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The article in Cell Discovery discusses the structural insights into the agonist activity of the nonpeptide modulator JR14a on C3aR, a G protein-coupled receptor involved in immune responses. The study reveals that JR14a acts as an agonist of C3aR, inducing various cellular responses and chemotaxis of immune cells. Structural analysis shows that JR14a binds to C3aR in a unique manner, leading to selective activation of C3aR. The findings provide a basis for developing small-molecule therapies targeting C3aR for inflammatory diseases. [Extracted from the article]

Introduction: Neutrophil activation is important in systemic lupus erythematosus (SLE). We previously demonstrated that ribonucleoprotein (RNP) immune complexes (ICs) promoted neutrophil activation in a TLR7/8-dependent manner. However, it remains unclear if this mechanism occurs in patients. Here, we investigated the role of RNA recognition by evaluating TLR7/8 in plasma-mediated neutrophil activation in SLE. Methods: Plasma levels of neutrophil activation markers and ICs were measured by ELISA and flow cytometry in SLE patients (n=151) and healthy controls (HCs, n=31). Neutrophils were incubated with plasma and assessed for CD66b and CD11b up-regulation by flow cytometry in the presence of select inhibitors to define the mechanisms of neutrophil activation by SLE plasma. Results: SLE plasma induced higher levels of CD66b (p=0.0002) and CD11b (p=0.01) expression than plasma from HCs. Blocking FcγRIIA, targeting RNA sensing by adding RNase, or blocking TLR7/8, TLR8 only, or IRAK4, decreased plasma-mediated neutrophil activation (p<0.05). Consistent with the ability of selective TLR8 inhibitor to block plasma-mediated neutrophil activation, TLR8 agonists, but not TLR7 agonists induced robust neutrophil activation. Further, neutrophil mRNA expression of TLR8 was higher than TLR7. Finally, patients with plasma samples inducing neutrophil activation in RNA-dependent manner had increased levels of interferon alpha, IP-10 (p<0.05), ICs (p<0.05), and reduced complement C3 levels (p<0.01), indicative of IC-driven disease. Conclusion: The data support IC-driven RNA-sensing by TLR8 in neutrophils is a key mechanism of neutrophil activation in SLE. Patients with elevated neutrophil activation and presence of RNA-containing ICs, may benefit from TLR8 inhibition and other strategies targeting RNA removal. [ABSTRACT FROM AUTHOR]

IgA nephropathy (IgAN) is a common form of primary glomerulonephritis and represents an important cause of chronic kidney disease globally, with observational studies indicating that most patients are at risk of developing kidney failure within their lifetime. Several research advances have provided insights into the underlying disease pathogenesis, framed by a multi-hit model whereby an increase in circulating IgA1 that lacks galactose from its hinge region — probably derived from the mucosal immune system — is followed by binding of specific IgG and IgA antibodies, generating immune complexes that deposit within the glomeruli, which triggers inflammation, complement activation and kidney damage. Although treatment options are currently limited, new therapies are rapidly emerging that target different pathways, cells and mediators involved in the disease pathogenesis, including B cell priming in the gut mucosa, the cytokines APRIL and BAFF, plasma cells, complement activation and endothelin pathway activation. As more treatments become available, there is a realistic possibility of transforming the long-term outlook for many individuals with IgAN. IgA nephropathy (IgAN) is thought to result from multiple hits that culminate in immune complex deposition in the kidney. Here, the authors describe the latest insights into the pathogenesis of IgAN and how they have revealed novel therapeutic targets and approaches to this disease. Key points: IgA nephropathy (IgAN) is an important cause of progressive kidney disease and kidney failure globally, with most patients being at risk of developing kidney failure within their lifetime. Advances in the understanding of the pathogenesis of IgAN have highlighted an (auto)immune basis for the disease, with increased circulating levels of galactose-deficient IgA1 (Gd-IgA1) being associated with the presence of IgA and IgG antibodies specific to these IgA1 O-glycoforms. The circulating Gd-IgA1 that forms immune complexes and is deposited within the glomeruli in IgAN is probably mucosal in origin. The presence of elevated levels of Gd-IgA1 alone is insufficient to trigger IgAN; genetic and epigenetic factors contribute to the susceptibility of developing IgAN and the risk of progressive disease. Several therapies that target mucosal B cell priming, B cell production of Gd-IgA1, complement activity and the endothelin system are in development for the treatment of IgAN. [ABSTRACT FROM AUTHOR]

Periapical lesions (PLs) are common inflammatory diseases primarily caused by microbial infections within root canals. These infections trigger complex immune responses in periapical tissues, with B lymphocytes playing dual roles: defending against pathogens while also contributing to tissue damage. This highlights the crucial role of B cells in the immunological processes of PLs. A comprehensive review of the literature on B cells in PLs was conducted using PubMed, Web of Science, Scopus, and ScienceDirect databases. The review included 120 studies that examined the distribution and subtypes of B cells, their dual functions in PLs, and the potential applications of B-cell–related therapies in treating apical periodontitis. This review enhances our understanding of the complex immune mechanisms in PLs and aids in the development of new therapeutic approaches from a B-cell perspective. [ABSTRACT FROM AUTHOR]

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]

Platelets are essential for blood clotting and maintaining normal hemostasis. In pathological conditions, platelets are increasingly recognized as crucial regulatory factors in various immune-mediated inflammatory diseases. Resting platelets are induced by various factors such as immune complexes through Fc receptors, platelet-targeting autoantibodies and other platelet-activating stimuli. Platelet activation in immunological processes involves the release of immune activation stimuli, antigen presentation and interaction with immune cells. Platelets participate in both the innate immune system (neutrophils, monocytes/macrophages, dendritic cells (DCs) and Natural Killer (NK) cells and the adaptive immune system (T and B cells). Clinical therapeutic strategies include targeting platelet activation, platelet-immune cell interaction and platelet-endothelial cell interaction, which display positive development prospects. Understanding the mechanisms of platelets in immunity is important, and developing targeted modulations of these mechanisms will pave the way for promising therapeutic strategies. [ABSTRACT FROM AUTHOR]

An innovative signal-transduction tag with glucose-doped calcium carbonate nanospheres was utilized as the label of a secondary antibody to design a nano-labelled immunosorbent assay (NLISA) of a carcinoembryonic antigen. The signal was achieved on a personal glucometer via the released glucose molecules from the nanospheres under acidic conditions after formation of the sandwiched immune complexes. The enzyme and the spectrometer in the conventional enzyme-linked immunosorbent assay (ELISA) were replaced by a glucose-doped calcium carbonate nanosphere and a glucometer. [ABSTRACT FROM AUTHOR]

The calcium (Ca2+) sensor ROD1 (RESISTANCE OF RICE TO DISEASES1) is a master regulator of immunity in rice. By screening suppressors of rod1 mutants, we show that ROD1 governs immune homeostasis by surveilling the activation of a canonical immune pathway. Mutations in OsTIR (TIR-only protein), OsEDS1 (enhanced disease susceptibility 1), OsPAD4 (phytoalexin deficient 4), and OsADR1 (activated disease resistance 1) all abolish enhanced disease resistance of rod1 plants. OsTIR catalyzes the production of second messengers 2′-(5″-phosphoribosyl)-5′-adenosine monophosphate (pRib-AMP) and diphosphate (pRib-ADP), which trigger formation of an OsEDS1-OsPAD4-OsADR1 (EPA) immune complex. ROD1 interacts with OsTIR and inhibits its enzymatic activity, whereas mutation of ROD1 leads to constitutive activation of the EPA complex. Thus, we unveil an immune network that fine-tunes immune homeostasis and multipathogen resistance in rice. [ABSTRACT FROM AUTHOR]

Background/Objectives: Lupus nephritis (LN) is a serious complication of systemic lupus erythematosus (SLE), involving immune complex deposition in the kidneys. While renal biopsy is the diagnostic gold standard, its invasiveness limits frequent use, driving the need for non-invasive urinary biomarkers to monitor disease progression and response to treatment. This study aimed to identify and validate urinary biomarkers for LN. Methods: Data from 10 LN-related omics databases, including urine, PBMCs, and kidney tissue, were analyzed. Differentially expressed proteins (DEPs) and genes (DEGs) were identified, and candidate biomarkers were validated via ELISA in an independent cohort of 87 urine samples. Results: We identified 78 biomarkers, with 14 overlapping across transcriptomic categories. Novel urinary biomarkers, including SERPING1, SLPI, and CD48, were validated. Urinary CD163, VCAM1, and ALCAM levels showed significant differences between LN and healthy controls, while urinary immune complexes (ICx) demonstrated superior diagnostic performance, with urinary ALCAM-ICx and CCL21-ICx achieving the highest AUC values. Conclusions: Our findings highlight the potential of urinary immune complexes and antigens as non-invasive biomarkers for LN. ALCAM, CD163, and SERPING1-ICx, in particular, were found as promising candidates for a urinary biomarker panel to aid in the diagnosis and monitoring of LN. [ABSTRACT FROM AUTHOR]

Background Dengue vascular permeability syndrome is the primary cause of death in severe dengue infections. The protective versus potentially pathogenic role of dengue nonstructural protein-1 (NS1) antibodies are not well understood. The main goal of this analysis was to characterize the relationship between free NS1 concentration and NS1 antibody titers in primary and secondary dengue infection to better understand the presence and duration of NS1 antibody complexes in clinical dengue infections. Methods Hospitalized participants with acute dengue infection were recruited from Northern Colombia between 2018 and 2020. Symptom assessment, including dengue signs and symptoms, chart review, and blood collection, was performed. Primary versus secondary dengue was assessed serologically. NS1 titers and anti-NS1 antibodies were measured daily. Results Patients with secondary infection had higher antibody titers than those in primary infection, and there was a negative correlation between anti-NS1 antibody titer and NS1 protein. We demonstrate that in a subset of secondary infection, there were indeed NS1 antigen-antibody complexes on the admission day during the febrile phase that were not detectable by the recovery phase. Furthermore, dengue infection status was associated with higher circulating sialidases. Discussion The negative correlation between antibody and protein suggests that antibodies may play a role in clearing this viral protein. [ABSTRACT FROM AUTHOR]

An immunochromatographic test system based on the indirect competitive format has been developed for the rapid control of cyanotoxin microcystin-LR (MC-LR) in drinking water. To increase the assay sensitivity, a hydroquinone-based reduction of silver ions on the surface of gold nanoparticles as part of the immune complexes formed on the immunochromatographic membrane has been carried out. This stage allows for the enhancement of the colouration in test strip zones. The developed test system is characterised by an instrumental limit of detection of 0.05 ng/mL, a cut-off of 0.5 ng/mL, and a working range of the detectable concentrations of 0.08–0.42 ng/mL. The assay duration was 17 min. The applicability of the test system for MC-LR detection in drinking water is demonstrated. The assay recoveries vary from 90% to 120%. [ABSTRACT FROM AUTHOR]

Objectives: An important pathogenic role for neutrophils in systemic lupus erythematosus (SLE) has been proposed. Neutrophils that lack brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1 (Bmal1), one of the clock genes, are defective in aging and proinflammatory responses. We assessed the role of Bmal1 in clinical and immunologic manifestations of murine lupus and in human SLE neutrophils. Methods: Myeloid-conditional Bmal1 knockout mice (Bmal1Mye−/−) and wild type (WT) were treated with epicutaneous TLR7/8 agonist (imiquimod; IMQ) for 6 weeks to induce a lupus phenotype. Upon euthanasia, immune responses, autoantibodies and renal manifestations were evaluated. NET formation and gene expression of bone marrow (BM)-derived murine neutrophils were evaluated. BMAL1 expression was quantified in SLE neutrophils and compared with clinical disease. Results: IMQ-treated Bmal1Mye−/− and WT displayed comparable systemic inflammation. While renal function did not differ, serum anti-dsDNA levels and renal immune complex deposition were significantly increased in Bmal1Mye−/−. While no differences were observed in NET formation, expression levels of April in BM neutrophils were significantly higher in Bmal1Mye−/−. Bulk RNA-sequence data showed that BM neutrophils in IMQ-treated Bmal1Mye−/− were relatively immature when compared with IMQ-treated WT. BM showed an enhanced April protein expression in Bmal1Mye−/− mice. BMAL1 levels in human SLE peripheral blood neutrophils correlated positively with serum C3 and negatively with serum anti-dsDNA levels. Conclusion: Bmal1 is associated with lower disease activity in SLE. These results indicate that perturbation in the circadian rhythm of neutrophils can have pathogenic consequences in SLE. [ABSTRACT FROM AUTHOR]

Interleukin-33 (IL-33) is a cytokine belonging to the IL-1 family. It is primarily associated with type 2 immune responses. It interacts with a receptor complex on immune cells in reaction to tissue damage or cellular injury. IL-33 is crucial in immune responses and is involved in various autoimmune and inflammatory diseases. Obesity is marked by chronic inflammation and is a known risk factor for several types of cancer. Recent studies have shown that IL-33 and its receptor complex are expressed in adipose (fat) tissue, suggesting they may play a role in obesity. While inflammation connects obesity and cancer, it is not yet clear whether IL-33 contributes to cancer associated with obesity. Depending on the cellular context, inflammatory environment, expression levels, and bioactivity, IL-33 can exhibit both protumorigenic and antitumorigenic effects. This review will explore the various functions of IL-33 in the inflammation linked to obesity and its relationship with cancer. [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]

Introduction: Allergic diseases, such as anaphylaxis and urticaria, pose significant health concerns. The quest for improved prognostic outcomes in these diseases necessitates the exploration of novel therapeutic avenues. To address this need, we have developed a novel mouse model of anaphylaxis, denoted as anaphylaxis-dependent spotted distribution of immune complex in skin (ASDIS). ASDIS manifests as distinct dotted symptoms in the skin, detectable through in vivo imaging, resembling urticarial symptoms. In this study, we investigated the potential underlying mechanisms giving rise to these dotted symptoms, exploring the role of vascular permeability and characterizing the ASDIS model as a new urticaria model. Methods: We employed haired and hairless HR mice (BALB/c background) and hairless HR-1 mice (a commercially available hairless strain with an unidentified genetic background). ASDIS was induced by the simultaneous intravenous injection of anti-ovalbumin IgE and fluorescein isothiocyanate (FITC)-ovalbumin, along with Evans blue – a recognized vascular permeability indicator. Anaphylaxis and scratching behavior were monitored through rectal temperature decrease and optical observation, respectively. Histamine, platelet-activating factor, and compound 48/80 were injected with or without FITC-ovalbumin for comparative analysis. The effects of an α1 adrenergic receptor agonist applied to the skin were also examined. Results: In hairless mice, the simultaneous injection of histamine, compound 48/80, or IgE with FITC-ovalbumin induced comparable rectal temperature decreases and vascular permeability. However, only the combination of FITC-ovalbumin and IgE triggered ASDIS, specifically the dotted urticaria-like symptom. Evans blue visualization and optical observation of dotted swelling confirmed that the vascular permeability mediated the phenomenon. Hairless mice exhibited a more pronounced temperature decrease than their haired counterparts when exposed to histamine, platelet-activating factor, compound 48/80, and IgE with FITC-ovalbumin. The application of an α1 adrenergic receptor agonist to the skin attenuated the topical urticaria-like symptom. Conclusion: Our experiments revealed four findings. The first is that ASDIS mirrors urticaria-like symptoms resulting from increased vascular permeability, akin to human urticaria. The second finding is that the development of dotted symptoms involves an IgE-induced, yet unidentified, mechanism not triggered by histamine or compound 48/80 alone. The third finding highlights the heightened susceptibility of hairless mice to ASDIS induction. The fourth finding demonstrates that the inhibition of ASDIS by the topical application of an α1 adrenergic receptor agonist hints at a potential anti-urticarial application for this vasoconstrictor. Further elucidation of these unidentified IgE-dependent mechanisms and the specific generation of dotted symptoms by IgE-immune complexes could provide novel insights into allergic response processes and therapeutic interventions for these conditions. Plain Language Summary: Urticaria, a skin allergy causing itchy bumps, is often treated with antihistamines. However, these treatments may not always be effective. To address this, researchers aim to develop new anti-allergic drugs. While several methods to induce urticaria-like symptoms in experimental animals have been explored, few are currently available. In a previous study, we successfully induced anaphylaxis-dependent spotted distribution of immune complex in skin (ASDIS) in hairless mice, resembling human urticaria. In this study, we investigated and clarified several key aspects using this method. First, we found that ASDIS in mice is mediated by an increase in vascular permeability, similar to human urticaria. This discovery supports the idea of considering mouse ASDIS as a model for human urticaria. Second, we demonstrated that ASDIS could be induced by IgE but not by histamine, a key mediator of vascular permeability increase. The unique plasma leakage induced by IgE was identified as a contributing factor to the urticaria-like symptoms in ASDIS. Third, a comparison of ASDIS and histamine-induced anaphylaxis in haired and hairless mice revealed that hairless mice were more sensitive. This suggests that hairless mice possess a unique mechanism induced by IgE, partially associated with histamine function. Finally, the inhibition of ASDIS by applying an adrenaline α1 receptor agonist to the skin strongly suggested the potential of this drug as an anti-allergic ointment. In summary, our mouse ASDIS model can be utilized as an urticaria model. Further detailed clarification of the underlying mechanisms of ASDIS induction will expedite the development of new anti-allergic drugs. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a common chronic inflammatory skin disease involving complex immune dysregulation, including the OX40-OX40L pathway. Rocatinlimab and amlitelimab, monoclonal antibodies targeting OX40 and OX40L, respectively, have shown promise in treating moderate-to-severe AD. Both therapies have demonstrated significant efficacy in reducing disease severity, with favorable safety profiles and no serious treatment-related adverse events. Both treatments outperformed placebo across key clinical endpoints, including skin clearance and symptom reduction, highlighting their potential as effective AD therapies. Although initial results are promising, further research is needed to evaluate the long-term effects, durability of response, and safety of these treatments. These findings support the therapeutic potential of targeting the OX40-OX40L pathway in AD, providing new options for patients with moderate-to-severe disease, with ongoing trials necessary to confirm their sustained benefits. [ABSTRACT FROM AUTHOR]

We studied the level of immunocompetent blood cells, phagocytic activity of neutrophils, concentrations of cytokines, circulating immune complexes and levels of cyclic nucleotides (cAMP and cGMP) in blood serum with different levels of soluble adhesion molecules NCAM (CD56) and immunoglobulin Fc-receptor III (CD16) in nearly healthy people living in the Arctic territory. An increase in serum concentrations of sCD56 and sCD16 in nearly healthy adults of working age was found to be associated with an increase in the level of cells bearing the corresponding membrane receptors. An increase in sCD56 concentrations was accompanied by an increase in the level of NK (CD3-CD16+CD56+) and T-NK cells (CD3+CD16+CD56+), whereas an increase in sCD16 level, by a decrease in the counts of lymphocytes circulating in blood, mainly, T-helper cells (CD3+CD4+), cytotoxic T-lymphocytes (CD3+CD8+), and activated T-lymphocytes (CD3+HLADR+). Elevated sCD56 concentrations were associated with the increased levels of pro-inflammatory IL-1β, IL-6, TNF-α, and anti-inflammatory IL-10 cells. Concentrations of circulating immune complexes rose with increasing sCD16 and sCD56 levels. The signal conduction activity grew with increasing concentrations of CD16+ and CD56+ leukocytes of peripheral blood and sCD56+ leukocytes, and the shedding of these molecules occurred against the background of cAMP and cGMP decreasing concentrations. [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]

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Common cold viruses are leading triggers of asthma attacks, causing nearly two million hospitalizations per year and productivity losses approaching $40B. They also increase susceptibility to bacterial infections driving antibiotic use. Post-market clinical studies have questioned the efficacy of most over the counter (OTC) cough and cold ingredients against placebo in treating various symptoms. To our knowledge, only aspirin significantly improved overall illness severity compared to placebo and that was by about 25–30%. In this double-blind randomized placebo-controlled trial involving 157 participants, we sought to determine whether a throat spray containing a mucosal immune complex (MIC) (comprised of lysozyme, lactoferrin, and aloe) along with anti-inflammatory salicylates can increase the hereto reported efficacy of aspirin at reducing common cold symptoms. Previously published reports showed that the MIC can protect respiratory epithelia and lower inflammatory cytokines. Salicylates are naturally occurring plant compounds found in many common foods as well as wintergreen oil and are chemically similar precursors to aspirin (acetyl salicylate). Participants self-administered treatments (throat sprays every hour and tablets every four hours) and completed surveys at home over two days. Treatments included MIC spray mixed with 6 mg aspirin + placebo tablet (Treatment 1), MIC spray mixed with 6 mg wintergreen oil+ placebo tablet (Treatment 2), MIC spray mixed with 6mg wintergreen oil+ 325 mg aspirin tablet (Treatment 3). Participants included adult volunteers ages 21–66 (average 44), 54% female, 46% male, 46% African American, 8% Asian, 39% Caucasian, and 7% Hispanic, having common cold symptoms lasting less than two days. The main outcome measures included Sore Throat Pain Intensity (STPIS) 0–100 at 36 hours (primary endpoint) and Modified Jackson Score (MJS), a combination of eight cold symptoms (secondary endpoint). Both primary and secondary endpoints were met. Sore throat pain as measured by STPIS decreased 68–75% by 36 hours depending on treatment. Other symptoms such as nasal discharge, congestion, sneezing, cough, sore throat, and malaise as measured by MJS decreased 38–68% depending on treatment. In repeated measure within group analysis observing the same participants over multiple time points; the mean change of STPIS values and their percentage change from baseline to 36 hours were as follows: Placebo (-7.84 [95% CI -14.20 to -1.47];(-14%)), Treatment 1 (-42.41 [95% CI -48.30 to -36.52];(-75%)), Treatment 2 (-38.60 [95% CI -46.64 to -31.56];(-68%)), and Treatment 3 (-44.19 [95% CI -52.11 to -36.27];(-79%)). In repeated measure within group analysis all treatments significantly reduced cold symptom severity (MJS) from Days 1–2. Results were as follows: Treatment 1 (-2.26 [95% CI -3.04 to -1.47] (-38%)), Treatment 2 (-3.81 [95% CI -4.82 to -2.80];(-53%)), Treatment 3 (-4.49 [95% CI -5.62 to -3.57];(-69%)). As a result of this study, we conclude that supporting upper respiratory epithelia and reducing COX-mediated inflammation may be used to effectively treat common cold symptoms. Trial registration: ClinicalTrials.gov Identifier: NCT06106880 Posted 30/10/2023. [ABSTRACT FROM AUTHOR]

LN is a serious complication of systemic lupus erythematosus (SLE), affecting up to 60% of patients with SLE and may lead to end-stage renal disease (ESRD). Macrophages play multifaceted roles in the pathogenesis of LN, including clearance of immune complexes, antigen presentation, regulation of inflammation, and tissue repair. Macrophages are abundant in the glomeruli and tubulointerstitium of LN patients and are positively correlated with serum creatinine levels and the severity of renal pathology. It has been shown that the infiltration of macrophages is closely associated with several clinical indicators, such as serum creatinine and complement C3 levels, anti-dsDNA antibody titers, Austin score, interstitial fibrosis and renal tubular atrophy. Moreover, cytokines expressed by macrophages were upregulated at LN onset and downregulated after remission, suggesting that macrophages may serve as markers of LN pathogenesis and remission. Therapies targeting macrophages have been shown to alleviate LN. There are two main types of macrophages in the kidney: kidney-resident macrophages (KRMs) and monocyte-derived macrophages (MDMs). KRMs and MDMs play different pathological roles in LN, with KRMs promoting leukocyte recruitment at sites of inflammation by expressing monocyte chemokines, while MDMs may exacerbate autoimmune responses by presenting immune complex antigens. Macrophages exhibit high plasticity and can differentiate into various phenotypes in response to distinct environmental stimuli. M1 (proinflammatory) macrophages are linked to the progression of active SLE, whereas the M2 (anti-inflammatory) phenotype is observed during the remission phase of LN. The polarization of macrophages in LN can be manipulated through multiple pathways, such as the modulation of signaling cascades including TLR 2/1, S1P, ERS, metabolic reprogramming, and HMGB1. This paper provides a comprehensive overview of the role of macrophages in the progression of lupus nephritis (LN), and elucidates how these cells and their secretory products function as indicators and therapeutic targets for the disease in the context of diagnosis and treatment of LN. [ABSTRACT FROM AUTHOR]

In systemic lupus erythematosus, immune complexes deposited in the kidney vasculature represent a potent inflammatory trigger with a high potential to progress to glomerulonephritis and organ failure. These immune complexes can be recognized by multiple effector cells via complement and Fcγ receptors. The transcriptome of CD16-bearing NK cells has been documented in kidneys from patients with SLE. In this study, we show that NK cells accumulate in the kidney in response to immune complex deposition and modulate the behavior of local T cells. Depletion of NK cells transiently ameliorated disease, suggesting NK cells may play a role in lupus nephritis and other immune complex-mediated conditions. [ABSTRACT FROM AUTHOR]

Group A streptococcus (GAS) is a pathogen typically transmitted through respiratory droplets and skin contact, causing an estimated 700 million mild non-invasive infections worldwide each year. There are approximately 650 000 infections that progress to severe invasive infections, even resulting in death. Therefore, the ability to detect GAS rapidly, accurately and in real time is important. Herein, we developed a nanozyme linked multi-array gas driven sensor (NLMAGS) to point-of-care testing of GAS within 2 h. The NLMAGS demonstrated excellent performance as it combined the advantages of nanozyme techniques, immunoassay techniques, and 3D printing techniques. Platinum- and palladium-rich nanozyme particles (Au@Pt@PdNPs) were synthesized and used to label monocloning antibodies as detection probes. Magnetic beads were labeled with monocloning antibodies as capture probes to establish a double-antibody sandwich immunoassay for the detection of GAS. The sandwich immune complex can catalyze the H2O2 substrate and produce O2. GAS quantification can be achieved by measuring the distance that the O2 pushes the ink drops forward in the sensor. Under optimized conditions, the NLMAGS quantitatively detected 24 spiked samples with a limit of detection (LOD) of 62 CFU mL−1, which was 5 times lower than that of ELISA (334 CFU mL−1). A strong correlation with the conventional ELISA was found (r = 0.99, P < 0.001). In comparison, the traditional lateral flow immunoassay based on Au@Pt@PdNPs-mAb2 (Au@Pt@PdNPs-LFIA) had a LOD of 104 CFU mL−1, which was significantly higher than that of NLMAGS. The NLMAGS demonstrated excellent sensitivity to GAS. The intra- and inter-assay precisions of the sensor were below 15%. Overall, the established NLMAGS has promising potential as a rapid and quantitative method for detecting GAS and can also be used to detect various pathogens. [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]

Background: Single-cell RNA sequencing experiments commonly use 10x Genomics (10x) kits due to their high-throughput capacity and standardized protocols. Recently, Parse Biosciences (Parse) introduced an alternative technology that uses multiple in-situ barcoding rounds within standard 96-well plates. Parse enables the analysis of more cells from multiple samples in a single run without the need for additional reagents or specialized microfluidics equipment. To evaluate the performance of both platforms, we conducted a benchmark study using biological and technical replicates of mouse thymus as a complex immune tissue. Results: We found that Parse detected nearly twice the number of genes compared to 10x, with each platform detecting a distinct set of genes. The comparison of multiplexed samples generated from 10x and Parse techniques showed 10x data to have lower technical variability and more precise annotation of biological states in the thymus compared to Parse. Conclusion: Our results provide a comprehensive comparison of the suitability of both single-cell platforms for immunological studies. [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]

Background: Systemic Lupus Erythematosus (SLE) is characterized by dysregulated immune responses, with neutrophil extracellular traps (NETs) playing a significant role. NETs are recognized by autoantibodies in SLE patients, exacerbating pathology. Both excessive NET formation and impaired degradation contribute to SLE pathophysiology. Objective: To investigate the immunomodulatory effects of Dexamethasone-primed Wharton's jelly (WJ) derived MSCs CM (DW) and IFN-γ-primed WJ-MSCs-CM (IW) on NETosis and associated protein markers in SLE patients' LPS or ribonucleoprotein immune complexes (RNP ICs) induced neutrophils and in pristane induced lupus (PIL) model. And to elucidate the mechanism involved therein. Methods: We investigated the immunomodulatory effects of DW and IW on NETosis in SLE. Utilizing ex vivo and in vivo models, we assessed the impact of preconditioned media on NET formation and associated protein markers neutrophil elastase (NE), citrullinated histone (citH3), myeloperoxidase (MPO), cytoplasmic and mitochondrial ROS production. We also examined the involvement of key immunomodulatory factors present in DW and IW, including prostaglandin E2 (PGE2), indoleamine 2,3-dioxygenase (IDO), and transforming growth factor-beta (TGF-β). Results: Preconditioned media effectively suppressed NETosis and reduced ROS generation in SLE neutrophils, indicating their immunomodulatory potential. Inhibition studies implicated IDO and PGE2 in mediating this effect. Combined treatment with DW or IW together with hydroxychloroquine (HCQ) demonstrated superior efficacy over HCQ alone, a standard SLE medication. In PIL mouse model, DW and IW treatments reduced NETosis, ROS generation, as evidenced by decreased NET-associated protein expression in vital organs. Conclusion: Our study highlights the multifaceted impact of IW and DW on NETosis, ROS dynamics, and lupus severity in SLE. These findings underscore the potential of preconditioned media for the development of targeted, personalized approaches for SLE treatment. [ABSTRACT FROM AUTHOR]

Background: Sjögren's disease (SjD) is an autoimmune disease marked by lymphocytic infiltration of salivary and lacrimal glands, leading to glandular dysfunction, where CD4-positive helper T (Th) cells and their cytokines are crucial in the pathogenesis. Recent studies have demonstrated that Toll-like receptors (TLRs), particularly those recognizing immune complexes containing DNA and RNA, contribute to Th cell activation in various autoimmune diseases. This study explores the expression and function of these TLRs in SjD. Methods: DNA microarray analysis of salivary gland tissue from six SjD patients and real-time PCR (n = 32) was used to identify overexpressed TLRs. Single-cell RNA sequencing (scRNA-seq) was performed using tissue lesions and integrated with published scRNA-seq data from tissues and peripheral blood mononuclear cells to examine gene expression in macrophages and monocytes. Finally, multi-color immunofluorescence staining was conducted to confirm TLR8 expression and function in SjD lesions (n = 19). Results: DNA microarray analysis revealed the up-regulation of TLR8 , along with other TLRs and innate immune response genes in SjD. Real-time PCR showed significant up-regulation of TLR7 and TLR8. TLR8 up-regulated in both analyses. In scRNA-seq analysis, the TLR8 -expressing cluster comprised macrophages and monocytes, which also produced T cell activation genes like CD86. TLR8-positive macrophages infiltrated inflammatory sites and frequently expressed CD86 in quantitative imaging approaches. Conclusions: These results suggest that infiltrating monocytes and macrophages may produce cytokines and chemokines through TLR8 stimulation, potentially enhancing B7 molecule expression, promoting the adaptive immune response, and contributing to SjD pathogenesis. [ABSTRACT FROM AUTHOR]

Despite the unique advantages of IgG3 over other IgG subclasses, such as mediating enhanced effector functions and increased flexibility in antigen binding due to a long hinge region, the therapeutic potential of IgG3 remains largely unexplored. This may be attributed to difficulties in recombinant expression and the reduced plasma half-life of most IgG3 allotypes. Here, we report plant expression of two SARS-CoV-2 neutralizing monoclonal antibodies (mAbs) that exhibit high (P5C3) and low (H4) antigen binding. P5C3 and H4-IgG1 mAbs were subclass-switched to IgG3 formats, designed for efficient production and increased PK values, carrying three allotypic variations, referred to as -WT, -H, and -KVH. A total of eight mAbs were produced in glycoengineered plants that synthesize fucose-free complex N-glycans with great homogeneity. Antigen, IgG-FcγR immune complex and complement binding studies demonstrated similar activities of all mAbs. In accordance, P5C3 Abs showed minor alterations in SARS-CoV-2 neutralization (NT) and antibody-dependent cell-mediated virus inhibition (ADCVI). Clear functional differences were observed between H4 variants with superior ADCVI and NT potencies of H4 IgG3 H. Our comparative study demonstrates the production of an IgG3 variant carrying an Fc domain with equivalent or enhanced functions compared to IgG3-WT, but with the stability and PK values ​​of IgG1. Our data also demonstrate that both allotypic variability and antibody specificity are important for fine-tuning of activities, an important information for the development of future therapeutics. [ABSTRACT FROM AUTHOR]

Neutrophils (PMNs) are key players of innate immune responses through the release of cytoplasmic granule content and the formation of neutrophil extracellular traps (NETs). RNASET2 is an acidic ribonuclease, recently proposed as an alarmin signal associated with inflammatory responses. Here we show that, along the neutrophil maturation cascade, RNASET2 is expressed in segmented and mature PMNs. In human PMNs, RNASET2 colocalized with primary and tertiary granules and was found to be associated with NETs following PMA or Nigericin stimulation. Similarly, activation of PMNs by soluble immune complexes, a hallmark of several autoimmune diseases, also induced RNASET2-associated NETs. Genome-wide association studies recently identified RNASET2 among a cluster of genes associated with increased susceptibility to develop autoimmune diseases, including rheumatoid arthritis (RA). RNASET2 was found expressed by PMNs and macrophages infiltrating inflamed joints in a murine model of RA (K/BxN Serum-Transfer-Induced Arthritis, STIA), by immunostaining. Similar results were found in synovial biopsies of RA patients with active disease. In addition, we demonstrate that RNASET2 circulating levels correlated with the onset and the severity of disease in two mouse models of inflammatory arthritis, STIA and CIA (Collagen-Induced Arthritis) and in serum of RA patients. These results show that PMNs are an important source of RNASET2 and that its circulating levels are associated with RA development suggesting a role for RNASET2 in the pathogenesis of immune-mediated diseases. [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]

BACKGROUND: Membranous nephropathy (MN), also known as membranous glomerulonephritis, is a leading cause of adult nephrotic syndrome. The main pathological features encompass the deposition of immune complexes within the glomerular basement membrane epithelial cells, thickening of the basement membrane, and fusion of the foot process. OBJECTIVE: This study aims to investigate the role of the immune and inflammatory modulator miR-223 in the immunosuppressive and anti-inflammatory effects of cyclophosphamide (CTX) on membranous nephropathy (MN). METHODS: miR-223 mimetics or inhibitors was used to regulate miR-223 levels. LPS induced inflammatory cell model and cell polarization. CTX was used to treat Lipopolysaccharides (LPS) induced inflammatory response and polarization. Cationic bovine serum albumin (c-BSA) induced BALB/c mouse MN model, while CTX was used to treat c-BSA induced MN. RESULTS: The miR-223 level in LPS induced inflammatory model cells was lower than that in control cells. The levels of inflammatory factors in LPS + miR-223 mimetics and CTX + miR-223i cells were lower than those in LPS and miR-223i cells. The protein levels of LPS + miR-223 mimic, CTX + miR-223i macrophage M2 phenotype markers Arginase-1 (Arg1), transforming growth factor β 1 (TGF- β 1), anti-inflammatory factors interleukin-4 (IL4) and interleukin-13 (IL13) were significantly higher than those of LPS and miR-223i. The effect of CTX was confirmed in a BALB/c mouse MN model induced by cationic bovine serum albumin (c-BSA). CONCLUSION: CTX upregulates the expression of miR-223, promotes polarization of M2 macrophages, alleviates the inflammatory response and renal injury of MN. [ABSTRACT FROM AUTHOR]

ABSTRACT: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by damage to organs and cells, initially mediated by tissue-binding autoantibodies and immune complexes. Lymphomas have been frequently reported, but the association of SLE with acute leukemia is rare and likely coincidental. We report a case of a 40-year-old female admitted for an etiological diagnosis of fever and dyspnea with peripheral edema. She had a history of SLE diagnosed 2 years prior and had been on immunosuppressive therapy since then. Hematological investigations showed leukocytosis, anemia, and thrombocytopenia. Further diagnostic testing could not be done as she passed away 3 days after acute leukemia was diagnosed. This case highlights the challenges of diagnosing hematological malignancies in immunosuppressed SLE patients where symptoms may be obscured. [ABSTRACT FROM AUTHOR]

The overexpression of interleukin-17A (IL-17A) is closely associated with the pathogenesis of autoimmune diseases and cancer, rendering precise identification of IL-17A level critical for disease diagnosis and prognosis monitoring. In this study, CsPbBr3 nanoclusters (NCs) were embedded in C16H14Br2O6Pb2 organometallic compound (Pb-MA MOC) via a hot injection approach. Through this way, the issue of CsPbBr3 NCs susceptible to decomposition in water was solved, and the photocurrent intensity that is generated by CsPbBr3 was significantly enhanced. A highly sensitive photoelectrochemical (PEC) sensor for detecting IL-17A in human serum was developed using CsPbBr3/Pb-MA as the photoactive material. The electrode was initially modified with CsPbBr3/Pb-MA. Then, antibody-modified Fe3O4 magnetic nanoparticles (MNs) with target analyte IL-17A captured, and IL-17A antibody-modified Au@CuNi diatomic catalyst (DAC) formed sandwich immune complex structure on the electrode. The existence of CuNi DAC led to a substantial reduction in photoelectric signal intensity due to oxidation of ascorbic acid in the supporting electrolyte. The photocurrent intensity exhibited linear correlation with IL-17A concentration within the range 15-750 pg/mL, and achieving an impressive detection limit of 1 pg/mL. Moreover, the sensor was successfully applied to the determination of IL-17A in human serum, suggesting its potential clinical applications. [ABSTRACT FROM AUTHOR]

Immune complexes (ICs) between antigens and antibodies are naturally immunogenic by virtue of enhanced uptake by antigen-presenting cells. Recombinant ICs have been generated by molecular engineering, which opens the path for scale-up manufacturing and consistent formulation. Several iterations of recombinant ICs have been generated and tested as vaccine candidates for immunogenicity and protection against infectious diseases. Plant biotechnology has emerged as an alternative and cheaper production system to mammalian cell platforms, raising the prospect for scalable, low-cost production of recombinant IC-based vaccines. Recombinant IC technology is now poised to enter the clinical phase of testing and development. New vaccine technologies are needed to combat many existing infections and prepare better for those that may emerge in the future. The conventional technologies that rely on protein-based vaccines are still severely restricted by the sparsity and poor accessibility of available adjuvants. One possible solution to this problem is to enhance antigen immunogenicity by a more natural means by complexing it with antibodies in the form of immune complexes (ICs). However, natural ICs are impractical as vaccines, and significant research efforts have been made to generate them in recombinant form, with plant bioengineering being at the forefront of these efforts. Here, we describe the challenges and progress made to date to make recombinant IC vaccines applicable to humans. [ABSTRACT FROM AUTHOR]

IgA nephropathy (IgAN) is the most common type of primary glomerulonephritis worldwide; however, the underlying mechanisms of this disease are not fully understood. This review explores several animal models that provide insights into IgAN pathogenesis, emphasizing the roles of aberrant IgA1 glycosylation and immune complex formation. It discusses spontaneous, immunization, and transgenic models illustrating unique aspects of IgAN development and progression. The animal models, represented by the grouped ddY (gddY) mouse, have provided guidance concerning the multi-hit pathogenesis of IgAN. In this paradigm, genetic and environmental factors, including the dysregulation of the mucosal immune system, lead to increased levels of aberrantly glycosylated IgA, nephritogenic immune complex formation, and subsequent glomerular deposition, followed by mesangial cell activation and injury. Additionally, this review considers the implications of clinical trials targeting molecular pathways influenced by IgAN (e.g., a proliferation-inducing ligand [APRIL]). Collectively, these animal models have expanded the understanding of IgAN pathogenesis while facilitating the development of therapeutic strategies that are currently under clinical investigation. Animal-model-based studies have the potential to facilitate the development of targeted therapies with reduced side effects for IgAN patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Cytokines are substances important in the regulation of the immune system. The cytokine interleukin-6 (IL-6) is important for the normal function of the immune system and also plays a pathogenic role in multiple diseases such as chronic inflammation, autoimmunity cancer, sepsis, and cardiovascular disease. A new immunoregulatory mechanism is described. Proteolytic degradation of serum albumin generates immunoregulatory neo-structures, one of which has the capacity to induce IL-6, Il-6-inducing factor, IL-6IF. The serum concentration of this factor is significantly increased in advanced stages of colon cancer and is associated with cancer-specific survival of the patients. IL-6IF is immunogenic, resulting in the production of autoantibodies with the capacity to inhibit IL-6IF-induced IL-6 synthesis. The specificity of these autoantibodies, using the single B-cell technique, enables the production of human monoclonal antibodies, which therapeutically can be used to specifically inhibit pathological IL-6 production, leaving IL-6 for the normal function of the immune system intact. Background: Interleukin-6 is dysregulated in multiple pathological conditions, e.g., cancer and inflammatory diseases. Aim: To investigate new mechanisms for the regulation of pathological IL-6 production. Methods: PBMCs (peripheral blood mononuclear cells) stimulated by cancer serum factors or specific peptides produce interleukin-6 (IL-6). Immunoregulatory albumin neo-structures and peptides were identified with 2D gel electrophoresis and MALDI-TOF-MS (matrix-assisted laser desorption/ionization time-of-flight mass spectrometry) analyses. Il-6 and albumin neo-structures were determined by ELISA (enzyme-linked immunosorbent assay). Results: Conformational changes in normal serum albumin by proteolytic degradation generates an IL-6-inducing neo-structure, IL-6-inducing factor (IL-6IF). This neo-structure is immunogenic which results in the production of autoantibodies. IL-6 production induced by IL-6IF and cancer patient sera is inhibited by specific antibodies. The serum concentration of IL-6IF is significantly higher in advanced cancer stages, and its presence is significantly correlated with the survival of the patients. Conclusions: A new mechanism for the induction IL-6 synthesis is presented. Based on this mechanism, the pathological IL-6 production related to enhanced proteolytic activity can be diagnosed and selectively inhibited by specific antibodies. Such antibodies were identified and purified. Thus, the neo-structure, inducing pathological IL-6 production, associated with a reduced survival of cancer patients, can be selectively removed by the therapeutic administration of antibodies leaving the function of IL-6 needed for the normal activity of the immune system intact. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a complex multi-organ autoimmune disease marked by the production of autoantibodies against nuclear structures, formation of immune complexes, and chronic inflammation triggered by their tissular deposition. SLE is characterized by alternating periods of relapse and remission and each flare has the potential to cause new organ damage related to either the disease process or the medication toxicity. Despite remarkable progress across its multiple domains, SLE is still an area with many unmet needs, calling for innovative and practical solutions. The efforts of the drug development programme in lupus have led to considerable growth in the last decade, owing to the approval of belimumab, anifrolumab, and voclosporin. The increasing understanding of the pathogenesis of the disease has enabled the exploration of novel therapeutic strategies. New discoveries in the intricate cytokine kaleidoscope of lupus have made the concept of targeted therapy an attractive and promising research focus. JAK inhibitors are oral targeted therapies approved for a wide variety of diseases across the Rheumatology, Gastroenterology, Dermatology, and Haematology fields. Multiple JAKis are currently being investigated in SLE. This paper aims to summarize existing data coming from both clinical trials and case reports regarding the use of JAK inhibitors in SLE. [ABSTRACT FROM AUTHOR]

Japanese spotted fever is an emerging rickettsiosis caused by Rickettsia japonica and is characterized by high fever, rash, and eschar formation. Other symptoms are often vague and nonspecific and include headaches, nausea, vomiting, and myalgia. We present a case of a 46-year-old woman with Japanese spotted fever, complicated by transient bilateral sensorineural hearing loss and presenting cutaneous IgM/IgG immune complex vasculitis. The patient was admitted with a history of several days of high fever, generalized skin erythema, and hearing impairment. Laboratory findings revealed thrombocytopenia and elevated liver enzyme and C-reactive protein levels. Pure-tone audiometry revealed bilateral sensorineural hearing loss, and a skin biopsy revealed leukocytoclastic vasculitis with deposition of C3 and IgM on the vessel walls. Under the tentative diagnosis of rickettsiosis, scrub typhus, or Japanese spotted fever, the patient was treated with minocycline, and her symptoms improved within approximately 10 days. A definitive diagnosis was made on the basis of a serological test showing increased antibody levels against Rickettsia japonica. Japanese spotted fever can cause transient sensorineural hearing loss, a rare complication that presents with cutaneous IgM/IgG immune complex vasculitis. [ABSTRACT FROM AUTHOR]

Les vascularites sont définies par une inflammation des endothéliums vasculaires, elles sont rares et de diagnostic difficile. Cet article n'évoquera que les vascularites primitives non infectieuses, comme cela est fait dans la nomenclature internationale de Chapel Hill dont la deuxième version impose le remplacement des dénominations éponymes des maladies par des expressions en lien avec leur mécanisme physiopathologique ou leurs caractéristiques histologiques. Cette nomenclature des vascularites prend en compte la taille des vaisseaux et les mécanismes physiopathologiques qui, dans l'atteinte des petits et moyens vaisseaux, sont des mécanismes immunologiques. Il s'agit d'une part des vascularites à dépôts de complexes immuns, comprenant les vascularites cryoglobulinémiques, les vascularites à dépôts d'IgA, les vascularites urticariennes hypocomplémentémiques (maladie de McDuffie) et les vascularites à Acs anti-membrane basale glomérulaire (maladie de Goodpasture), et d'autre part des vascularites à Acs anticytoplasme des polynucléaires neutrophiles (ANCA pour Anti-Neutrophil Cytoplasmic Antibodies), qui comprennent la granulomatose avec polyangéite (ex-syndrome de Wegener), la granulomatose à éosinophiles avec polyangéite (ex-syndrome de Churg et Strauss) et la polyangéite microscopique. Dans cet article, les mécanismes physiopathologiques de ces vascularites immunologiques et les outils biologiques seront développés, permettant aux biologistes de participer au diagnostic de ces maladies rares et fréquemment sévères. Vasculitis is defined by inflammation of the vascular endothelium, it is rare and difficult to diagnose. This article will only discuss primary non-infectious vasculitis, as is done in the international nomenclature of Chapel Hill, the second version of which aimed to replace the eponymous names of diseases with expressions related to their pathophysiological mechanism or their histological characteristics. This nomenclature of vasculitis takes into account the size of the vessels and the pathophysiological mechanisms which, in the involvement of small and medium-sized vessels, are immunological mechanisms. These are first, vasculitis with immune complex deposition, including cryoglobulinemic vasculitis, vasculitis with IgA deposits, hypocomplementemic urticarial vasculitis (McDuffie's disease) and vasculitis with anti-glomerular basement membrane Abs (Goodpasture's disease), and second, vasculitis with anti-neutrophil cytoplasmic Abs (ANCA), including granulomatosis with polyangiitis (formerly Wegener's syndrome), eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss syndrome) and microscopic polyangiitis. In this article, the pathophysiological mechanisms of these immunological vasculitides and the biological diagnostic tools will be developed, allowing biologists to participate in the diagnosis of these rare and frequently severe diseases. [ABSTRACT FROM AUTHOR]

Postmyocardial syndrome (Dressler syndrome) is a form of secondary pericarditis with or without pericardial effusion resulting from myocardial damage. Dressler syndrome is not a common disease, but it should be suspected in patients with pathognomonic symptoms after a myocardial infarction (MI). The article presents a clinical case of a 65-year-old man, a smoker who is overweight, with a history of hypertension, MI with ST segment elevation, stenting of the envelope branch of the left coronary artery, thrombospiration. According to coronary angiography, the patient revealed a multivessel lesion of the coronary arteries. Two weeks after stenting, the patient’s condition worsened: shortness of breath, pain in the left half of the chest, fever appeared. During the examination at the outpatient stage, bilateral hydrothorax and hydropericardium were revealed. He was hospitalized, was treated with ibuprofen 600 mg 3 times a day for 7 days, with a positive effect. Ten days after discharge, the patient noted an increase in shortness of breath, an increase in body temperature, a recurrence of dull chest pain. He was hospitalized at the Vorokhobov City Clinical Hospital No. 67, where bilateral hydrothorax, hydropericardium, pneumonitis were detected during the examination. the diagnosis "Postmyocardial syndrome, recurrent course" was established. Hospital treatment was carried out with colchicine, methylprednisolone, acetylsalicylic acid, ticagrelor, losartan, bisoprolol, amlodipine, spironolactone. Against the background of the therapy, the condition improved, the patient began to notice an increase in exercise tolerance, a gradual regression of dull chest pain on the left, body temperature decrease to subfebrile figures. Positive dynamics of laboratory parameters was noted.

Metastatic breast cancer (MBC) is generally considered an incurable disease and even though new treatments are available, the median survival is approximately three years. The introduction of immune therapies for MBC highlights the importance of the immune system in cancer progression and treatment. CD163+ anti-inflammatory myeloid cells, including tumor associated macrophages (TAMs), are known to be of relevance in early breast cancer but their role in MBC is not yet established. Here we determine the levels of CD163+ immune cells in 139 patients with newly diagnosed MBC by using Immunohistochemistry (IHC) and gene expression analyses (GEX). We aim to determine changes and distribution of CD163+ immune cells during tumor progression from primary tumors (PT) to lymph node metastases (LNM) and distant metastases (DM). In addition, we evaluate associations between CD163+ immune cells, clinicopathological factors and disease outcome (progression-free and overall survival; PFS and OS, respectively). Despite similar distribution, high levels of CD163+ immune cells in the tumor nest of PT, but not in LNM or DM, associated with adverse prognostic features including higher grade and molecular subtype, as well as with shorter PFS and OS, however this observation was not significant after adjusted multivariate analyses. Finally, high levels of CD163+ immune cells in PT, as well as GEX in PT and synchronous LNM associated with shorter OS from the initial diagnosis. These results indicate that evaluating the levels of CD163+ immune cells may identify MBC patients with a worse prognosis. Unraveling the role of CD163+ immune cells in the complex immune responses in MBC is highly relevant for improving future immune therapies. [ABSTRACT FROM AUTHOR]

Glomerulonephritis (GN) is a group of heterogeneous immune-mediated kidney diseases that causes inflammation within the glomerulus. Autoantibodies (auto-Abs) are considered to be central effectors in the pathogenesis of several types of GN. Immunoglobulin A nephropathy (IgAN) is the most common GN worldwide and is characterized by the deposition of IgA in the glomerular mesangium of the kidneys, which is thought to be mediated by immune complexes containing non-specific IgA. However, we recently reported that IgA auto-Abs specific to mesangial cells (anti-mesangium IgA) were found in the sera of gddY mice, a spontaneous IgAN model, and patients with IgAN. We identified two autoantigens (β2-spectrin and CBX3) that are selectively expressed on the mesangial cell surface and targeted by anti-mesangial IgA. Our findings redefined IgAN as a tissue-specific autoimmune disease. Regarding the mechanisms of production of anti-mesangium IgA, studies using gddY mice have revealed that the production of anti-CBX3 IgA is induced by particular strains of commensal bacteria in the oral cavity, possibly through their molecular mimicry to CBX3. Here, we discuss a new concept of IgAN pathogenesis from the perspective of this disease as autoimmune GN caused by tissue-specific auto-Abs. [ABSTRACT FROM AUTHOR]

Introduction: Erythema nodosum (EN) is the most common form of panniculitis. EN can be idiopathic or secondary to an underlying systemic disease, infection, drug use, or tumor. CD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL) is a relapsed and refractory lymphoma, and further understanding of its pathology is required. We report a case of newly diagnosed CD5+ DLBCL with concomitant EN. Within the scope of our search, there were no reports of CD5+ DLBCL complicated with EN. Case Presentation: A 79-year-old woman experienced swelling, warmth, redness, and pain in both legs and a mass lesion on the right side of the back at almost the same time. The respective lesions were diagnosed as EN and CD5+ DLBCL by biopsy. With chemotherapy, the lymphoma and EN improved in parallel courses. The patient has completed scheduled chemotherapy, and there has been no recurrence of swelling in the legs or mass on the right side of the back. Discussion: The lymphoma and EN developed simultaneously and followed a parallel clinical course after chemotherapy, suggesting that EN was a paraneoplastic symptom of CD5+ DLBCL. Recognizing and treating underlying malignancies in patients presenting with EN is crucial.

Complement activation through antibody-antigen complexes is crucial in various pathophysiological processes and utilized in immunotherapies to eliminate infectious agents, regulatory immune cells, or cancer cells. The tertiary structures of the four IgG antibody subclasses are largely comparable, with the most prominent difference being the hinge regions connecting the Fab and Fc domains, providing them with unique structural flexibility. Complement recruitment and activation depend strongly on IgG subclass, which is commonly rationalized by differences in hinge flexibility and the respective affinities for C1, the first component of the classical complement pathway. However, a unifying mechanism of how these different IgG subclass properties combine to modulate C1 activation has not yet been proposed. We here demonstrate that complement activation is determined by their varying ability to form IgG oligomers on antigenic surfaces large enough to multivalently bind and activate C1. We directly visualize the resulting IgG oligomer structures and characterize their distribution by means of high-speed atomic force microscopy, quantify their complement recruitment efficiency from quartz crystal microbalance experiments, and characterize their ability to activate complement on tumor cell lines as well as in vesicle-based complement lysis assays. We present a mechanistic model of the multivalent interactions that govern C1 binding to IgG oligomers and use it to extract kinetic rate constants from real-time interaction data from which we further calculate equilibrium dissociation constants. Together, we provide a comprehensive view on the parameters that govern complement activation by the different IgG subclasses, which may inform the design of future antibody therapies. [ABSTRACT FROM AUTHOR]

Chronic antibody-mediated rejection in kidney transplantation is a common cause of graft loss in the late post-transplant period. In this process, the role of the classical complement activation pathway is crucial due to the formation of immune complexes between donor-specific antibodies (DSAs) and donor antigens and the attachment of the C1q complement fragment. This study aimed to determine the levels of circulating C1q immunocomplexes (CIC-C1q) and complement activation (CH50), in sensitized kidney transplant recipients (KTRs). In this cross-sectional study we used serum samples from KTRs with de novo or preformed DSAs (n = 14), KTRs without DSAs (n = 28), and 22 subjects with no history of chronic kidney disease (controls). C1q immunocomplexes and CH50 concentration in serum were measured with the enzyme immunoassay (EIA) kit MicroVue CIC-C1q (Quidel, Athens, OH, USA) and EIA kit MicroVue CH50 (Quidel, OH, USA), respectively. Higher concentrations of CIC-C1q was observed in KTRs with DSAs in comparison with controls and with KTRs with no DSAs (6.8 ± 2.7 and 4.8 ± 1.9 vs. 5.0 ± 1.2 μg Eq/mL, respectively, p < 0.01). We found no difference in CIC-C1q between KTRs with no DSAs and controls. CIC-C1q levels were positively correlated with DSA titer. CH50 levels were decreased in KTRs with DSAs in comparison with controls and KTRs with no DSAs (39 ± 15 vs. 68 ± 40 and 71 ± 34 U Eq/mL, respectively, p < 0.01). There was no difference in CH50 between DSA-negative KTRs and controls. Kidney transplant recipients with DSAs had increased serum levels of C1q immunocomplexes and increased classical pathway complement activation. [ABSTRACT FROM AUTHOR]

Hepatitis E virus (HEV) infection, one of the most common forms of hepatitis worldwide, is often associated with extrahepatic, particularly renal, manifestations. However, the underlying mechanisms are incompletely understood. Here, we report the development of a de novo immune complex-mediated glomerulonephritis (GN) in a kidney transplant recipient with chronic hepatitis E. Applying immunostaining, electron microscopy, and mass spectrometry after laser-capture microdissection, we show that GN develops in parallel with increasing glomerular deposition of a non-infectious, genome-free and non-glycosylated HEV open reading frame 2 (ORF2) capsid protein. No productive HEV infection of kidney cells is detected. Patients with acute hepatitis E display similar but less pronounced deposits. Our results establish a link between the production of HEV ORF2 protein and the development of hepatitis E-associated GN in the immunocompromised state. The formation of glomerular IgG-HEV ORF2 immune complexes discovered here provides a potential mechanistic explanation of how the hepatotropic HEV can cause variable renal manifestations. These findings directly provide a tool for etiology-based diagnosis of hepatitis E-associated GN as a distinct entity and suggest therapeutic implications. It's poorly understood how renal manifestations develop in HEV infection in patients. Here, the authors observe glomerular accumulation of the viral protein ORF2 in complex with host IgG in immunocompromised patients with chronic or acute HEV infection who developed glomerulonephritis. [ABSTRACT FROM AUTHOR]

Identifying antibodies that neutralize specific antigens is crucial for developing effective immunotherapies, but this task remains challenging for many target antigens. The rise of deep learning-based computational approaches presents a promising avenue to address this challenge. Here, we assess the performance of a deep learning approach through two benchmark tests aimed at predicting antibodies for the receptor-binding domain of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. Three different strategies for constructing input sequence alignments are employed for predicting structural models of antigen-antibody complexes. In our initial testing set, which comprises known experimental structures, these strategies collectively yield a significant top-ranked prediction for 61% of cases and a success rate of 47%. Notably, one strategy that utilizes the sequences of known antigen binders outperforms the other two, achieving a precision of 90% in a subsequent test set of ~1,000 antibodies, balanced between true and control antibodies for the antigen, albeit with a lower recall of 25%. Our results underscore the potential of integrating deep learning methods with single B cell sequencing techniques to enhance the prediction accuracy of antigen-antibody interactions. [ABSTRACT FROM AUTHOR]

Unlike most other picornaviruses, foot-and-mouth disease (FMD) intact virions (146S) dissociate easily into small pentameric subunits (12S). This causes a dramatically decreased immunogenicity by a mechanism that remains elusive. Here, we present the high-resolution structures of 12S (3.2 Å) and its immune complex of a single-domain antibody (VHH) targeting the particle interior (3.2 Å), as well as two 146S-specific VHHs complexed to distinct sites on the 146S capsid surface (3.6 Å and 2.9 Å). The antigenic landscape of 146S is depicted using 13 known FMD virus-antibody complexes. Comparison of the immunogenicity of 146S and 12S in pigs, focusing on the resulting antigenic sites and incorporating structural analysis, reveals that dissociation of 146S leads to structural alteration and destruction of multiple epitopes, resulting in significant differences in antibody profiles/lineages induced by 12S and 146S. Furthermore, 146S generates higher synergistic neutralizing antibody titers compared to 12S, whereas both particles induce similar total FMD virus specific antibody titers. This study can guide the structure-based rational design of novel multivalent and broad-spectrum recombinant vaccines for protection against FMD. Foot-and-mouth disease vaccine efficacy is reduced when full virion 146S dissociates into pentameric 12S subunit. Here, the authors elucidate the molecular basis of this compromised immunogenicity by comparing antigenicity, humoral immunogenicity and structures of 146S and 12S particles. [ABSTRACT FROM AUTHOR]