Autoimmune Inflammation Research Articles

Case report: VEXAS syndrome with excellent response to treatment with azacitidine.

Vacuoles, E1 enzyme, X-linked, auto inflammatory, somatic (VEXAS) syndrome is an inflammatory disorder caused by somatic UBA1 variants and is characterized by late-onset systemic autoimmune inflammation and blood abnormalities. Glucocorticoids ameliorate symptoms effectively. However, other treatment options have limited efficacy and a transient effect. Herein, we describe a case of a 69-year-old male patient with VEXAS syndrome with skin, lung and hematologic involvement. He was treated with glucocorticoids and after the failure with anti IL-1 he began treatment with azacitidine with excellent hematological and clinical response. Azacitidine may be a suitable option for treating VEXAS syndrome, especially due to the relationship between inflammatory symptoms and response to azacitidine.

The effects of curcumin supplementation on inflammatory markers in systemic lupus erythematosus patients: a randomized placebo-controlled trial.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with multisystem involvement. This study was designed to examine the effects of curcumin, a polyphenolic compound isolated from turmeric rhizomes, on inflammatory markers in SLE patients. Seventy 18-60 years old SLE patients were recruited in this randomized triple-blinded placebo-controlled trial, and 62 completed the study. Curcumin group received 1000mg curcumin daily and the placebo group received placebo capsules for 10 weeks. Dietary intakes and serum levels of complement C3 and C4, complement hemolytic 50%, rheumatoid factor, anti-double stranded DNA (anti-ds DNA), erythrocyte sedimentation rate, high-sensitivity C-reactive protein, interlukine-6 (IL-6) and tumor necrosis factor-α were assessed before and after intervention period. Curcumin supplementation caused a significant reduction in anti-ds DNA and IL-6 levels at the end of the trial in comparison with baseline (52.57 ± 40.21 vs. 43.27 ± 28.34, p = 0.014 and 127.11 ± 76.63 vs. 101.49 ± 59.08, p = 0.002, respectively). Analysis of covariance which was adjusted for confounding variables also revealed that anti-ds DNA and IL-6 levels decreased significantly in curcumin group compared to placebo group by the end of the intervention period (change:-9.30 ± 19.59 vs. -2.55 ± 17.55, p = 0.018 and - 25.62 ± 42.33 vs. -7.34 ± 34.32, p = 0.043, respectively). No significant changes were observed in levels of other variables during the study (p > 0.05). Curcumin as an effective and safe adjuvant therapy, ameliorated the autoimmune activity and inflammation in SLE patients via reducing anti-ds DNA and IL-6 levels. irct.behdasht.gov.ir, identifier: IRCT20210425051077N1.

Tertiary Lymphoid Structures and Immunotherapy: Challenges and Opportunities.

Tertiary lymphoid structures (TLS)are accumulations of lymphoid cells that arise in ectopic sites through the process of lymphoid neogenesis in chronic inflammation in autoimmunity, microbial infections, organ rejection, aging, and cancer. Their cellular composition and function and regulation via members of the lymphotoxin (LT)/tumor necrosis factor (TNF) family resemble that of secondary lymphoid organs (SLOs). Tumor-associated (TA)-TLS can be associated with favorable clinical outcomes. Immunotherapy in the form of immune checkpoint inhibitors (ICI) has contributed to tremendous advances in cancer therapy. However, ICI are effective in only some tumors, can give rise to resistance, and can precipitate immune-related adverse events (irAEs), many of which appear to have hallmarks of autoimmunity and can resemble TLS. TA-TLS correlate with a positive response to immunotherapy, but they can also be associated with susceptibility to irAEs, suggesting that TA-TLS in combination with ICI could lead to uncontrolled autoimmunity. The tumor environment can be manipulated to ensure that, not only the number of TLS, but also their cellular composition and appropriate function allow for judicious combinations of TLS and immunotherapy that can synergize and contribute to better outcomes with a minimum of destructive irAEs. Strategies include directed delivery of lymphoneogenic cytokines and chemokines or vascular growth factors directly, via transgenes or via adenovirus vectors.

The role of histohematologic barriers and the possibility of using polarization biomedical optics methods in the diagnosis of autoimmune thyroiditis

Background. Violation of the integrity of the histohematologic barriers (blood-brain, blood-testis, blood-ocular, blood-labyrinth, blood-thyroid) leads to autoimmune damage to these organs. One of the manifestations of the latter is autoimmune thyroiditis, the structural and quantitative changes of which can be more informatively accurately assessed by polarization biomedical optics. The purpose of the study was to substantiate the possibility of using polarization biomedical optics methods in the diagnosis of autoimmune thyroiditis based on the use of pathophysiological analysis of blood-brain barrier integrity disorders. Materials and methods. Two groups of patients were studied: control group 1 — healthy donors (n = 51), study group 2 — people with autoimmune thyroiditis (n = 51) who underwent a puncture biopsy of the thyroid gland for diagnostic purposes. Instrumental laser methods were used: polarization, interference, multifractal. The statistical parameters of polarization ellipticity maps, polarization ellipticity of phase and multifractal spectra of digital microscopic images of native thyroid histological sections in patients with autoimmune thyroiditis were quantified: mean, dispersion, asymmetry, and kurtosis. The probability of differences compared to the controls, taken as 100 %, was evaluated using the Student’s parametric test (p < 0.05). Results. A significant increase in the mean and variance at inhibition of the asymmetry and kurtosis of polarization ellipticity, as well as in the mean and variance at reduction of the asymmetry and kurtosis of polarization ellipticity of phase digital microscopic images of thyroid native histological sections was revealed. There were a significant increase in dispersion and a decrease in the asymmetry and kurtosis of multifractal spectra of polarization ellipticity maps of digital microscopic images of native histological sections. Conclusions. A significant increase in the biophysical optical parameters of digital microscopic images of thyroid native histological sections from patients with autoimmune thyroiditis was found due to the growth of connective tissue in the interstitium as a result of an autoimmune inflammation. There was a significant inhibition of the asymmetry and kurtosis of the ellipticity of polarization of phase digital and multifractal spectra of polarization ellipticity maps of microscopic images of native histological sections in patients with autoimmune thyroiditis due to a decrease in the amount of colloids as a crystalline component caused by damage to the blood-thyroid barrier.

Circulating Autoantibodies in Adults with Hashimoto's Thyroiditis: New Insights from a Single-Center, Cross-Sectional Study.

Hashimoto's thyroiditis (HT) is a common autoimmune thyroid disorder characterized by elevated anti-thyroid peroxidase (A-TPO) antibodies. HT frequently coexists with other autoimmune conditions, which are marked by organ-specific and non-organ-specific autoantibodies, reflecting a deregulated immune response. However, the burden and clinical significance of these circulating autoantibodies in adult patients with HT remains unclear. A cross-sectional study was conducted at the University Hospital "R. Dulbecco" in Catanzaro, Italy, from November 2023 to May 2024, involving 200 euthyroid adults. The study population comprised 100 A-TPO-positive HT patients and 100 A-TPO-negative controls, matched for age and sex. Laboratory assessments included thyroid function tests and detection of autoantibodies [e.g., antinuclear antibodies (ANA), anti-parietal cell antibodies (APCA), and anti-neutrophil cytoplasmic antibodies (ANCA)]. Cytokine profiles were also measured using sensitive chemiluminescent multi-array technology. HT patients were predominantly female (77.0%) with a median age of 56 years. Compared to controls, HT patients had higher median thyroid stimulating hormone (TSH) levels (2.215 vs. 1.705 μIU/mL, p = 0.025). Circulating autoantibodies were more prevalent in the HT group, with higher rates of APCA positivity (16.3% vs. 4.1%, p = 0.008) and atypical ANCA positivity (27.3% vs. 10.2%, p = 0.003). This suggests an increased risk for autoimmune gastritis and systemic inflammation. Additionally, HT patients with positive atypical ANCA showed elevated inflammatory cytokines, particularly interleukin-1 alpha (IL-1α), in female patients (p = 0.035). HT is significantly associated with a higher prevalence of circulating autoantibodies, such as APCA and atypical ANCA, which may indicate a heightened risk for autoimmune gastritis and broader autoimmune involvement. Detecting these autoantibodies in HT patients could serve as markers for more severe autoimmune dysfunction. These findings emphasize the need for proactive screening, especially in older patients and those with elevated A-TPO levels. Further research is essential to better understand the clinical implications and develop targeted management strategies for these patients.

Comparative analysis of the parameters of local immunity of oral fluid and the duration of the course in children with systemic lupus erythematosus, juvenile scleroderma, juvenile dermatomyositis, juvenile idiopathic arthritis and systemic vasculitis

Immunoglobulins are considered to be the main factor of specific antimicrobial protection of oral tissues.The study was conducted on the basis of the University Children’s Clinical Hospital of the I.M. Sechenov First Moscow State Medical University of the N.F. Filatov Clinical Institute of Child Health, in the Department of Rheumatology. The study involved 316 children, with diseases: systemic lupus erythematosus (SLE), juvenile dermatomyositis (YDM), juvenile limited scleroderma (YOSD), juvenile systemic scleroderma (YSSD), juvenile idiopathic arthritis (JIA), systemic vasculitis (SV) and Behcet’s disease (BB) and were divided into age groups according to the duration of the course of the underlying disease. The analysis of the results revealed a decrease in the content of IgG, IgA, sIgA in saliva in children with rheumatic diseases in all age groups compared with the control group (children without somatic diseases). With the duration of the course of the disease up to 2 years, the most pronounced decrease in the content of IgG, IgA, sIgA in saliva was revealed, more than 4–10 times (p<0.05), and with a duration of more than 2 years, a decrease of 2–3 times (p<0.01), compared with the control group. The deficiency of these immunoglobulins shows that in children with rheumatic diseases, regardless of the nosology, there is a violation of the local immunity of the oral cavity, especially at the onset of the underlying disease (in groups up to 2 years of the duration of the course of the underlying disease), with pronounced autoimmune inflammation of tissues and blood vessels, and this is also facilitated by the reception, during this period of shock doses of glucocorticosteroids, cytostatics, immunosuppressors, which leads to severe inflammatory processes of the oral mucosa, periodontal and hard tissues of the teeth.

Spatial transcriptomics of meningeal inflammation reveals inflammatory gene signatures in adjacent brain parenchyma.

While modern high efficacy disease modifying therapies have revolutionized the treatment of relapsing-remitting multiple sclerosis, they are less effective at controlling progressive forms of the disease. Meningeal inflammation is a recognized risk factor for cortical gray matter pathology which can result in disabling symptoms such as cognitive impairment and depression, but the mechanisms linking meningeal inflammation and gray matter pathology remain unclear. Here, we performed magnetic resonance imaging (MRI)-guided spatial transcriptomics in a mouse model of autoimmune meningeal inflammation to characterize the transcriptional signature in areas of meningeal inflammation and the underlying brain parenchyma. We found broadly increased activity of inflammatory signaling pathways at sites of meningeal inflammation, but only a subset of these pathways active in the adjacent brain parenchyma. Subclustering of regions adjacent to meningeal inflammation revealed the subset of immune programs induced in brain parenchyma, notably complement signaling and antigen processing/presentation. Trajectory gene and gene set modeling analysis confirmed variable penetration of immune signatures originating from meningeal inflammation into the adjacent brain tissue. This work contributes a valuable data resource to the field, provides the first detailed spatial transcriptomic characterization in a model of meningeal inflammation, and highlights several candidate pathways in the pathogenesis of gray matter pathology.

Spatial transcriptomics of meningeal inflammation reveals inflammatory gene signatures in adjacent brain parenchyma

While modern high efficacy disease modifying therapies have revolutionized the treatment of relapsing-remitting multiple sclerosis, they are less effective at controlling progressive forms of the disease. Meningeal inflammation is a recognized risk factor for cortical gray matter pathology which can result in disabling symptoms such as cognitive impairment and depression, but the mechanisms linking meningeal inflammation and gray matter pathology remain unclear. Here, we performed magnetic resonance imaging (MRI)-guided spatial transcriptomics in a mouse model of autoimmune meningeal inflammation to characterize the transcriptional signature in areas of meningeal inflammation and the underlying brain parenchyma. We found broadly increased activity of inflammatory signaling pathways at sites of meningeal inflammation, but only a subset of these pathways active in the adjacent brain parenchyma. Subclustering of regions adjacent to meningeal inflammation revealed the subset of immune programs induced in brain parenchyma, notably complement signaling and antigen processing/presentation. Trajectory gene and gene set modeling analysis confirmed variable penetration of immune signatures originating from meningeal inflammation into the adjacent brain tissue. This work contributes a valuable data resource to the field, provides the first detailed spatial transcriptomic characterization in a model of meningeal inflammation, and highlights several candidate pathways in the pathogenesis of gray matter pathology.

Pathogenesis of psoriatic arthritis: new insights from a bone marrow perspective.

Psoriatic arthritis is an immune-mediated disease that primarily affects the skin and joints. It falls under the umbrella term of rheumatic diseases, which describes a group of closely related yet distinct disorders with many common underlying molecular pathways. Despite the distinct clinical manifestation of each disorder, the shared therapeutic strategies attest to the commonality of cellular and molecular underpinnings. Herein we provide a concise yet comprehensive overview of the interleukin (IL)-23/IL-17 axis and its involvement in mechanistic pathways leading to the pathogenesis of this dual skin and joint clinical manifestation which is characteristic of psoriatic arthritis and other rheumatic diseases. The interconnection between activated innate immune cells and adaptive immunity has transformed current thinking to include other organs such as the bone marrow as potential tissue of disease origin. A plethora of animal models and genetic studies converge on the critical role of IL-23/IL-17 axis, and highlight the importance of myeloid cell activation as common pathways between autoinflammatory and autoimmune diseases and chronic inflammation. These findings underscore the intricate immune mechanisms involved in inflammatory arthritis and highlight molecular mechanisms in disease pathogenesis. These insights pave the way for the development of novel diagnostic and therapeutic strategies, with a focus on translating these findings into improved clinical practice.

The role of the cGAS-STING pathway in chronic pulmonary inflammatory diseases.

The innate immune system plays a vital role in the inflammatory process, serving as a crucial mechanism for the body to respond to infection, cellular stress, and tissue damage. The cGAS-STING signaling pathway is pivotal in the onset and progression of various autoimmune diseases and chronic inflammation. By recognizing cytoplasmic DNA, this pathway initiates and regulates inflammation and antiviral responses within the innate immune system. Consequently, the regulation of the cGAS-STING pathway has become a prominent area of interest in the treatment of many diseases. Chronic inflammatory lung diseases, such as chronic obstructive pulmonary disease (COPD), asthma, and pulmonary fibrosis, are characterized by persistent or recurrent lung inflammation and tissue damage, leading to diminished respiratory function. This paper explores the mechanism of action of the cGAS-STING signaling pathway in these diseases, examines the development of STING inhibitors and nanomaterial applications, and discusses the potential clinical application prospects of targeting the cGAS-STING pathway in chronic inflammatory lung diseases.

The Role of miR-155 in Modulating Gene Expression in CD4+ T Cells: Insights into Alternative Immune Pathways in Autoimmune Encephalomyelitis.

CD4+ T cells are considered the main orchestrators of autoimmune diseases. Their disruptive effect on CD4+ T cell differentiation and the imbalance between T helper cell populations can be most accurately determined using experimental autoimmune encephalomyelitis (EAE) as an animal model of multiple sclerosis (MS). One epigenetic factor known to promote autoimmune inflammation is miRNA-155 (miR-155), which is significantly upregulated in inflammatory T cells. The aim of the present study was to profile the transcriptome of immunized mice and determine their gene expression levels based on mRNA and miRNA sequencing. No statistically significant differences in miRNA profile were observed; however, substantial changes in gene expression between miRNA-155 knockout (KO) mice and WT were noted. In miR-155 KO mice, mRNA expression in CD4+ T cells changed in response to immunization with the myeloid antigen MOG35-55. After restimulation with MOG35-55, increased Ffar1 (free fatty acid receptor 1) and Scg2 (secretogranin-2) expression were noted in the CD4+ T cells of miR-155-deficient mice; this is an example of an alternative response to antigen stimulation.

A distinct metabolic and epigenetic state drives trained immunity in HSC-derived macrophages from autoimmune mice

Here, we investigate the contribution of long-term hematopoietic stem cells (HSCsLT) to trained immunity (TI) in the setting of chronic autoimmune disease. Using a mouse model of systemic lupus erythematosus (SLE), we show that bone marrow-derived macrophages (BMDMs) from autoimmune mice exhibit hallmark features of TI, including increased Mycobacterium avium killing and inflammatory cytokine production, which are mechanistically linked to increased glycolytic metabolism. We show that HSCs from autoimmune mice constitute a transplantable, long-term reservoir for macrophages that exhibit the functional properties of TI. However, these BMDMs exhibit reduced glycolytic activity and chromatin accessibility at metabolic genes while retaining elevated expression of TI-associated transcriptional regulators. Hence, HSC exposed to autoimmune inflammation can give rise to macrophages in which the functional and metabolic properties of TI are decoupled. Our data support a model in which TI is characterized by a spectrum of molecular and metabolic states driving augmented immune function.

8229 Prevalence of Thyroid Cancer in Patients with Hashimotos Thyroiditis Presenting Concomitant Thyroid Nodular Disease

Abstract Disclosure: M.A. Alvarez Castillo: None. L. Sanchez Arriaga: None. A. Segovia Palomo: None. Introduction: Hashimoto's thyroiditis (HT) is the most frequent autoimmune thyroid disease and the main cause of goiter and hypothyroidism; it induces a process of aseptic autoimmune inflammation. Fibroinflammatory changes lead to the development of thyroid nodules (TN), additionally chronic inflammation is an important player in the development of cancer, although this association is controversial. The prevalence of thyroid cancer (TC) in patients with HT ranges from 0.61-58.4% (25.01%), being higher than in patients with TN without concomitant HT. Objective: To know the prevalence of malignancy in patients with HT who present thyroid nodular disease. Methodology: An observational, descriptive, retrospective, and longitudinal study was carried out. Patients with HT diagnosis were selected by measuring Ab TPO and/or Ab TG who presented an ultrasound diagnosis of TN and FNAB of the thyroid lesion had been performed. Descriptive statistics and linear regression were used. Results: 87 patients: 6 (6.9%) men and 81 (93.1%) women aged 47.9 (12.7) years. 4 (4.5%) required FNAB in 2 TN, for a total of 91 TN studied. 64% had a diagnosis of hypothyroidism and were taking LT4, TSH 4.40 (4.44) mUI/mL, FT4 1.00 (0.27) ng/dL. Mean Ab TPO was 794.7 ± 1354.6. Diagnosis time 19.5 (29.1) months. 39.6% the detection was made by the patient and 35.2% by the doctor. Major axis was 18.8 (12.1) mm. Ultrasound pattern of single TN 58.2% and multinodular 41.8%. Median TIRADS was 4, with a mode of 5. 81.3% reported Bethesda II and 18.7% malignant or suspected, were sent for surgery, malignancy was confirmed in 16/ 17 lesions. 14 (15.3%) were TPC and 2 lymphomas, the main subtypes were classic papillary and NHL, respectively. Mode of ATA risk was intermediate. Multivariate analysis only TIRADS represented risk factor (OR 2.08) Conclusions: The frequency of TC in our population was 15.3%, which reflects a higher prevalence of malignancy in thyroid nodules in patients with chronic thyroiditis, in accordance with what has been reported in other series. Presentation: 6/3/2024

8705 Autoimmune Polyglandular Syndrome Type 2 Presenting As Recurrent Cardiac Tamponade

Abstract Disclosure: E.M. Niedzialkowska: None. D. Shelden: None. Introduction: Autoimmune polyglandular syndrome type 2 (APS2) is a rare endocrinopathy with co-occurrence of autoimmune adrenal insufficiency, autoimmune thyroiditis and/or type 1 diabetes. In rare cases, APS2 can predispose patients to recurrent pericardial effusion and tamponade. Case presentation: 32 y.o male with medical history of hypothyroidism on replacement therapy diagnosed 2 weeks prior to admission presented with progressive dyspnea and hypotension. The patient was found to have pericardial effusion with tamponade requiring pressor support. Initial lab tests showed TSH 148.7 uIU/ml (N 0.4-4.5), free t4 0.7 ng/dl(N 0.7-1.5 ), free t3 2 pg/ml (N 1.7-3.5), Hb a1c 4.7% (N <5.6%), thyroglobulin antibody 851 IU/ml (N <20), TPO antibody >1 000 IU/ml (N<=35), TSI 0.1 IU/l (<0.1), sodium 127 mmol/l (N 135-145), and a negative adrenal antibody panel. The patient was started on IV levothyroxine (400 mcg daily) and stress dose steroids in the setting of shock requiring 4 pressors. Shock resolved after pericardiocentesis and the patient was weaned off pressor support. Pericardial fluid showed neutrophil predominance and was negative for an infectious process, lab tests showed negative ANA, ANCA and GBM. The day following admission lab tests showed TSH of 23.86 uIU/ml, ft4 1.3 ng/dl, the patient was transitioned to oral levothyroxine 125 mcg and the steroid regimen was tapered and discontinued. Follow up tests showed normal TSH and resolution of pericardial effusion. Four weeks after initial admission the patient was readmitted due to hypotension. Laboratory tests showed random cortisol <1.0 ug/dl (N 2.9-19.4), ACTH 17 pg/ml (N 6-48), adrenal antibody titers 1:20 (N < 1:10), cosyntropin stimulation test was positive for adrenal insufficiency and the patient was started on steroid regimen with symptomatic improvement. He was diagnosed with APS type 2 based on his constellation of endocrinopathies. Repeat echocardiogram was negative for pericardial effusion. Two months later, the patient presented with chest pain. Imaging was positive for recurrent pericardial effusion requiring pressor support and pericardiocentesis. The patient was subsequently started on colchicine. Infectious and rheumatologic workup continued to be negative. The patient did not exhibit symptoms of connective tissue disease. Seven months after the initial presentation the patient was readmitted with COVID-19 infection complicated by hypotension and a small pericardial effusion. Symptoms improved after initiation of stress dose steroids. Conclusion: Cardiac tamponade is a rare presentation of APS2 with 9 cases reported in the literature up to date. Increased incidence of pericardial effusion is presumed to be a result of autoimmune inflammation leading to fluid accumulation. The patients are prone to tamponade due to intravascular volume depletion, decreased vascular tone and impaired stress response. Presentation: 6/3/2024

Inflammatory Myopathies and Autoimmune Gluten-related Disorders: A Scoping Review of Pathophysiological Interconnections and Hypothesis

Introduction: Anecdotal reports describe patients with concurrent idiopathic inflammatory myopathy (IIM) and celiac disease (CeD) in whom the introduction of a gluten-free diet led to dramatic improvement of myositis. We first systematically reviewed all peer-reviewed publications on concomitant IIM and duodenal biopsy-verified CeD. The collected evidence was suggestive of associations between myositis disease activity and gluten exposure in some patients with IIM-CeD. Objective/Methods: To investigate possible explanations for the observations, an exploratory review of basic pathophysiological relationships between IIM and gluten-related disorders was performed using a combined strategy of systematic and non-systematic literature searches and forward and backward citation tracking. Results: The investigations revealed close pathophysiological associations between IIM and the autoimmune gluten-related disorders CeD, dermatitis herpetiformis, and gluten ataxia. Common traits include shared genetic predisposition through HLA-DQ2.5/-DQ8, disease activity-associated autoantibodies, histopathological parallels with inflammatory cell infiltrates, and similarly distributed structural homologous transglutaminases (TGs). HLA-DQ2.5-restricted gluten-specific CD4+ T cells of a rare, uniform phenotype are reported in CeD and connective tissue disease. Expanded T-cell clones with identical phenotypes and CDR3β motifs indicate the presence of a continuous, antigen-driven T-cell response. Conclusion: The investigations revealed that the main components involved in the adaptive immune response in the CeD gut may be present in HLA-DQ2.5+/-DQ8+ IIM muscle. The collected evidence supports the notion that in some genetically predisposed patients with IIM, gluten may act as an exogenous antigen driving myositis. Further Research/Clinical Implications: To test the above hypothesis, clinical trials combined with immunological studies are needed. Meanwhile, the inclusion of HLA-DQ typing may be justified, and subsequent small-intestinal biopsies in HLA-DQ2.5/8+ individuals with IIM.

Immunogenicity and Adverse Events after Coronavirus Disease 2019 (COVID-19) Vaccination in Patients with Systemic Inflammatory Autoimmune Diseases

Immunogenicity and Adverse Events after Coronavirus Disease 2019 (COVID-19) Vaccination in Patients with Systemic Inflammatory Autoimmune Diseases

Immunomodulatory and anti-inflammatory properties of immunoglobulin G antibodies.

Antibodies provide an essential layer of protection from infection and reinfection with microbial pathogens. An impaired ability to produce antibodies results in immunodeficiency and necessitates the constant substitution with pooled serum antibodies from healthy donors. Among the five antibody isotypes in humans and mice, immunoglobulin G (IgG) antibodies are the most potent anti-microbial antibody isotype due to their long half-life, their ability to penetrate almost all tissues and due to their ability to trigger a wide variety of effector functions. Of note, individuals suffering from IgG deficiency frequently produce self-reactive antibodies, suggesting that a normal serum IgG level also may contribute to maintaining self-tolerance. Indeed, the substitution of immunodeficient patients with pooled serum IgG fractions from healthy donors, also referred to as intravenous immunoglobulin G (IVIg) therapy, not only protects the patient from infection but also diminishes autoantibody induced pathology, providing more direct evidence that IgG antibodies play an active role in maintaining tolerance during the steady state and during resolution of inflammation. The aim of this review is to discuss different conceptual models that may explain how serum IgG or IVIg can contribute to maintaining a balanced immune response. We will focus on pathways depending on the IgG fragment crystallizable (Fc) as pre-clinical data in various mouse model systems as well as human clinical data have demonstrated that the IgG Fc-domain recapitulates the ability of intact IVIg with respect to its ability to trigger resolution of inflammation. We will further discuss how the findings already have or are in the process of being translated to novel therapeutic approaches to substitute IVIg in treating autoimmune inflammation.

Harnessing marine natural products to inhibit PAD4 triple mutant: A structure-based virtual screening approach for rheumatoid arthritis therapy

Peptidylarginine deiminase type4 (PAD4) is a pivotal pro-inflammatory protein within the human immune system, intricately involved in both inflammatory processes and immune responses. Its role extends to the generation of diverse immune cell types, including T cells, B cells, natural killer cells, and dendritic cells. PAD4 has recently garnered attention due to its association with a spectrum of inflammatory and autoimmune disorders, notably rheumatoid arthritis (RA). Mutations in the PAD4 gene, leading to the conversion of arginine to citrulline, have emerged as significant factors in the pathogenesis of RA and related conditions. As a calcium-dependent enzyme, PAD4 is central to the citrullination process, a crucial post-translational modification implicated in disease pathophysiology. Its critical role in autoimmune disorders and inflammation makes PAD4 a prime candidate for therapeutic intervention in RA. Inhibiting PAD4 presents a promising avenue for mitigating inflammatory responses and curtailing joint degradation and impairment. To explore its therapeutic potential, a structure-based virtual screening (SBVS) approach was employed, harnessing an array of marine natural products (MNPs) sourced from databases such as CMNPD, MNPD, and Seaweed. Notably, MNPD10752, CMNPD12680, and CMNPD2751 emerged as potential hit molecules, exhibiting adherence to essential pharmacokinetic properties and favorable toxicity profiles. Quantum mechanics studies using density functional theory (DFT) calculations revealed the inhibitory potential of these identified natural products. Further structural elucidation through molecular dynamics simulations (MDS) and principal component-based free energy landscape (FEL) analysis shed light on the stability of MNP-bound PAD4 complexes. In conclusion, this computational study serves as a stepping stone for further experimental evaluation, aiming to explore the potential of MNPs in addressing PAD4-related human pathologies.

The role of CD24hiCD27+ regulatory B cells in human chronic rhinosinusitis with/without nasal polyps

BackgroundRegulatory B cells (Bregs) reduce allergic and autoimmune inflammation. However, their role in chronic rhinosinusitis (CRS) remains unknown. This study investigated the frequency and function of Breg subsets in the peripheral blood of patients with CRS. MethodsThe demographic and clinical characteristics were compared among control, CRSsNP, neCRSwNP, and eCRSwNP groups. The expression of various Breg subtypes was evaluated in peripheral blood mononuclear cells (PBMCs) of patients with eosinophilic CRS with nasal polyps (eCRSwNP), non-eosinophilic CRS with nasal polyps (neCRSwNP), CRS without nasal polyps (CRSsNP). CD19+CD24hiCD27+ B cells (B10 cells) were isolated by flow cytometry, followed by RNA sequencing (RNA-seq). Finally, IL-10 secreted by B10 cells were evaluated through the intracellular stain. ResultsA higher number of eosinophils in peripheral blood and nasal polyps were found in eCRSwNP compared with neCRSwNP, CRSsNP, and control groups. The frequency of B10 in the peripheral blood B cells (B10%) of patients with eCRSwNP was significantly lower than that in the neCRSwNP and control groups. B10% was negatively correlated with the quantity of tissue eosinophils, and the percentage and absolute value of peripheral blood eosinophils. The eCRSwNP, neCRSwNP and control groups had 1403 differentially expressed genes, 35 of which were identified in four highly enriched pathways. Additionally, the frequency of IL-10+B10 cells in peripheral blood was lower in patients with eCRSwNP than in the neCRSwNP and control groups. ConclusionThis study is the first to reveal differences in both the quantity and IL-10 secretion of B10 cells in patients with eCRSwNP and neCRSwNP. These variations were strongly negatively associated with eosinophils in nasal polyps and peripheral blood. IL-10+B10 cells may play a key role in the pathological mechanisms of CRS, particularly the recurrence of eCRSwNP.

Unraveling the Genetics of Shared Clinical and Serological Manifestations in Patients With Systemic Inflammatory Autoimmune Diseases.

Systemic inflammatory autoimmune diseases (SIADs) such as systemic lupus erythematosus (SLE), primary Sjögren disease (pSS), and idiopathic inflammatory myopathies (myositis) are complex conditions characterized by shared circulating autoantibodies and clinical manifestations, including skin rashes, among others. This study was aimed at elucidating the genetics underlying these common features. We performed targeted DNA sequencing of coding and regulatory regions from approximately 1,900 immune-related genes in a large cohort of 2,292 well-characterized Scandinavian patients with SIADs with SLE, pSS, and myositis as well as 1,252 controls. A gene-based functionally weighted genetic score for aggregate testing of all genetic variants, including rare variants, was complemented by in silico functional analyses and in vitro reporter experiments. Case-control association analysis detected known and potentially novel genetic loci in agreement with previous genetic and transcriptomics findings linked to the SIAD autoimmune background. Intriguingly, case-case comparisons between patient subgroups with and without specific autoantibodies revealed that the subgroups defined by antinuclear antibodies and anti-double-stranded DNA antibodies have unique genetic profiles reflecting their heterogeneity. When focusing on clinical features, we overall showed that dual-specificity phosphatase 1 (DUSP1) protective genetic variants lead to increased gene expression and potentially to anti-inflammatory effects on the SIAD-associated skin phenotype. This is consistent with recent genetic findings on eczema and with the previously reported down-regulation of the MAPK signaling-related gene DUSP1 in other skin disorders. Together, this suggests common molecular mechanisms potentially underlying overlapping clinical manifestations shared among different disorders and informs clinical heterogeneity, which could be translated to improve disease diagnostic and treatment, also in more generalized disease frameworks.