Search

Glomerulonephritis (GN) is an important cause of renal inflammation resulting from kidney‐targeted adaptive and innate immune responses and consequent glomerular damage. Given the lack of autoantibodies, immune complexes, or the infiltrating immune cells in some forms of GN, for example, focal segmental glomerulosclerosis and minimal change disease, along with paraneoplastic syndrome and a special form of renal involvement in some viral infections, the likeliest causative scenario would be secreted factors, mainly cytokine(s). Since cytokines can modulate the inflammatory mechanisms, severity, and clinical outcomes of GN, it is rational to consider the umbrella term of cytokine GN as a new outlook to reclassify a group of previously known GN. We focus here, particularly, on cytokines that have the central "canonical effect" in the development of GN. [ABSTRACT FROM AUTHOR]

Objectives: Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease characterized by the presence of autoantibodies against nuclear antigens and immune complex deposition. The pathogenesis of SLE is not fully understood; however, there are alterations in neutrophils and lymphocytes. Recent parameters assessing both neutrophil activations (Neut‐RI, Neut‐GI, IG) and activated lymphocytes (Re‐Lymp, As‐Lymp) can be used to assess the activation of immune cells. The aim of this study was to explore the potential role of this parameter in detecting active SLE. Methods: Cross‐sectional study using secondary data from Hasan Sadikin Lupus Registry. Parameters were examined using Sysmex XN‐1500. Lupus activity was determined according to SLEDAI‐2K. Results: This study included 30 active (SLEDAI 2K ≥ 4) and 30 inactive SLE patients. Compared to inactive SLE, active SLE showed significantly higher Neut‐RI (51.5 vs. 49.6 FL, p = 0.004), and lower Re‐Lymph (0.09 vs. 0.14 × 103/mm3, p = 0.024). There was no significant difference in Neut‐GI (150 vs. 151.6 SI, p = 0.359), As‐Lymp (0.02 vs. 0.01 × 103/mm3, p = 0.621), and IG (0.11 vs. 0.06 × 103/mm3, p = 0.384) between active and inactive SLE. Neut‐RI/Re‐Lymp ratio cutoff > 0.47 could distinguish between active and inactive SLE with AUC 0.689, 66.7% sensitivity, and 70.0% specificity. Conclusion: In active SLE, there is an elevation in Neut‐RI and a reduction in Re‐Lymp. Neut‐RI/Re‐Lymp ratio exceeding 0.47 could be used to detect active SLE. [ABSTRACT FROM AUTHOR]

COVID‐19, the disease caused by SARS‐CoV‐2, particularly causes severe inflammatory disease in elderly, obese, and male patients. Since both aging and obesity are associated with decreased testosterone and estradiol expression, we hypothesized that decreased hormone levels contribute to excessive inflammation in the context of COVID‐19. Previously, we and others have shown that hyperinflammation in severe COVID‐19 patients is induced by the production of pathogenic anti‐spike IgG antibodies that activate alveolar macrophages. Therefore, we developed an in vitro assay in which we stimulated human macrophages with viral stimuli, anti‐spike IgG immune complexes, and different sex hormones. Treatment with levels of testosterone reflecting young adults led to a significant reduction in TNF and IFN‐γ production by human macrophages. In addition, estradiol significantly attenuated the production of a very broad panel of cytokines, including TNF, IL‐1β, IL‐6, IL‐10, and IFN‐γ. Both testosterone and estradiol reduced the expression of Fc gamma receptors IIa and III, the two main receptors responsible for anti‐spike IgG‐induced inflammation. Combined, these findings indicate that sex hormones reduce the inflammatory response of human alveolar macrophages to specific COVID‐19‐associated stimuli, thereby providing a potential immunological mechanism for the development of severe COVID‐19 in both older male and female patients. [ABSTRACT FROM AUTHOR]

Cross‐presentation by MHCI is optimally efficient in type 1 dendritic cells (DC) due to their high capacity for antigen processing. However, through specific pathways, other DCs, such as type 2 DCs and inflammatory DCs (iDCs) can also cross‐present antigens. FcγR‐mediated uptake by type 2 DC and iDC subsets mediates antibody‐dependent cross‐presentation and activation of CD8+ T cell responses. Here, an important role for the p84 regulatory subunit of PI3Kγ in mediating efficient cross‐presentation of exogenous antigens in otherwise inefficient cross‐presenting cells, such as type 2 DCs and GM‐CSF‐derived iDCs is identified. FcγR‐mediated cross‐presentation is shown in type 2 and iDCs depend on the enzymatic activity of the p84/p110γ complex of PI3Kγ, which controls the activity of the NADPH oxidase NOX2 and ROS production in murine spleen type 2 DCs and GM‐CSF‐derived iDCs. In contrast, p84/p110γ is largely dispensable for cross‐presentation by type 1 DCs. These findings suggest that PI3Kγ‐targeted therapies, currently considered for oncological practice, may interfere with the ability of type 2 DCs and iDCs to cross‐present antigens contained in immune complexes. [ABSTRACT FROM AUTHOR]

ABSTRACT Objectives Methods Results Conclusions To evaluate the tolerability of crovalimab versus eculizumab in C5 inhibitor (C5i)‐naive and ‐experienced patients with PNH from COMMODORE 2, 3 and 1 (NCT04434092, NCT04654468 and NCT04432584).Pooled safety data were assessed in the total crovalimab and eculizumab populations and by C5i‐naive versus C5i‐switched status in patients receiving crovalimab. Analyses include 6.5 months of additional follow‐up from the COMMODORE 2 and 1 primary analyses.COMMODORE safety data (crovalimab, 393 patients [naive, 192 patients; switched, 201 patients]; eculizumab, 111 patients) were analysed. The total patient years (PY) were 503.9 and 51.1 in the total crovalimab and eculizumab populations, respectively, with 471 and 581 adverse events (AEs) per 100 PY. Serious infection rates were 8.9 and 13.7 AEs per 100 PY, respectively; no meningococcal infections were reported. Fatal AEs occurred in eight (2%) patients receiving crovalimab (naive, six patients; switched, two patients) and one (1%) receiving eculizumab, all treatment unrelated. In C5i‐switched patients, 39 (19%) had transient immune complex reactions (risk when switching between C5i and crovalimab); the majority were Grades 1–2 arthralgia and rash, and 16 (8%) had Grade 3 events.Crovalimab's safety profile was consistent with eculizumab's and was generally comparable between C5i‐naive and C5i‐switched patients. [ABSTRACT FROM AUTHOR]

Summary: Antibodies are able to up‐ or downregulate antibody responses to the antigen they bind. Two major mechanisms can be distinguished. Suppression is most likely caused by epitope masking and can be induced by all isotypes tested (IgG1, IgG2a, IgG2b, IgG3, IgM, and IgE). Enhancement is often caused by the redistribution of antigen in a favorable way, either for presentation to B cells via follicular dendritic cells (IgM and IgG3) or to CD4+ T cells via dendritic cells (IgE, IgG1, IgG2a, and IgG2b). IgM and IgG3 complexes activate complement and are transported from the marginal zone to follicles by marginal zone B cells expressing complement receptors. IgE–antigen complexes are captured by CD23+ B cells in the blood and transported to follicles, delivered to CD8α+ conventional dendritic cells, and presented to CD4+ T cells. Enhancement of antibody responses by IgG1, IgG2a, and IgG2b in complex with proteins requires activating FcγRs. These immune complexes are captured by dendritic cells and presented to CD4+ T cells, subsequently helping cognate B cells. Endogenous feedback regulation influences the response to booster doses of vaccines and passive administration of anti‐RhD antibodies is used to prevent alloimmunization of RhD‐negative women carrying RhD‐positive fetuses. [ABSTRACT FROM AUTHOR]

Changes in the immune status and the content of blood transport components reflect adaptations in the human body in response to adverse factors, showcasing the organism's adaptive capabilities and functional state. In this study, we aimed to determine the features of the immune system and levels of transport components of the blood system in residents of the Arctic of the Russian Federation. Methods: The peripheral venous blood of 191 residents of the Arctic of the Russian Federation (Murmansk Oblast) aged 21–55 analyzed comprehensively. Blood was sampled from the ulnar vein on an empty stomach in the morning. The hemogram, phagocytic activity of neutrophils, lymphocyte content with CD3, CD4, CD8, CD10, CD19, CD16, CD71, CD25, HLA‐DR and CD95 phenotypes, concentrations of cytokines: TNF‐α, IFN‐γ, IL‐6, IL‐10, extracellular receptor pool: sCD71, sCD62L, sApo‐1/Fas, sFasL, circulating immune complexes (CIC) and blood transport components: haptoglobin (Hp), transferrin, IgM, IgG, IgA, IgE (immunoglobulins M, G, A and E) low‐density lipoproteins (LDL), and high density lipoprotein (HDL) were evaluated. The results were analyzed using descriptive statistics and comparative, factorial, and regression analyses. Results: Residents of the Murmansk Oblast exhibit a high prevalence of erythrocytosis (62.3%), thrombocytosis (25.0%), leukocytosis (20.1%), and increased hemoglobin (Hb) concentrations (42.5%), coupled with a significantly decreased level of active phagocytes (47.6%). A significantly decreased level of lymphocytes with phenotypes CD3 (92.4%), CD4 (40.4%), CD71 (62.3%) was revealed, coupled with the activation of lymphocytes with phenotypes CD16 (50.1%), CD8 (37.5%), CD19 (15.9%) and increased concentrations of pro‐inflammatory IFN‐γ (47.9%), IL‐6 (33.3%), and TNF‐α (20.1%). Elevated levels of sCD71 (56.6%), sCD62L (32.1%), sApo‐1/Fas (22.1%), sFasL (10.2%), and autoantibodies to double‐stranded DNA (57.1%), RNA (10.4%), and oLDL (oxidized‐modified LDL) (16.3%) were recorded in residents of the Murmansk Oblast. Arctic residents showed elevated concentrations of Hp (63.3%), IgM (63.9%), IgA (42.4%), IgE (18.8%), LDL (24.9%), and a decreased level of HDL (21.1%) owing to an ApoA‐I ligand deficiency (58.1%). Elevated levels of Hp in the blood are associated with increased erythrocyte aggregation frequency, T‐lymphocyte activation, and increased concentration of free receptors of the extracellular pool. Increased IgM and IgA levels in the blood are attributed to the need to bind components of the extracellular receptor pool sCD71, sCD62L, sApo‐1/Fas, sFasL and are associated with decreased levels lymphocyte with CD8 and CD16 phenotypes. The humoral immune response in Arctic residents is triggered when the cellular component of immunity is under strain which compounded by ineffective clearance of metabolic byproducts owing to imbalanced LDL and HDL lipid transport complexes. Conclusions: The immune system of Arctic residents is characterized by excessive cytotoxic activity of lymphocytes and increased concentrations of pro‐inflammatory cytokines, free forms of receptors of the extracellular pool, and autoantibodies. The change in the content of transport components of the blood system is directed at maintaining homeostasis by exhibiting antioxidant, anti‐inflammatory, and immunoregulatory properties. [ABSTRACT FROM AUTHOR]

The CCL2–CCR2 axis is involved in lupus nephritis, however the precise roles in the mechanisms by which different pathological lesions develop after glomerular immune complex deposition remain elusive. Previously, we demonstrated that genetic CCR2 inhibition induced a histological switch from glomerular endocapillary hypercellularity to wire‐loop lesions in murine lupus nephritis. This study aimed to clarify the CCL2–CCR2 axis‐mediated cellular mechanism in the formation of these different pathological lesions. We injected MRL/lpr mouse‐derived monoclonal IgG3 antibody‐producing hybridomas, 2B11.3 or B1, into wild‐type (WT) mice to selectively induce glomerular endocapillary hypercellularity or wire‐loop lesions. The expression of chemokine and chemokine receptors was analyzed using RT‐quantitative PCR and/or immunofluorescence. We found 2B11.3 caused glomerular endocapillary hypercellularity in WT mice with glomerular infiltration of larger numbers of CCR2‐expressing macrophages and neutrophils phagocyting immune complex, whereas B1 induced wire‐loop lesions. In glomerular endocapillary hypercellularity, CCL2 was identified as the ligand involved in the CCR2‐positive cell infiltration; it was expressed by glomerular endothelial cells and macrophages. Notably, 2B11.3‐induced glomerular endocapillary hypercellularity converted to wire‐loop lesions with reduced glomerular macrophage and neutrophil infiltration in CCL2‐deficient (Ccl2−/−) mice similarly observed in Ccr2−/− mice. Moreover, this histological conversion was also observed when both glomerular macrophage and neutrophil infiltration were inhibited in anti‐Ly6G antibody‐treated Ccr5−/− mice but not when only glomerular macrophage infiltration was inhibited in Ccr5−/− mice or when only glomerular neutrophil infiltration was inhibited in anti‐Ly6G antibody‐treated WT mice. In contrast, B1 injection caused wire‐loop lesions in Ccl2−/− and Ccr2−/− mice, as observed in WT mice. Moreover, 2B11.3 induced CCL2 from glomerular endothelial cells to a larger extent than B1 when injected into Ccr2−/− mice. In conclusion, the CCL2–CCR2 axis determines whether glomerular endocapillary hypercellularity or wire‐loop lesions develop by regulating glomerular infiltration of phagocytic cells: macrophages and neutrophils. © 2024 The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Kidney complications can occur due to infective endocarditis, one of which is glomerulonephritis. Most often, an immune complex or complement‐mediated glomerulonephritis is seen on kidney biopsy. In a minor subset of cases, pauci‐immune glomerulonephritis may be present. Most often, such patients will demonstrate the presence of antineutrophil cytoplasmic antibodies (ANCA) on serologic testing. A growing number of cases of ANCA‐associated glomerulonephritis due to Bartonella endocarditis have been reported. This type of endocarditis can present diagnostic difficulties given that these patients are often culture negative. Herein, we report a challenging case of ANCA‐negative pauci‐immune glomerulonephritis showing florid crescents on biopsy that was associated with Bartonella endocarditis. [ABSTRACT FROM AUTHOR]

Summary: The prevalence of allergies has been globally escalating. While allergies could appear at any age, they often develop in early life. However, the significant knowledge gap in the field is the mechanisms by which allergies affect certain people but not others. Investigating early factors and events in neonatal life that have a lasting impact on determining the susceptibilities of children to develop allergies is a significant area of the investigation as it promotes the understanding of neonatal immune system that mediates tolerance versus allergies. This review focuses on the research over the recent 10 years regarding the potential maternal factors that influence offspring allergies with a view to food allergy, a potentially life‐threatening cause of anaphylaxis. The role of breast milk, maternal diet, maternal antibodies, and microbiota that have been suggested as key maternal factors regulating offspring allergies are discussed here. We also suggest future research area to expand our knowledge of maternal–offspring interactions on the pathogenesis of food allergy. [ABSTRACT FROM AUTHOR]

This article discusses the pathogenesis of IgA nephropathy (IgAN), a kidney disease characterized by the presence of immunodeposits containing IgA, IgG, and C3 in the glomeruli. The article highlights the role of abnormal O-glycosylation of IgA1 in the development of IgAN, as well as the genetic factors and cytokines involved in this process. It also explores the formation of pathogenic immune complexes consisting of galactose-deficient IgA1 bound by IgG autoantibodies, which contribute to kidney injury. The article concludes by emphasizing the need for further research in genomics and glycomics to inform the development of new therapeutic approaches for IgAN. [Extracted from the article]

Type I hypersensitivity, also known as classical allergy, is mediated via allergen‐specific IgE antibodies bound to type I FcR (FcεRI) on the surface of mast cells and basophils upon cross‐linking by allergens. This IgE‐mediated cellular activation may be blocked by allergen‐specific IgG through multiple mechanisms, including direct neutralization of the allergen or engagement of the inhibitory receptor FcγRIIb which blocks IgE signal transduction. In addition, co‐engagement of FcεRI and FcγRIIb by IgE‐IgG‐allergen immune complexes causes down regulation of receptor‐bound IgE, resulting in desensitization of the cells. Both, activation of FcεRI by allergen‐specific IgE and engagement of FcγRIIb by allergen‐specific IgG are driven by allergen‐binding. Here we delineate the distinct roles of antibody affinity versus avidity in driving these processes and discuss the role of IgG subclasses in inhibiting basophil and mast cell activation. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the presence of large amounts of autoantibodies and immune complex formation. Because of their atypical clinical symptoms, SLE patients with digestive system involvement may not be recognized or treated precisely and extensively. Clinicians should pay close attention to SLE with digestive system involvement, as these conditions can easily worsen the condition and possibly endanger the patient's life. In this review we summarized the pathogenesis, pathological characteristics, clinical manifestations, diagnosis, and therapies for digestive system involvement in SLE. [ABSTRACT FROM AUTHOR]

The cyclic GMP–AMP synthase (cGAS), a prominent intracellular DNA sensor in mammalian cells, controls the innate immune response and the stimulator of interferon genes (STING)‐mediated synthesis of pro‐inflammatory cytokines, such as type‐I interferon (IFN‐I). For decades, IFN‐I has been hypothesized to be essential in the development of systemic lupus erythematosus (SLE), a chronic multisystem autoimmunity characterized by immune complex (IC) deposition in small vessels. Recent findings revealed that the activation of the cGAS–STING pathway by self‐DNA would propagate the autoimmune responses via upregulating IFN‐I production in SLE. In this review, we aimed to provide a comprehensive outlook of the role of the cGAS–STING pathway in SLE pathobiology, as well as, a better understanding of current therapeutic opportunities targeting this axis. [ABSTRACT FROM AUTHOR]

Over the past century, multichannel fluorescence imaging has been pivotal in myriad scientific breakthroughs by enabling the spatial visualization of proteins within a biological sample. With the shift to digital methods and visualization software, experts can now flexibly pseudocolor and combine image channels, each corresponding to a different protein, to explore their spatial relationships. We thus propose psudo, an interactive system that allows users to create optimal color palettes for multichannel spatial data. In psudo, a novel optimization method generates palettes that maximize the perceptual differences between channels while mitigating confusing color blending in overlapping channels. We integrate this method into a system that allows users to explore multi‐channel image data and compare and evaluate color palettes for their data. An interactive lensing approach provides on‐demand feedback on channel overlap and a color confusion metric while giving context to the underlying channel values. Color palettes can be applied globally or, using the lens, to local regions of interest. We evaluate our palette optimization approach using three graphical perception tasks in a crowdsourced user study with 150 participants, showing that users are more accurate at discerning and comparing the underlying data using our approach. Additionally, we showcase psudo in a case study exploring the complex immune responses in cancer tissue data with a biologist. [ABSTRACT FROM AUTHOR]

Summary: Splenectomised β‐thalassaemia/haemoglobin E (HbE) patients have increased levels of circulating microparticles or medium extra‐cellular vesicles (mEVs). The splenectomised mEVs play important roles in thromboembolic complications in patients since they can induce platelet activation and endothelial cell dysfunction. However, a comprehensive understanding of the mechanism of mEV generation in thalassaemia disease has still not been reached. Thalassaemic mEVs are hypothesised to be generated from cellular oxidative stress in red blood cells (RBCs) and platelets. Therefore, a proteomic analysis of mEVs from splenectomised and non‐splenectomised β‐thalassaemia/HbE patients was performed by liquid chromatography with tandem mass spectrometry. A total of 171 proteins were identified among mEVs. Interestingly, 72 proteins were uniquely found in splenectomised mEVs including immunoglobulin subunits and cytoskeleton proteins. Immunoglobulin G (IgG)‐bearing mEVs in splenectomised patients were significantly increased. Furthermore, complement C1q was detected in both mEVs with IgG binding and mEVs without IgG binding. Interestingly, the percentage of mEVs generated from RBCs with IgG binding was approximately 15–20 times higher than the percentage of RBCs binding with IgG. This suggested that the vesiculation of thalassaemia mEVs could be a mechanism of RBCs to eliminate membrane patches harbouring immune complex and may consequently prevent cells from phagocytosis and lysis. [ABSTRACT FROM AUTHOR]

Background: To identify specific human neutrophil antigen (HNA) antibodies, assays using neutrophils such as monoclonal antibody‐specific immobilization of granulocyte antigens (MAIGA) are recommended. However, these assays are limited by labor‐intensive neutrophil preparation and varying antigen expression levels. Methods: We evaluated a newly developed immunocomplex capture fluorescence assay (ICFA) for identifying HNA‐1 antibodies and compared it to MAIGA and LABScreen Multi (LABM), which utilizes recombinant HNA‐coated Luminex beads. For ICFA, HNA‐1a or HNA‐1b transfected cells replaced neutrophils. Cells incubated with serum were lysed, and immune complexes were captured using five CD16 monoclonal antibody‐conjugated Luminex beads. Nine antisera with known specificity and 26 samples suspected of containing HNA antibodies were analyzed by ICFA and MAIGA using neutrophils or transfected cells (ICFA‐N or ICFA‐T, and MAIGA‐N or MAIGA‐T, respectively). Results: ICFA‐T and MAIGA‐N accurately determined the specificity of all antibodies in the nine antiserum samples. The ICFA‐T detection limit was 2048‐fold for anti–HNA‐1a and 256‐fold for anti‐HNA‐1b; the limits of MAIGA‐T, MAIGA‐N, and LABM were 32‐, 4 ~ 64‐, and 128‐fold for anti‐HNA‐1a and 64‐, 16 ~ 64‐, and 32‐fold for anti–HNA‐1b, respectively. Twelve and 7 of the remaining 26 samples tested negative and positive, respectively, in both ICFA‐T and MAIGA‐N. Antibody specificity against HNA‐1a or HNA‐1b determined using ICFA‐T agreed with that determined using MAIGA‐N and LABM. Another seven samples tested positive in ICFA‐T but negative in MAIGA‐N. Conclusion: The novel ICFA is highly sensitive and exhibits specificity similar to MAIGA and LABM for detecting HNA‐1 antibodies. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Non‐lupus full house nephropathy is a rare entity that is still poorly understood. It can complicate post‐transplant kidneys and result in a de novo process. Treatment is difficult but can be possibly achieved with optimization of immune suppression. Non‐lupus full house nephropathy is a rare entity with an unclear incidence. It describes the kidney biopsy findings of positive deposits for IgG, IgA, IgM, C3, and C1q on immunofluorescence in the absence of the classical diagnostic features of systemic lupus nephritis. This disease entity is becoming more recognized but further studies are still needed to evaluate the incidence, etiologies, and management of this condition. Transplant glomerulopathy is a major cause for renal graft loss. It can present with a wide variety of manifestations; it can cause AKI, CKD, or glomerular inflammations through an immune complex or autoimmune‐mediated damage. [ABSTRACT FROM AUTHOR]

Immunoglobulin E (IgE)-mediated food allergy is a rapidly growing public health problem. The interaction between allergens and IgE is at the core of the allergic response. One of the best ways to understand this interaction is through structural characterization. This review focuses on animal-derived food allergens, overviews allergen structures determined by X-ray crystallography, presents an update on IgE conformational epitopes, and explores the structural features of these epitopes. The structural determinants of allergenicity and cross-reactivity are also discussed. Animal-derived food allergens are classified into limited protein families according to structural features, with the calcium-binding protein and actin-binding protein families dominating. Progress in epitope characterization has provided useful information on the structural properties of the IgE recognition region. The data reveals that epitopes are located in relatively protruding areas with negative surface electrostatic potential. Ligand binding and disulfide bonds are two intrinsic characteristics that influence protein structure and impact allergenicity. Shared structures, local motifs, and shared epitopes are factors that lead to cross-reactivity. The structural properties of epitope regions and structural determinants of allergenicity and cross-reactivity may provide directions for the prevention, diagnosis, and treatment of food allergies. Experimentally determined structure, especially that of antigen-antibody complexes, remains limited, and the identification of epitopes continues to be a bottleneck in the study of animal-derived food allergens. A combination of traditional immunological techniques and emerging bioinformatics technology will revolutionize how protein interactions are characterized. [ABSTRACT FROM AUTHOR]

IgA nephropathy is a mucosally driven disease and new therapeutic approaches are specifically targeting the mucosal production of IgA in the hope that this will lead to a reduction in circulating IgA immune complexes and mesangial IgA deposition. In this lecture, I discuss the rationale for targeting the mucosal immune system of the gut and the existing data from clinical trials supporting such an approach as a disease modifying treatment for IgA nephropathy. [ABSTRACT FROM AUTHOR]

This article explores the pathogenesis of IgA nephropathy (IgAN), a kidney disease characterized by abnormal production of immunoglobulin A (IgA). The source and triggers for the production of pathogenic IgA in IgAN are still unknown. The article discusses the structure and function of IgA, highlighting the differences between mucosal and circulatory IgA. It suggests that the pathogenic IgA in IgAN may originate from the mucosal immune system, specifically from cells in the mucosal associated lymphoid tissue or the bone marrow. However, emerging data also suggest that IgA-producing cells from the mucosal compartment may migrate to other locations in the body. Further research is needed to fully understand the nature and source of pathogenic IgA in IgAN. [Extracted from the article]

Summary at a glance: Complement plays a vital role in the pathogenesis of IgA nephropathy. Kidney biopsies with IgA nephropathy show glomerular immune complex deposits with evidence of complement activation by the alternative pathway and in a subset of cases the mannose binding lectin pathway. The recent development of specific drugs targeting these complement pathways represent a potentially important new approach to treating IgA nephropathy. [ABSTRACT FROM AUTHOR]

Background and Purpose: Millions of patients with inflammatory diseases are treated with tumour necrosis factor (TNF) inhibitors (TNFi). Individual treatment response varies, in part related to variable drug clearance. The role of TNF–TNFi complexes in clearance of the different TNFi is controversial. Moreover, mechanistic insight into the structural aspects and biological significance of TNF–TNFi complexes is lacking. We hypothesized a role for Fc‐mediated clearance of TNF–TNFi immune complexes. Therefore, we investigated circulating TNF–TNFi complexes upon treatment with certolizumab—lacking Fc tails—in comparison with adalimumab, golimumab, infliximab and etanercept. Experimental Approach: Drug‐tolerant ELISAs were developed and used to quantify TNF during adalimumab, golimumab, etanercept, certolizumab and infliximab treatment in patients with inflammatory arthritis or ulcerative colitis for a maximum follow‐up of 1 year. Effects on in vitro TNF production and Fc‐mediated uptake of TNF–TNFi complexes were investigated for all five TNFi. Key Results: Circulating TNF concentrations were >20‐fold higher during certolizumab treatment compared with adalimumab, reaching up to 23.1 ng·ml−1. Internalization of TNF–TNFi complexes by macrophages depended on Fc valency, with efficient uptake for the full antibody TNFi (three Fc tails), but little or no uptake for etanercept and certolizumab (one and zero Fc tail, respectively). TNF production was not affected by TNFi. Total TNF load did not affect clearance rate of total TNFi. Conclusions and Implications: Differences in TNFi structure profoundly affect clearance of TNF, while it is unlikely that TNF itself significantly contributes to target‐mediated drug disposition of TNFi. [ABSTRACT FROM AUTHOR]

Introduction: Allergen‐specific IgE‐blocking IgG antibodies contribute to successful allergen immunotherapy (AIT), however, not much is known about their affinity. Since affinity measurements of polyclonal antibodies in serum are technically challenging we evaluated the applicability of acidic disruption of antibody‐allergen complexes by a modified ELISA protocol with monoclonal antibodies (mAbs) specific for the relevant major allergens Betv1 and Mald1. Then, AIT‐induced blocking and non‐blocking Mald1‐specific antibodies in sera from individuals with or without reduced apple allergy were compared. Methods: After testing their pH stability coated recombinant allergens were incubated with (i) mAbs diluted in PBS or human serum and (ii) sera from individuals after sublingual administration of Mald1 or Betv1 for 16 weeks. Immune complexes were exposed to buffers in the pH range of 6.4–3.4 and residual antibodies were measured. Avidity indexes (AI), defined as the pH removing 50% of antibodies, were compared to the dissociation constants (KD) of mAbs determined by surface plasmon resonance. Results: The selected pH range was applicable to disrupt allergen complexes with highly affine mAbs without compromising allergen integrity. AIs of mAbs accorded with KD values and were unaffected by epitope specificity or the presence of serum proteins. The inter‐assay variability was <4% CV. Protective Mald1‐specific IgG antibodies from individuals with reduced apple allergy showed a higher collective binding strength than that of the non‐protective antibodies of individuals without reduced apple allergy. Conclusion: Acidic disruption of allergen‐antibody complexes may be used to estimate the net‐binding force of polyclonal serum antibodies and eases the investigation of affinity‐related research questions in AIT. [ABSTRACT FROM AUTHOR]

Summary: Inborn errors of immunity (IEI) comprise a diverse spectrum of 485 disorders as recognized by the International Union of Immunological Societies Committee on Inborn Error of Immunity in 2022. While IEI are monogenic by definition, they illuminate various pathways involved in the pathogenesis of polygenic immune dysregulation as in autoimmune or autoinflammatory syndromes, or in more common infectious diseases that may not have a significant genetic basis. Rapid improvement in genomic technologies has been the main driver of the accelerated rate of discovery of IEI and has led to the development of innovative treatment strategies. In this review, we will explore various facets of IEI, delving into the distinctions between PIDD and PIRD. We will examine how Mendelian inheritance patterns contribute to these disorders and discuss advancements in functional genomics that aid in characterizing new IEI. Additionally, we will explore how emerging genomic tools help to characterize new IEI as well as how they are paving the way for innovative treatment approaches for managing and potentially curing these complex immune conditions. [ABSTRACT FROM AUTHOR]

Background: Cold ischemia‐reperfusion injury (IRI) is an unavoidable complication of kidney transplantation. We investigated the role of regulatory T cells (Treg) in cold IRI and whether the interleukin (IL)‐2/anti‐IL‐2 antibody complex (IL‐2C) can ameliorate cold IRI. Methods: We developed a cold IRI mouse model using kidney transplantation and analyzed the IL‐2C impact on cold IRI in acute, subacute and chronic phases. Results: Treg transfer attenuated cold IRI, while Treg depletion aggravated cold IRI. Next, IL‐2C administration prior to IRI mitigated acute renal function decline, renal tissue damage and apoptosis and inhibited infiltration of effector cells into kidneys and pro‐inflammatory cytokine expression on day 1 after IRI. On day 7 after IRI, IL‐2C promoted renal regeneration and reduced subacute renal damage. Furthermore, on day 28 following IRI, IL‐2C inhibited chronic fibrosis. IL‐2C decreased reactive oxygen species‐mediated injury and improved antioxidant function. When IL‐2C was administered following IRI, it also increased renal regeneration with Treg infiltration and suppressed renal fibrosis. In contrast, Treg depletion in the presence of IL‐2C eliminated the positive effects of IL‐2C on IRI. Conclusion: Tregs protect kidneys from cold IRI and IL‐2C inhibited cold IRI by increasing the renal Tregs, suggesting a potential of IL‐2C in treating cold IRI. Key Points: Interleukin (IL)‐2/anti‐IL‐2 antibody complex attenuated acute renal injury, facilitated subacute renal regeneration and suppressed chronic renal fibrosis after cold ischemia‐reperfusion injury (IRI) by increasing the renal Tregs.IL‐2/anti‐IL‐2 antibody complex decreased reactive oxygen species‐mediated injury and improved antioxidant function.This study suggests the therapeutic potential of the IL‐2/anti‐IL‐2 antibody complex in kidney transplantation‐associated cold IR. [ABSTRACT FROM AUTHOR]

Internalization and processing by antigen‐presenting cells such as dendritic cells (DCs) are critical steps for initiating a T‐cell response to therapeutic antibodies. Consequences are the production of neutralizing antidrug antibodies altering the clinical response, the presence of immune complexes, and, in some rare cases, hypersensitivity reactions. In recent years, significant progress has been made in the knowledge of cellular uptake mechanisms of antibodies in DCs. The uptake of antibodies could be directly related to their immunogenicity by regulating the quantity of materials entering the DCs in relation to antibody structure. Here, we summarize the latest insights into cellular uptake mechanisms and pathways in DCs. We highlight the approaches to study endocytosis, the impact of endocytosis routes on T‐cell response, and discuss the link between how DCs internalize therapeutic antibodies and the potential mechanisms that could give rise to immunogenicity. Understanding these processes could help in developing assays to evaluate the immunogenicity potential of biotherapeutics. [ABSTRACT FROM AUTHOR]

Objective: The level of immunological reactivity of the indigenous inhabitants of the Far North may depend on the extreme‐discomfort factors of the climatic environment and genetic traits of the population. Therefore, the aim of this study was to identify the distinctive elements of the immune status of the Kola Saami and Russians living in the Far North (Murmansk Region). Methods: A complex immunological study of peripheral venous blood composition was performed and involved 67 Saami and 81 Russian inhabitants of the Far North (Murmansk Region) who were aged 21–55. Blood was collected from the cubital vein on an empty stomach in the morning. For the peripheral venous blood, we obtained a hemogram and phagocytic activity of neutrophils, determined the content of lymphocytes with CD4, CD8, CD16, and CD71 phenotypes by indirect immunoperoxidase reaction and flow cytometry using an Epics XL apparatus (Beckman Coulter, United States), obtained concentrations of IL‐6, IFN‐γ, IL‐10, IgA, M, G, E, sCD54, and sCD62L, transferrin, and sCD71 by enzyme immunoassay using the "Evolis" enzyme immunoassay analyzer from Bio‐RAD (Germany), and obtained circulating immune complexes by precipitation using 3.5%, 4.0%, and 7.5% PEG‐6000. The sIgA content was determined in morning saliva, urine, and gastrointestinal tract secretions. The results were analyzed using descriptive statistics, independent sample t‐criterion, and Pearson correlation coefficient. Results: A decrease in the total number of leukocyte cells in the Saami was associated with a high incidence of leukopenia, lymphopenia, and neutropenia. Deficiency in active phagocytes and serum IgA and sIgA concentrations was revealed as well as increased contents of CD4+ and CD8+ receptor lymphocytes, membrane and free adhesion molecules, and transferrin. Leukocytosis, lymphocytosis, neutrophilia, monocytosis, and eosinophilia with increased contents of natural killer cells, IL‐6, and IL‐10 were recorded more frequently in the Russians. High levels of IgE and IFN‐γ, which have the most pronounced cytotoxicity and are indicative of strained immune mechanisms, were characteristic of the Saami and Russians. Conclusion: The distinctive aspects of the immune status of the Kola Saami is related to the deficit in the active phagocyte and serum IgA and sIgA concentrations as well as the increase in the contents of cytotoxic lymphocytes, intercellular adhesion molecules, transferrin, and IFN‐γ proinflammatory cytokines. The Russian inhabitants of the Far North are characterized by an adaptive response manifested by an increase in antibody‐dependent cytotoxicity, involving IL‐6 and IL‐10. [ABSTRACT FROM AUTHOR]

Nonspecific hypergammaglobulinemia (HGG) occurs in symptomatic human visceral leishmaniasis (VL) caused by L. L. infantum. This study assessed this finding in experimental infection in hamsters and natural infection in dogs. The serum concentration of proteins, albumin and globulins was determined through the biuret and bromocresol green reaction, where the HGG was better expressed through the albumin/globulin (A/G) ratio. HGG was associated with a higher concentration of specific anti‐glycan antibodies (BSA‐G)/promastigote soluble extract (PSE) and the presence of circulating immune complexes (IC) by dissociative enzyme‐linked immunoassay (ELISA). The study found monovalent IC in 37.9% (PSE) and 50% (BSA‐G) of sera from infected hamsters, with increased frequency as the disease progressed. HGG was found in >60% of the samples in dogs with VL, associated with higher levels of specific immunoglobulin (Ig)A and IgM, but not IgG, determined using the PSE and BSA‐G ELISA. HGG was associated with the presence of monovalent IC in 58.9% (PSE) and 63.4% (BSA‐G) positive dog samples. HGG may result not only from the nonspecific activation of B cells, with greater production of specific and nonspecific antibodies, but also due to lower IgG excretion due to the presence of soluble monovalent IC. HGG correlates to the progression of VL and may be a marker for manifested disease. [ABSTRACT FROM AUTHOR]

Immunoglobulin (Ig) G4 has a distinctive nature, and its involvement in autoimmune disorders is a subject of ongoing debate and uncertainty. A growing body of evidence indicates that IgG4 may play a pathogenic role in the development of systemic lupus erythematosus (SLE). The IgG4 autoantibodies have the capability to bind autoantigens in a competitive manner with other Ig classes, thereby forming immune complexes (ICs) that are noninflammatory in nature. This is due to the low affinity of IgG4 for both the Fc receptors and the C1 complement molecule, which results in a diminished inflammatory response in individuals with SLE. The present study aims to elucidate the significance of IgG4 in SLE. The present discourse pertains to the nascent and suggested modalities through which IgG4 might participate in the pathogenesis of SLE and the potential ramifications for therapeutic interventions in SLE. [ABSTRACT FROM AUTHOR]

Insect immune‐associated phospholipase A2 (PLA2) is an important target of pathogen invasion. Melanization, an effective defense response, has significant correlations with other immune responses to coordinate immune attack against invaders. However, the effect of PLA2 on melanization has not yet been reported in insects or other arthropods. In this work, we cloned a PLA2 gene (BmsPLA2), and its protein had characteristic features of secreted PLA2 (sPLA2). After injection of bacteria, BmsPLA2 expression and sPLA2 activity in hemolymph significantly increased. BmsPLA2 fluorescence was transferred from the cytoplasm to the cell membranes of circulating hemocytes. These results indicated that BmsPLA2 was related to hemolymph immunity in silkworms. Interestingly, reducing BmsPLA2 by RNA interference decreased melanosis (melanistic hemocytes) levels in vivo and in vitro, while BmsPLA2 overexpression had the opposite effect. The larval survival and melanization rate in the hemocoel both slowed depending on the PLA2 inhibitor dosage. These results demonstrated that BmsPLA2 plays a role in melanization during the immune process of silkworms. Surprisingly, the level of BmDDC matched the degree of melanization in various observations. BmDDC expression showed a significant increase, with the peak occurring later than that of BmsPLA2 after injection of bacteria, implying that BmsPLA2 was activated prior to BmDDC. Moreover, the alteration of BmsPLA2 by RNA interference or overexpression led to altered BmDDC levels. These results suggested that BmsPLA2 regulates the melanization response in silkworms through BmDDC. Our study proposes a new regulatory mechanism of the melanization response and new directions for understanding the complex immune networks of insects. [ABSTRACT FROM AUTHOR]

Background: Recent studies have shown deposition of immunoglobulin G4 (IgG4) and food proteins in the esophageal mucosa of eosinophilic esophagitis (EoE) patients. Our aims were to assess whether co‐localization of IgG4 and major cow's milk proteins (CMPs) was associated with EoE disease activity and to investigate the proteins enriched in proximity to IgG4 deposits. Methods: This study included adult subjects with EoE (n = 13) and non‐EoE controls (n = 5). Esophageal biopsies were immunofluorescence stained for IgG4 and CMPs. Co‐localization in paired samples from active disease and remission was assessed and compared to controls. The proteome surrounding IgG4 deposits was evaluated by the novel technique, AutoSTOMP. IgG4‐food protein interactions were confirmed with co‐immunoprecipitation and mass spectrometry. Results: IgG4‐CMP co‐localization was higher in the active EoE group compared to paired remission samples (Bos d 4, p =.02; Bos d 5, p =.002; Bos d 8, p =.002). Co‐localization was also significantly higher in the active EoE group compared to non‐EoE controls (Bos d 4, p =.0013; Bos d 5, p =.0007; Bos d 8, p =.0013). AutoSTOMP identified eosinophil‐derived proteins (PRG 2 and 3, EPX, RNASE3) and calpain‐14 in IgG4‐enriched areas. Co‐immunoprecipitation and mass spectrometry confirmed IgG4 binding to multiple food allergens. Conclusion: These findings further contribute to the understanding of the interaction of IgG4 with food antigens as it relates to EoE disease activity. These data strongly suggest the immune complex formation of IgG4 and major cow's milk proteins. These immune complexes may have a potential role in the pathophysiology of EoE by contributing to eosinophil activation and disease progression. [ABSTRACT FROM AUTHOR]

Receptor-like kinases (RLKs) are plant proteins that form signaling circuits to transduce information through the plant cell membrane to the nucleus and activate processes that direct growth, development, stress response, and disease resistance. Upon sensing various environmental stress stimuli, RLKs interact with specific targets and recruit several other proteins to initiate the defense mechanism. Among many RLK subfamilies, leucine-rich repeat RLKs (LRR-RLKs) are the largest. Xa21, a member of LRR-RLK, is a vital receptor protein in rice plants that binds with bacterial RaxX21-sY, whereas OsSERK2 is a somatic embryogenic receptor kinase (SERK) that acts as a coreceptor in this process. This study focuses on the effect of a substitution mutation of aspartate128 with asparagine128 (D128N) in OsSERK2 on the interdependent binding pattern of the Xa21, RaxX21-sY, and OsSERK2 D128N proteins. The in silico results showed that the D128N mutation in OsSERK2 can significantly change the interaction pattern of the critical residues of the OsSERK2 and affects its receptor-ligand (Xa21-RaxX21-sY) interaction in the complex. These findings are expected to significantly contribute to the study of the structural basis of Xa21-mediated immunity and the first layer of plant defense mechanisms, thereby aiding further research on these structures and their phenotypic implications. [ABSTRACT FROM AUTHOR]

A 70-year-old Caucasian male presented with diffuse plane xanthoma, characterized by yellow discoloration of the skin in specific regions. The patient had macular patches and yellowish plaques on the inner thighs and axillae. Further examination revealed CD68-positive foamy macrophages in the skin, indicating diffuse plane xanthoma associated with monoclonal gammopathy. Treatment for this condition may include excision of lesions or other cosmetic procedures. The presence of multiple plane xanthomas without hyperlipidemia warrants investigation for underlying blood dyscrasia. [Extracted from the article]

Monitoring the highly dynamic and complex immune response remains a great challenge owing to the lack of reliable and specific approaches. Here, we develop a strategy to monitor the cascade of tumor immune response through the cooperation of pore‐forming alginate gel with chemoenzymatic proximity‐labeling. A macroporous gel containing tumor‐associated antigens, adjuvants, and pro‐inflammatory cytokines is utilized to recruit endogenous DCs and enhance their maturation in vivo. The mature DCs are then modified with GDP‐fucose‐fucosyltransferase (GDP‐Fuc‐Fuct) via the self‐catalysis of fucosyltransferase (Fuct). Following the migration of the obtained Fuct‐DCs to the draining lymph nodes (dLNs), the molecular recognition mediated interaction of DCs and T cells leads to the successful decoration of T cells with GDP‐Fuc‐azide through the Fuct catalyzed proximity‐labeling. Therefore, the activated tumor‐specific T cells in dLNs and tumors can be identified through bioorthogonal labeling, opening up a new avenue for studying the immune mechanism of tumors in situ. [ABSTRACT FROM AUTHOR]

Immune complexes (ICs) skew immune responses toward either a pro- or anti-inflammatory direction based on the type of stimulation. Immunoglobulin E (IgE) is associated with Th2 immune responses and known to activate innate immune cells. However, roles of antigen (Ag)-specific-IgE ICs in regulating human eosinophil responses remain elusive; therefore, this study builts upon the mechanism of which ovalbumin (Ova)-IgE ICs affects eosinophilic responses utilizing human EoL-1 cell line as a model. Eosinophils are granulocytes functioning through pattern recognition receptors (PRRs) and destructive granule contents in allergic inflammation and parasitic infections. One of the PRRs that eosinophils express is NLRC4, a member of the CARD domain containing nucleotide-binding oligomerization (NOD)-like receptor (NLR) family. Upon recognition of its specific ligand flagellin, NLRC4 inflammasome is formed and leads to the release of interleukin-1β (IL-1β). We exhibited that Ova-IgE ICs induced the NLRC4-inflammasome components, including NLRC4, caspase-1, intracellular IL-1β, and secretion of IL-1β, as well as the granule contents MMP9, TIMP1, and TIMP2 proteins via TLR2 signaling; these responses were suppressed, when NLRC4 inflammasome got actived in the presence of ICs. Furthermore, Ova-IgE ICs induced mRNA expressions of MMP9, TIMP2, and ECP and protein expressions of MMP9 and TIMP2 in EoL-1 through FcɛRII. Interestingly, TLR2 ligand and Ova-IgE ICs costimulation elevated the number of CD63+ cells, a degranulation marker, as compared to the native IgE. Collectively, our findings provide a mechanism for the impacts of Ova-IgE ICs on eosinophilic responses via NLRC4-inflammasome and may help understand eosinophil-associated diseases, including chronic eosinophilic pneumonia, eosinophilic esophagitis, eosinophilic granulomatosis, parasitic infections, allergy, and asthma. [ABSTRACT FROM AUTHOR]

Using model systems in infection biology has led to the discoveries of many pathogen‐encoded virulence factors and critical host immune factors to fight pathogenic infections. Studies of the remarkable Pseudomonas aeruginosa bacterium that infects and causes disease in hosts as divergent as humans and plants afford unique opportunities to shed new light on virulence strategies and host defence mechanisms. One of the rationales for using model systems as a discovery tool to characterise bacterial factors driving human infection outcomes is that many P. aeruginosa virulence factors are required for pathogenesis in diverse different hosts. On the other side, many host signalling components, such as the evolutionarily conserved mitogen‐activated protein kinases, are involved in immune signalling in a diverse range of hosts. Some model organisms that have less complex immune systems also allow dissection of the direct impacts of innate immunity on host defence without the interference of adaptive immunity. In this review, we start with discussing the occurrence of P. aeruginosa in the environment and the ability of this bacterium to cause disease in various hosts as a natural opportunistic pathogen. We then summarise the use of some model systems to study host defence and P. aeruginosa virulence. [ABSTRACT FROM AUTHOR]

Objective: The endothelial surface layer (ESL), a layer of macromolecules on the surface of endothelial cells, can both impede and facilitate leukocyte recruitment. However, its role in monocyte and neutrophil recruitment in glomerular capillaries is unknown. Methods: We used multiphoton intravital microscopy to examine monocyte and neutrophil behavior in the glomerulus following ESL disruption with hyaluronidase. Results: Constitutive retention and migration of monocytes and neutrophils within the glomerular microvasculature was unaltered by hyaluronidase. Consistent with this, inhibition of the hyaluronan‐binding molecule CD44 also failed to modulate glomerular trafficking of these immune cells. To investigate the contribution of the ESL during acute inflammation, we induced glomerulonephritis via in situ immune complex deposition. This resulted in increases in glomerular retention of monocytes and neutrophils but did not induce marked reduction in the glomerular ESL. Furthermore, hyaluronidase treatment did not modify the prolonged retention of monocytes and neutrophils in the acutely inflamed glomerular microvasculature. Conclusions: These observations indicate that, despite evidence that the ESL has the capacity to inhibit leukocyte‐endothelial cell interactions while also containing adhesive ligands for immune cells, neither of these functions modulate trafficking of monocytes and neutrophils in steady‐state or acutely‐inflamed glomeruli. [ABSTRACT FROM AUTHOR]

Immune‐mediated regression of melanocytic neoplasms is predominantly lymphocytic, driven by CD8+ anti‐tumoral T‐cells and, rarely, natural killer cells. Histopathologic features of regression include effacement of the epidermis, replacement of tumor cells by a fibrotic stroma, varying degrees of chronic inflammation (usually lymphocytes) and melanophages, as well as vascular ectasia and angioplasia. The understanding of regression and the complex immune response in melanoma has led to the development of targeted immunotherapy in melanoma. Here, we report a case of near‐complete regression of a melanocytic neoplasm associated with neutrophilic and eosinophilic inflammation, suggesting a non‐traditional pathway of regression that has yet to be explored. [ABSTRACT FROM AUTHOR]

Objectives: B cells drive the production of autoreactive antibody‐secreting cells (ASCs) in autoimmune diseases such as Systemic Lupus Erythematosus (SLE) and Sjögren's syndrome, causing long‐term organ damage. Current treatments for antibody‐mediated autoimmune diseases target B cells or broadly suppress the immune system. However, pre‐existing long‐lived ASCs are often refractory to treatment, leaving a reservoir of autoreactive cells that continue to produce antibodies. Therefore, the development of novel treatment methods targeting ASCs is vital to improve patient outcomes. Our objective was to test whether targeting the epigenetic regulator BMI‐1 could deplete ASCs in autoimmune conditions in vivo and in vitro. Methods: Use of a BMI‐1 inhibitor in both mouse and human autoimmune settings was investigated. Lyn−/− mice, a model of SLE, were treated with the BMI‐1 small molecule inhibitor PTC‐028, before assessment of ASCs, serum antibody and immune complexes. To examine human ASC survival, a novel human fibroblast‐based assay was established, and the impact of PTC‐028 on ASCs derived from Sjögren's syndrome patients was evaluated. Results: BMI‐1 inhibition significantly decreased splenic and bone marrow ASCs in Lyn−/− mice. The decline in ASCs was linked to aberrant cell cycle gene expression and led to a significant decrease in serum IgG3, immune complexes and anti‐DNA IgG. PTC‐028 was also efficacious in reducing ex vivo plasma cell survival from both Sjögren's syndrome patients and age‐matched healthy donors. Conclusion: These data provide evidence that inhibiting BMI‐1 can deplete ASC in a variety of contexts and thus BMI‐1 is a viable therapeutic target for antibody‐mediated autoimmune diseases. [ABSTRACT FROM AUTHOR]

The complement system, an arm of the innate immune system plays a critical role in both health and disease. The complement system is highly complex with dual possibilities, helping or hurting the host, depending on the location and local microenvironment. The traditionally known functions of complement include surveillance, pathogen recognition, immune complex trafficking, processing and pathogen elimination. The noncanonical functions of the complement system include their roles in development, differentiation, local homeostasis and other cellular functions. Complement proteins are present in both, the plasma and on the membranes. Complement activation occurs both extra‐ and intracellularly, which leads to considerable pleiotropy in their activity. In order to design more desirable and effective therapies, it is important to understand the different functions of complement, and its location‐based and tissue‐specific responses. This manuscript will provide a brief overview into the complex nature of the complement cascade, outlining some of their complement‐independent functions, their effects at different locale, and their implication in disease settings. [ABSTRACT FROM AUTHOR]

IgA nephropathy (IgAN) is the most common glomerular autoimmune disease and has severe long‐term consequences for patients, with 40% of the patients eventually progressing to end‐stage renal disease. Despite the severity, no causal treatment is currently available. While the pathogenesis of IgAN is complex, disease severity is linked to autoantibodies against the gd‐IgA1 epitope, a stretch in the hinge region of IgA1 that lacks O‐glycans and is found in the characteristic immune complexes deposited in the kidneys of IgAN patients. One elegant, causal approach would be to remove the anti‐gd‐IgA1 autoantibodies and consequently reduce the immune complex burden on the kidneys. The administration of synthetic polymers that present autoantigens in a multivalent manner have been established as promising therapeutic strategies in other autoimmune diseases and may be applied to IgAN. We here present an improved protocol for the synthesis of the gd‐IgA1 epitope, its successful coupling to a poly‐L‐lysine polymer and proof‐of‐concept experiments that the polymer‐bound synthetic glycopeptide is able to capture the IgAN autoantibodies, making this approach a promising way forward for developing a targeted treatment option for IgAN patients. [ABSTRACT FROM AUTHOR]

Progress in structural biology research has led to a high demand for powerful and yet complementary analytical tools for structural characterization of proteins and protein complexes. This demand has significantly increased interest in native mass spectrometry (nMS), particularly native top‐down mass spectrometry (nTDMS) in the past decade. This review highlights recent advances in nTDMS for structural research of biological assemblies, with a particular focus on the extra multi‐layers of information enabled by TDMS. We include a short introduction of sample preparation and ionization to nMS, tandem fragmentation techniques as well as mass analyzers and software/analysis pipelines used for nTDMS. We highlight unique structural information offered by nTDMS and examples of its broad range of applications in proteins, protein‐ligand interactions (metal, cofactor/drug, DNA/RNA, and protein), therapeutic antibodies and antigen‐antibody complexes, membrane proteins, macromolecular machineries (ribosome, nucleosome, proteosome, and viruses), to endogenous protein complexes. The challenges, potential, along with perspectives of nTDMS methods for the analysis of proteins and protein assemblies in recombinant and biological samples are discussed. [ABSTRACT FROM AUTHOR]

Kawasaki disease (KD) is an acute self‐limiting systemic vasculitis of unknown etiology affecting predominantly the coronary arteries. The role of circulating immune complexes (ICs) in the pathogenesis of KD has been studied using the sera of patients with KD. It has been proposed that ICs are triggered by single or multiple unknown causative agents as well as vasculitis. The outbreak of severe acute respiratory syndrome coronavirus 2 infections caused similar pathophysiology in producing vasculitis, and the RNA virus may have triggered signs and symptoms similar to KD. For clinicians and researchers alike, detecting the causative agents of KD remains a challenge. According to studies in animal models, type III hypersensitivity reactions caused by serum sickness are a prototype for IC vasculitis. The signs and symptoms of coronary artery dilation in swine are similar to those of KD. These models may be used to evaluate new pharmacological agents for KD. The pathogenesis of KD is complex and remains inadequately understood at present. However, circulating ICs may play a key role in the pathophysiology of KD and coronary artery vasculitis. Various therapeutic agents are being explored in the management of KD and these agents act at various stages of the production of pro‐inflammatory cytokines and chemokines. In this review, we discuss recent developments in the pathogenesis of KD and provide insights into the innate immune response and mechanisms behind coronary artery damage in KD. We specifically explore the potential role of ICs in the pathogenesis of KD. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Immune dysfunction can manifest in unexpected ways. We present the case of a patient with systemic lupus erythematosus (SLE) in whom the first sign of disseminated histoplasmosis and consequent macrophage activation syndrome (MAS) was tongue necrosis. In those with immune dysfunction, a high index of clinical suspicion for atypical infections is warranted. [ABSTRACT FROM AUTHOR]

Dermatomyositis (DM) is an idiopathic inflammatory myopathy belonging to the spectrum of autoimmune connective tissue diseases. DM patients present with antinuclear antibodies against Mi‐2, also known as Chromodomain‐helicase‐DNA‐binding protein 4 (CHD4). CHD4 is upregulated in DM skin biopsies and could potentially affect DM pathophysiology as it binds endogenous DNA with a high affinity (KD = 0.2 nM ± 0.076 nM) and forms CHD4‐DNA complexes. The complexes are localized in the cytoplasm of UV‐radiated and transfected HaCaTs and amplify the expression of interferon (IFN) regulated genes and the amount of functional CXCL10 protein stronger than DNA alone. The enhancement of the type I IFN pathway activation in HaCaTs through CHD4‐DNA signalling suggests a possible mechanism for the sustainment of the pro‐inflammatory vicious cycle in DM skin lesions. [ABSTRACT FROM AUTHOR]

Background: The aryl hydrocarbon receptor (AhR) is a critical regulator of the pathogenesis of autoimmune disorders. We aimed to investigate the therapeutic effect of the AhR agonist tapinarof during the development of systemic lupus erythematosus (SLE). Methods: MRL/lpr mice were intraperitoneally injected with 1 or 5 mg/kg tapinarof for 6 weeks. Kidney histopathology was evaluated using hematoxylin and eosin (H&E) and Periodic‐Acid‐Schiff (PAS) staining. Immunofluorescence microscopy was performed to detect immune complex renal depositions. Flow cytometry (FCM) analysis was carried out to determine the proportions of T and B cell subsets. Realtime qPCR was used to quantify the expression of Tfh cell‐associated genes. We conducted an in vitro polarization experiment to observe the effect of tapinarof on Tfh differentiation. Western blotting was used to detect the expression of target proteins. Results: We found that tapinarof treatment ameliorated lupus phenotypes, including splenomegaly, lymph node enlargement, kidney damages, immune complex deposition, and excessive secretion of antibodies. Additionally, we showed that Treg subpopulation frequencies significantly increased in MRL/lpr mice treated with tapinarof, while the proportion of Th1/Th2 cells was reduced after tapinarof administration. Moreover, tapinarof suppressed Tfh cell differentiation and germinal center (GC) reaction in vivo. The inhibitory effect of tapinarof on Tfh cells was further verified in the in vitro Tfh cell polarization experiment. Realtime qPCR revealed that tapinarof repressed the expression of Tfh signature genes. Mechanistically, tapinarof significantly inhibited the phosphorylation levels of JAK2 and STAT3. The capacity for Tfh differentiation was partially rescued by the STAT3 activator Colivelin TFA. Furthermore, our in vitro Tfh polarization experiments indicated that tapinarof suppressed Tfh cell development in SLE. Conclusions: Our data demonstrated that tapinarof modulated the JAK2‐STAT3 pathway to suppress Tfh cell differentiation for the treatment of lupus symptoms in MRL/lpr mice. [ABSTRACT FROM AUTHOR]

This document is a reply to a response to an article titled "Hypersensitivity reaction during enzyme replacement therapy in lysosomal storage disorders: a systematic review of desensitization strategies." The response acknowledges and appreciates the feedback provided by the authors of the response. The article discusses the challenges of managing allergic reactions during enzyme replacement therapy (ERT) for metabolic disorders. It highlights the use of a combined method of rapid desensitization and Allergen Immunotherapy-like (AIT-like) desensitization as a promising strategy. The role of IgG-mediated responses in these reactions is still unclear, and further research is needed. Premedication strategies tailored to the nature of previous reactions are crucial in managing ERT-induced hypersensitivity reactions. The decision to reintroduce ERT after a reaction must consider premedication strategies and the patient's overall health. The document emphasizes the need for ongoing research and evolving strategies to ensure optimal patient outcomes and the efficacy of life-saving therapies. [Extracted from the article]

Background. The QuantiFERON®-Monitor (QFM) is an assay that measures interferon-γ production and was developed to provide an objective marker of complex immune response. In this study, we evaluated the use of the QFM test in patients with two forms of multiple sclerosis (MS), relapsing–remitting form treated with fingolimod (fMS) and secondarily progressive form not treated pharmacologically (pMS), and in healthy controls (HC). We hypothesized that IFN-γ levels would be lower in those subjects who are relatively more immunosuppressed and higher in those with normal or activated immune function. Methods. This single-center observational study was conducted from November 2020 to October 2021 and compared results in three groups of patients: 86 healthy controls, 96 patients with pMS, and 78 fMS. Combination of lyophilized stimulants was added to 1 ml heparinized whole blood within 8 hr of collection. Plasmatic IFN-γ was measured using the ELISA kit for the QFM and data were obtained in IU/ml. Results. The results showed that controls had nearly 2-fold higher levels of IFN-γ (QFM score) in median (q25, q75) 228.00 (112.20, 358.67) than the MS patient groups: pMS 144.80 (31.23, 302.00); fMS 130.50 (39.95, 217.07) which is statistically significant difference P-value: HC vs. pMS = 0.0071; HC vs. fMS = 0.0468. This result was also confirmed by a validation analysis to exclude impact of variable factors, such as disease duration and Expanded Disability Status Scale scores. Conclusions. Results showed that controls had higher levels of IFN-γ production than the MS patient groups and suggest that MS patients included in this study have a lower ability of immune system activation than HC. Results confirm that fingolimod is able to suppress production of IFN-γ. The fact that the QFM score of MS patients is significantly lower than that of HC may indicate a dysfunctional state of the immune system in baseline conditions. [ABSTRACT FROM AUTHOR]

Summary: In Arabidopsis, the receptor‐like kinase (RLK) FERONIA (FER) senses peptide ligands in the plasma membrane (PM), modulates plant growth and development, and integrates biotic and abiotic stress signaling for downstream adaptive responses. However, the molecular interplay of these diverse processes is largely unknown.Here, we show that FER, the receptor of Rapid Alkalinization Factor 1 (RALF1), physically interacts with C2 domain ABA‐related (CAR) proteins to control the nano‐organization of the PM. During this process, the RALF1‐FER pathway upregulates CAR protein translation, and then more CAR proteins are recruited to the PM. This acts as a rapid feedforward loop that stabilizes the PM liquid‐ordered phase. FER interacts with and phosphorylates CARs, thereby reducing their lipid‐binding ability and breaking the feedback regulation at later time points.The formation of the flg22‐induced FLS2‐BAK1 immune complex, which depends on the integrity of FER‐containing nanodomains, is impaired in fer and pentuple car14569 mutant.Together, we propose that the FER‐CAR module controls the formation of PM nano‐organization during RALF signaling through a self‐contained amplifying loop including both positive and negative feedback. [ABSTRACT FROM AUTHOR]