Serum IgA antibody level against porcine epidemic diarrhea virus is a potential pre-evaluation indicator of immunization effects in sows during parturition under field conditions.

BACKGROUND: Porcine Epidemic Diarrhea (PED) is a highly contagious disease caused by Porcine Epidemic Diarrhea Virus (PEDV), resulting in a mortality rate of suckling piglets as high as 100%. Vaccination is the primary strategy for controlling PEDV infection, however, there is currently a lack of reliable methods for assessing the efficacy of vaccination. This study aimed to analyze serum and colostrum samples from 75 parturient sows with a specific vaccination strategy to measure levels of IgG, IgA, and neutralizing antibodies (nAbs) against PEDV, and to investigate the correlation between serum and colostrum antibody levels, as well as to identify potential biomarkers that can be used to evaluate immunization effects under field conditions. RESULTS: The findings of correlation analysis between antibody levels of IgA, IgG, and nAbs in serum or colostrum samples revealed that IgG demonstrated the most robust correlation with nAbs exhibiting a correlation coefficient of 0.64 in serum samples. Conversely, IgA exhibited the highest correlation with nAbs, with a correlation coefficient of 0.47 in colostrum samples. Additionally, the correlation analysis of antibody levels between serum and colostrum samples indicated that serum IgA displayed the strongest correlation with colostrum IgA, with a coefficient of 0.63, indicating that serum IgA may serve as a viable alternative indicator for evaluating IgA levels in colostrum samples. To further evaluate the suitability of serum IgA as a substitute marker for colostrum IgA, levels of IgA antibodies in serum samples from sows were examined both pre- and post-parturition. The findings indicated that serum IgA levels were initially low prior to the initial immunization, experienced a notable rise 21 days after immunization, and maintained a significant elevation compared to pre-immunization levels from 21 days pre-parturition to 14 days postpartum, spanning a total of 35 days. CONCLUSIONS: Serum anti-PEDV IgA antibody levels may serve as a valuable predictor for immunization effects, allowing for the assessment of colostrum IgA antibody levels up to 21 days in advance. This insight could enable veterinarians to timely adjust or optimize immunization strategies prior to parturition, thereby ensuring adequate passive immunity is conferred to piglets through colostral transfer postpartum.

Rapid differentiation of MOGAD and MS after a single optic neuritis.

BACKGROUND: Optic neuritis (ON) is a common manifestation of multiple sclerosis (MS) and myelin-oligodendrocyte-glycoprotein IgG-associated disease (MOGAD). This study evaluated the applicability of optical coherence tomography (OCT) for differentiating between both diseases in two independent cohorts. METHODS: One hundred sixty two patients from seven sites underwent standard OCT and high-contrast visual acuity (HCVA) testing at least 6 months after first ON. Of these, 100 patients (32 MOGAD, 68 MS) comprised the primary investigational cohort, while 62 patients (31 MOGAD, 31 MS) formed a validation cohort. A composite score distinguishing between MOGAD and MS was developed using multivariate logistic regression. RESULTS: Bilateral simultaneous ON occurred more frequently in MOGAD compared to MS (46.9 vs. 11.8%, p < 0.001). OCT revealed more peripapillary retinal nerve fiber layer (pRNFL) atrophy in all segments in MOGAD compared to predominantly temporal pRNFL atrophy in MS (p < 0.001). HCVA was better preserved in MS (p = 0.007). pRNFL thickness in all except for temporal segments was suitable for differentiating MOGAD and MS. Simultaneous bilateral ON and critical atrophy in nasal (< 58.5 µm) and temporal superior (< 105.5 µm) segments were included into the composite score as three independent predictors for MOGAD. The composite score distinguished MOGAD from MS with 75% sensitivity and 90% specificity in the investigational cohort, and 68% sensitivity and 87% specificity in the validation cohort. CONCLUSION: Following a single ON-episode, MOGAD exhibits more pronounced global pRNFL atrophy and lower visual acuity after ON compared to MS. The introduced OCT-based composite score enabled differentiation between the two entities across both cohorts.

Clinicopathological characteristics of neural epidermal growth factor-like 1 protein-associated membranous glomerulonephritis.

Neural epidermal growth factor-like 1 protein (NELL1) is the second most common target antigen in membranous glomerulonephritis (MGN). However, data regarding the clinicopathological characteristics of NELL1-associated MGN are limited owing to its low prevalence. This study examined the prevalence and clinicopathological characteristics of NELL1-associated MGN in a Japanese cohort. Additionally, we compared the clinicopathological features of NELL1-positive MGN, phospholipase A2 receptor 1 (PLA2R1)-positive MGN, and MGN negative for all three antigens (NELL1, PLA2R1, and thrombospondin type-1 domain-containing 7A). Among 257 consecutive patients pathologically diagnosed with MGN at two centers in Japan, 24 (9.3%) were immunohistochemically positive for NELL1. Clinically, patients with NELL1-positive MGN were significantly older (p < 0.001) and had a higher frequency of bucillamine use (vs PLA2R1-positive MGN, p < 0.01). Histologically, NELL1-positive MGN exhibited significantly lower detection of spikes and crater formation (p < 0.001), higher prevalence of segmental spike distribution (vs PLA2R1-positive MGN: p < 0.001), and higher prevalence of stage I cases on electron microscopy (p < 0.01). There were no significant differences in the prognoses among the three groups. The characteristic histological feature of segmental distribution in NELL1-positive MGN may be related to bucillamine use and the early phase of the disease. Further investigations with larger numbers of patients may offer further insight into the prognosis of patients with NELL1-positive MGN.

Prognostic Value of Plasma Immunoglobulin G N-Glycome Traits in Pulmonary Arterial Hypertension.

BACKGROUND: B-type natriuretic peptide or N-terminal pro-B-type natriuretic peptide is the only blood biomarker in established risk calculators for pulmonary arterial hypertension (PAH). Profiling systemic-originated plasma immunoglobulin G (IgG) N-glycans, which reflect different components of the pathophysiology of PAH including immune dysregulation and inflammation, may improve PAH risk assessment. OBJECTIVES: This study sought to identify plasma IgG N-glycan biomarkers that predict survival in PAH to improve risk assessment. METHODS: This cohort study examined 622 PAH patients from 2 national centers (Beijing [discovery] cohort: n = 273; Shanghai [validation] cohort: n = 349). Plasma IgG N-glycomes were profiled by a robust mass spectrometry-based method. Prognostic IgG N-glycan traits were identified and validated in the 2 cohorts using Cox regression and Kaplan-Meier survival analyses. The added value of IgG N-glycan traits to previously established risk models was assessed using Harrell C-indexes and survival analysis. RESULTS: Plasma IgG fucosylation was found to predict survival independent of age and sex in the discovery cohort (HR: 0.377; 95% CI: 0.168-0.845; P = 0.018) with confirmation in the validation cohort (HR: 0.445; 95% CI: 0.264-0.751; P = 0.005). IgG fucosylation remained a robust predictor of mortality in combined cohorts after full adjustment and in subgroup analyses. Integrating IgG fucosylation into previously established risk models improved their predictive capacity, marked by an overall elevation in Harrell C-indexes. IgG fucosylation was useful in further stratifying the intermediate-risk patients classified by a previously established model. CONCLUSIONS: Plasma IgG fucosylation informs PAH prognosis independent of established factors, offering additional value for predicting PAH outcomes.

Effect of Polysaccharides Isolated from Saussurea salicifolia (L.) DC on Th2-Dependent Immune Response.

The effect of polysaccharides isolated from the aboveground parts of Saussurea salicifolia (L.) DC on Th2 type immune response reactions was studied. Administration of water-soluble polysaccharides presented by arabino-galacturonans (weight average molecular weight 158.49 kDa) to mice against the background of experimental Th2 immunity reduced the severity of anaphylactic and local immediate type hypersensitivity reactions. It also suppressed the production of ovalbumin-specific IgE and IgG1 and increased the stability of mast cell membranes. The studied polysaccharide complex increased IFNγ secretion and inhibited IL-4 synthesis. These findings suggest that these polysaccharides may be considered as potential anti-allergic agents that suppress the development of allergy in its early stages.

New insights into predictors of autoimmune pancreatitis relapse after steroid therapy.

OBJECTIVES: While autoimmune pancreatitis (AIP) responds well to steroid therapy, the high relapse rate in type 1 AIP remains a critical problem. The present study examined predictors of relapse of type 1 AIP following steroid therapy. MATERIALS AND METHODS: Nine factors potentially predictive of relapse were analyzed in 81 AIP patients receiving steroid therapy with follow-up ≥ 12 months. The rate of serum IgG4 decrease following steroid therapy was calculated by dividing the difference between serum IgG4 values before and at two months after the start of steroid by the IgG4 value before steroid. RESULTS: A relapse occurred in 11 patients (13.5%) during a median of 38 months. Multivariate analysis revealed that the presence of IgG4-related retroperitoneal fibrosis (HR: 5.59; 95% CI: 1.42-22.0; p = 0.014) and the low rate of serum IgG4 decrease after steroid therapy (HR: 0.048; 95% CI: 0.005-0.46; p = 0.008) were significant, independent predictors of AIP relapse. The cut-off value based on receiver operating characteristic curve data for the rate of serum IgG4 decrease before and at two months after steroid therapy distinguishing patients with and without a relapse was 0.65. Using this cut-off value, the area under the curve, sensitivity, and specificity were found to be 0.63, 0.73, and 0.60, respectively. CONCLUSION: The low rate of serum IgG4 decrease after the start of steroid therapy and the presence of IgG4-related retroperitoneal fibrosis were predictive of type 1 AIP relapse. Cautious, gradual tapering of steroid dosage and longer maintenance therapy are recommended for patients with these factors.

Development of a bioluminescent immunoassay based on Fc-specific conjugated antibody-nanoluciferase immunoreagents for determining aflatoxin B1.

Aflatoxin B1 (AFB1) is a potent carcinogen, and is among the most hazardous mycotoxins in agricultural products. Therefore, the development of sensitive and convenient detection methods for AFB1 is significant for food safety against mycotoxins. Herein, a bioluminescent enzyme immunoassay (BLEIA) was developed for ultrasensitive detection of AFB1, based on the novel Fc-specific antibody-nanoluciferase (Ab-Nluc) conjugates which were fabricated using an IgG-binding protein-assisted photo-conjugation strategy. In indirect competitive immunoassay format, the proposed BLEIA exhibited the detection limit of 0.0232 ng mL-1, which was 37.4-fold lower than that obtained using the classical enzyme-linked immunosorbent assay (ELISA) based on Ab-horseradish peroxidase (Ab-HRP) chemical conjugates (0.868 ng mL-1). Meanwhile, the BLEIA exhibited high accuracy and precision. Thus, the proposed Fc-specific Ab-Nluc conjugates-based BLEIA provides an ultrasensitive and reliable method for detecting toxins and has potential for use in food safety monitoring.

Phospholipase A2 receptor-negative membranous nephropathy presenting as a rare renal manifestation of IgG4-related disease.

IgG4-related disease is a fibroinflammatory condition characterized by dense lymphoplasmacytic infiltrates rich in IgG4-positive plasma cells affecting multiple organs. Though the most common renal manifestation of IgG4-related disease is tubulointerstitial nephritis, it can rarely present as secondary membranous nephropathy. We present a case of a 75-year-old male with phospholipase A2 receptor-negative membranous nephropathy as an atypical manifestation of IgG4-related disease. The patient presented with nephrotic syndrome and was found to have elevated serum IgG4 levels and IgG4-positive plasma cells in the kidney biopsy. He was successfully treated with corticosteroids and rituximab, resulting in significant improvement in proteinuria and normalization of IgG4 levels. This case highlights the importance of considering IgG4-related disease in patients with phospholipase A2 receptor-negative membranous nephropathy, especially in those with a history of other organ involvement. Early recognition and treatment of IgG4-related disease are crucial to prevent progressive kidney damage and improve patient outcomes.

Clinical and Immunological Features of Bronchial Asthma Comorbid Chronic Urticaria: A Retrospective Study.

INTRODUCTION: Asthma and chronic urticaria (CU) are two high prevalent diseases and often coexist. The underlying relationship and potential immunological mechanism between the two diseases are still unclear. The objective of this study was to investigate the clinical and immunological feature of asthma comorbid with CU. METHODS: A retrospective study was conducted. Fifty patients with asthma comorbid CU, 50 patients with asthma, and 50 patients with CU alone were included. Age and sex of the patients enrolled were matched. Data of demographic characteristics, clinical manifestations including disease severity (frequency of symptoms, age of onset, disease duration, symptom score, complication with allergic rhinitis) as well as serum immunological index including total IgE (tIgE), allergen-specific IgE (sIgE), and food-specific IgG4 (FS-IgG4), were collected and analyzed. RESULTS: No significant differences in the frequency of symptoms, age of onset, and disease duration were found among the three groups. The score of asthma control test (ACT) in patients with asthma comorbid CU was significantly lower than that of asthma (p = 0.005); however, compared with patients with CU, the 7-day urticaria activity score (UAS7) of patients with asthma comorbid CU did not show obvious differences. Immunological index showed that the positive rates of tIgE, house dust mite (HDM)-sIgE, and FS-IgG4 were different among the three groups (p < 0.05). Patients with asthma comorbid CU had the highest rate of positive tIgE, moderate and severe positive sIgE to HDM. Egg-specific IgG4 (egg-sIgG4) had the highest positive rate in all groups. Patients of asthma comorbid CU obtained the highest rate of severe positive of egg-sIgG4. CONCLUSION: Our results demonstrated that patients with asthma comorbid CU have lower control level of asthma symptoms, higher tIgE and HDM-sIgE level, and highest rate of severe positive egg-sIgG4. These results indicate that comorbidity of CU in asthma obviously increases the severity of allergens.

Subcutaneous efgartigimod PH20 in generalized myasthenia gravis: A phase 3 randomized noninferiority study (ADAPT-SC) and interim analyses of a long-term open-label extension study (ADAPT-SC+).

ADAPT-SC (NCT04735432) was designed to evaluate noninferiority of subcutaneous (SC) efgartigimod PH20 to intravenous (IV) efgartigimod in participants with generalized myasthenia gravis (gMG). ADAPT-SC+ (NCT04818671) is an open-label extension study designed to assess long-term safety, tolerability, and efficacy of efgartigimod PH20 SC. Adult participants in ADAPT-SC were randomly assigned to receive a treatment cycle of 4 once-weekly administrations of efgartigimod PH20 SC 1000 â€‹mg or efgartigimod IV 10 â€‹mg/kg, followed by 7 weeks of follow-up. Primary endpoint was percentage change from baseline in total immunoglobulin G (IgG) level at week 4 (1 week after the fourth administration). Secondary efficacy endpoints assessed number and percentage of Myasthenia Gravis Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) responders and mean change from baseline in total score for each measure. The primary endpoint was met, demonstrating noninferiority in total IgG reduction between efgartigimod PH20 SC 1000 â€‹mg and efgartigimod IV 10 â€‹mg/kg. Clinically meaningful improvements were seen as early as 1 week following the first administration in both treatment arms, with maximal improvements at week 4. Continued treatment cycles of efgartigimod PH20 SC in ADAPT-SC+ have demonstrated long-term safety and consistent improvements in MG-ADL total score. Findings from ADAPT-SC and ADAPT-SC+ demonstrate similar safety and efficacy as observed in the placebo-controlled ADAPT study. Collectively, these findings support noninferiority between efgartigimod PH20 SC 1000 â€‹mg and efgartigimod IV 10 â€‹mg/kg, as well as long-term safety, tolerability, and efficacy of efgartigimod PH20 SC for treatment of a broad population of patients with gMG.

Effects of Corticosteroid Treatment on Olfactory Dysfunction in LATY136F Knock-In Mice.

OBJECTIVE: Immunoglobulin G4-related disease (IgG4-RD) is a systemic inflammatory condition affecting multiple organs, including the pancreas, salivary glands, lungs, kidneys, skin, and lymph nodes. Clinically, it is characterized by elevated serum IgG and IgG4 levels and tissue infiltration by IgG4-positive plasma cells, lymphocytes, fibrosis, and phlebitis obliterans. IgG4-RD is linked to increased Th2-dominant cytokines, contributing to eosinophilia, elevated serum IgG4, and fibrosis. A notable feature is its good response to corticosteroid therapy. To investigate the effects of corticosteroid treatment on olfactory dysfunction in LATY136F knock-in mice, which exhibited increased production of Th2-type IgG1 (the murine homolog of human IgG4) and developed multiorgan tissue lesions similar to those observed in IgG4-RD patients. METHODS: LATY136F knock-in mice (n=24) were divided into groups that received prednisolone or saline at different ages. Olfactory function was assessed using a behavioral test with cycloheximide. Histological and immunohistochemical analyses were performed to evaluate the olfactory epithelium thickness as well as the presence of mature and immature olfactory neurons. RESULTS: Corticosteroid-treated mice exhibited significantly improved olfactory function compared to the controls. Histological analysis revealed a significant increase in olfactory epithelium thickness and mature (olfactory marker protein-positive) and immature (growth-associated protein 43-positive) olfactory neurons in the treated groups compared with the control group. CONCLUSION: Corticosteroid treatment effectively improved olfactory dysfunction and promoted olfactory epithelium regeneration in LATY136F knock-in mice, suggesting the potential therapeutic benefits of corticosteroid treatment for patients with IgG4-RD experiencing olfactory dysfunction. However, further research on topical nasal steroid therapy in untreated patients is warranted. The results support further investigation into topical nasal steroid therapies for treating olfactory dysfunction in untreated patients, potentially influencing clinical practice and patient management strategies for IgG4-RD globally.

SARS-CoV-2 spike protein antibody titers after the fourth dose of BNT162b2 vaccine among Japanese patients undergoing hemodialysis: a single-center study.

Patients undergoing hemodialysis are particularly vulnerable to severe outcomes of SARS-CoV-2 infection, with mortality rates higher than that of the general population. Vaccination reduces the risk of adverse outcomes, with booster doses being particularly beneficial. However, limited data are available on the effectiveness of subsequent vaccinations or their effect on increasing antibody levels. This single-center study aimed to investigate changes in SARS-CoV-2 IgG antibody titers following the fourth vaccination among 28 patients undergoing hemodialysis. Blood tests were conducted at various intervals post-vaccination, with a focus on identifying factors associated with antibody levels. The IgG antibody levels rapidly increased by Day 7 post-vaccination, with a median time to peak of 11 days. Antibody titers tended to be higher in male patients than in female patients. This study sheds light on the immune response to the fourth vaccination in patients undergoing hemodialysis. As this study included a small sample size, with a short observation period, further research is warranted to comprehensively understand the effectiveness of vaccination and the benefits of additional doses of vaccine.

Levels of Natural Antibodies Before and After Immunoglobulin Replacement Treatment Affect the Clinical Phenotype in Common Variable Immunodeficiency.

Natural antibodies (NAbs) occurring in individuals without prior exposure to specific antigens, provide direct first barrier protection against pathogens, and exert immunoregulation thus actively contributing to the maintenance of immune homeostasis, controlling inflammatory processes and preventing autoimmunity. Common variable immunodeficiency (CVID) is a heterogeneous group of disorders characterized by a compromised immune function that brings into focus the role of NAbs. Our aim was to explore whether NAb levels could serve as potential key indicators in CVID for monitoring disease progression and predicting outcomes. In this study, we analyzed a Hellenic cohort of 56 patients with CVID (31 newly diagnosed and 25 under immunoglobulin replacement therapy-IgRT) and 33 healthy controls, for total Ig levels and serum IgM and IgG NAb levels against five informative target-antigens of NAbs, namely, actin, DNA, carbonic anhydrase, F(ab΄)2 fragments of human IgG and TriNitroPhenyl. In addition, follow-up pre- and post- IgRT samples were analyzed in ten (10) patients of our cohort. Results showed that Ig-treated patients exhibited significantly lower IgM NAb levels than untreated patients and healthy controls against all panel antigens. In the follow-up samples, pre-treatment IgM NAb levels negatively correlated with total serum IgM. This imbalance was only partially restored after IgRT, with a significant decrease in IgM NAb levels observed in nine out of ten patients. Moreover, post-treatment patients with recurrent infections presented significantly lower IgM NAb levels, a reduction also observed in patients with bronchiectasis independently of treatment status. On the contrary, post-treatment patients with enteropathy had significantly higher IgM NAb levels against all panel antigens, an increase also noted in patients with autoimmune diseases. Regarding IgG NAbs, replacement therapy restored levels to those of healthy controls. In conclusion, impaired NAb levels are found in CVID patients, particularly related to certain phenotypes. Moreover, the significant decrease in IgM NAb levels after IgRT suggests a potential association with disease course and complications. The results suggest that administration of human IgM NAbs may be an effective combinatorial treatment in selected patients. Further research is needed to understand the functional roles of NAbs in CVID and its complex clinical phenotypes.

The immunological pathogenesis of IgG4-related disease categorized by clinical characteristics.

IgG4-related disease (IgG4-RD) is an immune disorder characterized by organ enlargement and fibrosis leading to functional impairment. Key immune cell subsets contributing to the pathogenesis of IgG4-RD include T follicular helper 2 cells (Tfh2), Tfh1, CX3CR1 + cytotoxic T cells (CX3CR1 + CTLs), Tregs and IgG4 + B cells. Tfh2 and Tregs are commonly involved in inducing IgG4 class-switching in this disease. Importantly, IgG4-RD can be classified into four clinical phenotypes based on the distribution of affected organs, with each phenotype showing different dominant immune cell subsets involved in its pathogenesis. Specifically, the clinical phenotype of retroperitoneal fibrosis/aortitis is characterized by CX3CR1 + CTLs as the dominant key immune cell subset, while Mikulicz disease with systemic involvement is dominated by Tfh2. In addition to classification based on organ distribution, IgG4-RD can also be categorized into phenotypes associated with malignancy or allergy. The malignancy phenotype is characterized by an increase in CXCR5 + CD2-double negative T cells compared to the allergy phenotype, along with a decrease in naive CD8 + T cells. Moreover, several autoantigens have been identified, and the presence of autoimmune phenotype has been revealed. Due to the pathogenicity of IgG1-type autoantibodies, Tfh1 may be important inducing IgG1 class-switching by IFNγ in autoimmune phenotype. In IgG4-RD with hypocomplementemia, activation of the complement pathway is thought to be induced by IgG1 or IgG2 antibodies, suggesting the involvement of Tfh1 in the disease pathogenesis. Therefore, elucidating the immunological features specific to each clinical characteristic is believed to lead to a deeper understanding of the pathogenesis of IgG4-RD and the discovery of novel therapeutic targets. This review provides an overview of the immunological mechanisms common to IgG4-RD as well as those specific to each clinical characteristic.

A rare disease with many faces: A multicenter registry of IgG4-related disease in children.

OBJECTIVES: We aimed to report the characteristics of pediatric IgG4-related disease (IgG4-RD) through a multicentre registry, to assess disease clusters, and to evaluate the performances of the 2019 American College of Rheumatology and European League Against Rheumatism (ACR/EULAR) classification criteria and the 2020 revised comprehensive diagnostic (RCD) criteria in this cohort. METHODS: Data of IgG4-RD patients in 13 pediatric rheumatology centers were recorded to a web-based registration system. The diagnosis of IgG4-RD was made according to the 2011 comprehensive diagnostic criteria. RESULTS: Thirty-five children (19 females and 16 males) with IgG4-RD were enrolled. The median age at diagnosis was 13.3 (25p-75p; 9.9-15.2) years. The most common organ involvement was the eye (n = 21, 60%), followed by lymph nodes (n = 12, 34.3%), musculoskeletal system (n = 12, 34.3%), and neurological system (n = 9, 25.7%). We identified three clusters in our study cohort: those with eye involvement (n = 11, 31.4%), those with eye involvement and neurological findings (n = 15, 42.9%), and those with pancreato-hepatobiliary disease and lymph node involvement (n = 9, 25.7%). Serum IgG4 levels were high in 19 out of 28 patients (67.8%). All patients except one received corticosteroid treatment, and azathioprine was the most preferred drug as a steroid-sparing agent. The sensitivities of the 2019 ACR/EULAR classification criteria and the 2020 RCD criteria were 5.7% and 88.5%, respectively. CONCLUSION: IgG4-RD has a wide variety of clinical manifestations, however in children the most common presentation was orbital involvement. The 2020 RCD criteria had a better performance whereas the 2019 ACR/EULAR classification criteria performed poorly in pediatric patients.

IL-33/ST2 enhances MMP-12 expression by macrophages to mediate inflammatory and immune response in IgG4-Related Ophthalmic Disease.

IgG4-Related Ophthalmic Disease (IgG4-ROD) is a chronic autoimmune-mediated fibrotic disease that predominantly affects the lacrimal glands, often leading to loss of function in the involved tissues or organs. Recent studies have demonstrated that MMP-12 is highly expressed in IgG4-ROD and plays a significant role in regulating immune responses. In this study, we reviewed nine patients diagnosed with IgG4-ROD based on clinical manifestations and histological analysis, and we investigated the expression of IL-33/ST2 and MMP-12 in IgG4-ROD lacrimal gland tissues using IHC. We found that IL-33 interacts with its specific receptor ST2, both of which are significantly overexpressed in IgG4-ROD tissues. Additionally, we successfully constructed a mouse model by introducing the LatY136F mutation into C57BL/6 mice to mimic IgG4-ROD lacrimal gland involvement, which helped elucidate the mechanisms involved in the induction of MMP-12. Furthermore, immunofluorescence staining confirmed that most MMP-12+ cells were derived from M2 macrophages, and an ELISA assay demonstrated that IL-33 upregulates MMP-12 in IgG4-ROD. Collectively, these data suggest that the IL-33/ST2/MMP-12 signaling pathway is activated in IgG4-ROD, with IL-33/ST2 potentially promoting M2 macrophage polarization and activation to produce MMP-12, which may serve as a novel therapeutic target for IgG4-ROD.

IgG-immunoadsorptions and eculizumab combination in STEC-hemolytic and uremic syndrome pediatric patients with neurological involvement.

BACKGROUND: Neurological complications pose a significant threat in pediatric hemolytic and uremic syndrome (HUS) resulting from infections with Shiga toxin-producing Escherichia coli (STEC), with no established treatment. The involvement of complement activation in the pathogenesis of STEC-HUS is acknowledged, and eculizumab (ECZ), a terminal complement blocker, has been documented in several pediatric series with inconsistent results. Antibody-mediated mechanisms have also been suggested, with IgG-immunoadsorption (IgIA) showing promise in adults with neurological complications. We aimed to assess the benefit of combining IgIA with ECZ in pediatric patients with neurological STEC-HUS compared to patients treated with ECZ alone or supportive care. METHODS: Multicenter retrospective study conducted on pediatric patients (< 18 years) with neurological STEC-HUS treated with IgIA + ECZ or ECZ alone from 2010 to 2020 in France. A historical cohort treated with supportive care served as controls. Primary outcome included survival and neurological evaluation at 1-year follow-up (dichotomized as normal vs. abnormal). RESULTS: A total of 42 children were included: 18 treated with IgIA + ECZ, 24 with ECZ alone, and 27 with supportive care. Although there was no significant difference in survival between groups, three deaths occurred in the control group in the acute phase, while none was reported in both the IgIA + ECZ and ECZ alone groups, despite presenting with more severe neurological symptoms for IgIA + ECZ patients. No significant association was found between treatment group and 1-year neurological evaluation after adjustment for age, sex, and initial neurological presentation. CONCLUSIONS: Systematic association of IgIA + ECZ is not supported for all neurological STEC-HUS pediatric patients; potential rescue therapy for severe cases warrants consideration.

Microbe-associated molecular patterns derived from fungi and bacteria promote IgG4 antibody production in patients with type 1 autoimmune pancreatitis.

Enhanced IgG4 antibody (Ab) response is a prominent feature of type 1 autoimmune pancreatitis (AIP). Innate immune responses associated with IgG4 Ab production are poorly defined. We have previously reported that peripheral blood mononuclear cells (PBMCs) isolated from patients with type 1 AIP produce large amounts of IgG4 Abs upon stimulation with bacterial cell wall components. In addition, we showed that activation of plasmacytoid dendritic cells producing interferon (IFN)-α, interleukin (IL)-33, and B cell-activating factor (BAFF) upon sensing intestinal bacteria mediates the development of experimental AIP. In this study, we attempted to clarify the role of innate immunity against fungi in inducing enhanced IgG4 Ab responses in type 1 AIP. PBMCs isolated from healthy controls and patients with type 1 AIP were stimulated with a broad range of bacterial and fungal cell wall components. The concentrations of IgG1, IgG4, and cytokines were measured using enzyme-linked immunosorbent assays. Cell wall components derived from bacteria and fungi induced IgG1 and IgG4 Ab production in patients with type 1 AIP. Various types of microbe-associated molecular pattern motifs enhanced IgG4 Ab production in patients with type 1 AIP compared with the limited motifs in healthy controls. The enhanced IgG1 and IgG4 Ab production that followed in response to bacterial and fungal cell wall components was parallel to that of IFN-α, IFN-γ, IL-10, IL-33, and BAFF. In conclusion, cell wall components derived from fungi as well as bacteria promote IgG4 Ab responses in patients with type 1 AIP.

Is There a Correlation Between Immune Thrombocytopenia and Immunoglobulin G4-Related Disease?

Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated condition causing organ swelling and fibrosis. Rarely, it coexists with primary immune thrombocytopenia (ITP), characterized by low platelet count (< 100 × 106/L) without an underlying cause. We present a case of a 56-year-old woman diagnosed with ITP in 2005, successfully treated with dexamethasone and intravenous immunoglobulins (IVIG). In 2011, she was diagnosed with IgG4-RD, type I autoimmune pancreatitis, initially treated with steroids then azathioprine with no response. ITP relapses were managed with prednisone/IVIG, rituximab, and thrombopoietin-receptor agonist therapy. Fostamatinib provided temporary relief, but platelet count dropped again in 2023. Combination therapy with small doses of prednisone and mycophenolate showed a partial response, maintaining platelet count over 50 × 106/L. Further investigation is warranted to explore any correlation between these two conditions, especially considering the patient's prolonged response to immunosuppressors.