs of Il1rl1 gene (rs10192157, rs1041973, rs10206753) coding for suppressor of tumorigenicity 2 (ST2) were genotyped in 179 GBS patients and 186 healthy controls by TaqMan Allelic Discrimination Assay. Plasma levels of IL-33 and sST2 were measured in a subset of GBS patients (n=80) and healthy controls (n=80) by ELISA. The frequencies of CC genotype of rs10192157 (p=0.043) and TT genotype of rs10206753 (p=0.036) SNPs of Il1rl1 gene differed significantly between GBS patients and healthy controls. Gene-gene interaction between Il33 and Il1rl1 genes also conferred significant risk for GBS. In addition, the plasma sST2 levels were significantly elevated in GBS patients compared to healthy subjects (24,934.31±1.81pg/ml vs. 12,518.97±1.51pg/ml, p<0.001). Plasma sST2 levels showed a significant correlation with the disability scores at the peak of neurological deficit in GBS patients. The IL-33/ST2 axis is suggested to influence the immunopathogenesis of GBS. Genetic variants of Il1rl1 gene might serve as a risk determinant of GBS and plasma sST2 levels might emerge as a biomarker of severity of GBS, if replicated further by other studies.

Topical Application of Tetrandrine Nanoemulsion Promotes the Expansion of CD4+Foxp3+ Regulatory T Cells and Alleviates Imiquimod-Induced Psoriasis in Mice.

There is compelling evidence that CD4+Foxp3+ regulatory T cells (Tregs) are indispensable in the inhibition of autoimmune inflammatory responses, including psoriasis. Recently, we showed that systemically treatment with tetrandrine (TET), a two-pore channel inhibitor identified from the Chinese herb Stephania tetrandra S. Moor, could promote the proliferative expansion of Tregs in mice through stimulation of TNF-TNFR2 interaction. We thus hypothesized that topical administration of TET might also expand Tregs and consequently inhibit psoriasis. To this end, we developed a TET nanoemulsion and examined its effect on the expansion of Tregs after topical administration on mouse psoriasis induced by imiquimod. The result of our experiment showed that topical treatment with TET nanoemulsion markedly increased the proportion and number of Tregs in the spleen, as well as TNFR2 and Ki-67 expression by Tregs, in WT and TNFR1 KO mice, but not in TNFR2 KO mice. Consequently, TET nanoemulsion potently inhibited IL-17-expressing cells in the spleen and lymph nodes of imiquimod-treated WT mice, accompanied by decreased serum levels of IL-17A, INF-γ, and TNF and their mRNA levels in the flamed lesion. Importantly, TET nanoemulsion treatment markedly inhibited the development of psoriasis-like disease in WT and TNFR1 KO mice but not in TNFR2 KO mice. Therefore, our study indicates that the topical administration of TET could also stimulate the expansion of Tregs through the TNF-TNFR2 pathway. This effect of TET and its analogs may be useful in the treatment of inflammatory skin diseases such as psoriasis.

Transcriptional analysis of peripheral memory T cells reveals Parkinson\u2019s disease-specific gene signatures

Parkinson’s disease (PD) is a multi-stage neurodegenerative disorder with largely unknown etiology. Recent findings have identified PD-associated autoimmune features including roles for T cells. To further characterize the role of T cells in PD, we performed RNA sequencing on PBMC and peripheral CD4 and CD8 memory T cell subsets derived from PD patients and age-matched healthy controls. When the groups were stratified by their T cell responsiveness to alpha-synuclein (α-syn) as a proxy for an ongoing inflammatory autoimmune response, the study revealed a broad differential gene expression profile in memory T cell subsets and a specific PD associated gene signature. We identified significant enrichment of transcriptomic signatures previously associated with PD, including for oxidative stress, phosphorylation, autophagy of mitochondria, cholesterol metabolism and inflammation, and the chemokine signaling proteins CX3CR1, CCR5, and CCR1. In addition, we identified genes in these peripheral cells that have previously been shown to be involved in PD pathogenesis and expressed in neurons, such as LRRK2, LAMP3, and aquaporin. Together, these findings suggest that features of circulating T cells with α-syn-specific responses in PD patients provide insights into the interactive processes that occur during PD pathogenesis and suggest potential intervention targets.

Increased concentration of soluble leukocyte-associated immunoglobulin-like receptor in sera from patients with blistering diseases: possible pathophysiological implications?

Autoimmune blistering diseases (AIBD), are a heterogeneous group. Despite their pathogenesis is not completely understood, autoantibodies against directed adhesion molecules of the skin and adjacent mucous membranes could play a key role. The leukocyte-associated-Ig-like-receptor (LAIR) family is a small group of immunoreceptor-tyrosine-based-inhibition-motif-containing inhibitory receptors, recognizing collagens. LAIR-1 is a transmembrane glycoprotein expressed on human-peripheral-blood-leukocytes. LAIR-2 is a secreted receptor mainly produced by CD4+ T-lymphocytes, and is able to regulate the inhibitory potential of LAIR-1. Both LAIRs have been associated with several autoimmune diseases and inflammatory responses. We evaluated circulating LAIRs in patients with different blistering skin diseases by ELISA. A significant increase of serum LAIR-2, and to a lesser extent of sLAIR-1 (with the exception of Pemphigus vulgaris), in the whole group of patients with bullous diseases, irrespective of the pathogenesis, compared to healthy controls was evident. Although the pathophysiological meaning of LAIR is not completely elucidated, the presence of increased concentration of LAIR proteins can somehow modulate the cascade of inflammatory phenomenon occurring in bullous skin diseases, in different way depending upon specific skin disease considered.