IgA Immune Complexes Research Articles

Mucosal targeting in IgA nephropathy targeting the gut associated lymphoid tissue.

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

#1257 Complement system is overactivated in patients with IgA nephropathy after COVID-19

Abstract Background and Aims Since the coronavirus disease of 2019 (COVID-19) pandemic swept across the world, the flare of immune-mediated disease following SARS-CoV-2 infection has emerged rapidly. IgA nephropathy (IgAN), which has been confirmed as a complement mediated autoimmune disease, is also one of the common glomerulonephritis associated with COVID-19. Here, we aim to investigate the clinical and immunological characteristics of patients with IgAN after COVID-19. Method From December 2022 to April 2023, 33 patients with renal biopsy-proven IgAN (Group CoV) at Beijing Anzhen hospital who had experienced COVID-19 before renal biopsy were enrolled. Meanwhile, 44 patients with IgAN (Group non-CoV) diagnosed from December 2018 to April 2019 (the same period in the previous year, with no COVID-19) were enrolled as control. Plasma FHR-5, MBL, C5a, soluble C5b-9, serum Gd-IgA1 and IgA immune complex were detected by enzyme-linked immunosorbent assay. Glomerular staining for FHR-5, C3c, MAC and Gd-IgA1 were detected by immunofluorescence. SARS-CoV-2 nucleocapsid was detected by immunohistochemistry. Clinicopathological and immunological features between the two groups were analyzed. Results The median time between onset of COVID-19 symptoms and the time of renal biopsy was 12 (6, 18) weeks, ranging from 1 to 26 weeks. SARS-CoV-2 nucleocapsid antigen expression in the renal tubular epithelial cells were observed in 11/33 (33.3%) patients. Compared with Group non-CoV, the level of eGFR was significantly lower in Group CoV[67.30 (52.94, 96.43) ml/min per 1.73 m2 vs. 101.04 (74.35, 120.98) ml/min per 1.73 m2, p = 0.010]. Histologically, compared with Group non-CoV, Group CoV presented with more percentages of segmental glomerulosclerosis/adhesion (p = 0.003) and less percentages of mesangial hypercellularity (p = 0.017). The level of plasma level of C5a [16.45 (10.48, 22.07) ng/ml vs. 3.68 (2.70, 4.47) ng/ml], soluble C5b-9 [614.43 (481.66, 770.02) ng/ml vs. 358.08 (304.83, 471.77) ng/ml], FHR5 [4.01 (3.51, 4.48) ug/ml vs. 2.73 (2.25, 3.21) ug/ml]were all significantly higher in Group CoV compared with Group non-CoV, respectively (p < 0.001). Although the plasma level of MBL showed no difference in Group CoV and Group non-CoV, the proportion of high levels of MBL in Group CoV was higher than in Group non-CoV (p = 0.025). Compared with Group non-CoV, the intensity of glomerular MAC deposition was much stronger in Group CoV. There were no significant differences in serum levels of IgA, Gd-IgA1, IgA immune complex between two Groups. However, a greater intensity of Gd-IgA1 deposition in glomerular mesangial and capillary areas has been exhibited in Group CoV than those in Group non-CoV (p = 0.005). Conclusion For IgAN after COVID-19, mucosal immune responses to SARS-CoV-2 infection may result in the overactivation of systemic and renal local complement system, which is the first hit, and increased glomerular deposition of Gd-IgA1 is the second hit. We think that these two hits may lead to renal dysfunction and promote renal progression in IgAN patients. It is crucial to emphasize the necessity for long term follow-up in these patients of IgAN after COVID-19. Additionally, we propose that inhibitors targeting the mediators of complement activation might be a promising therapy for these IgAN patients after SARS-CoV-2 infection.

#2043 Telitacicept in patients with IgA nephropathy

Abstract Background and Aims IgA nephropathy (IgAN) is typified by the renal deposition of IgA immune complexes. Advancements in understanding the pathogenesis of this disease have paved the way for innovative therapeutic approaches. Telitacicept is a fusion protein composed of transmembrane activator and calcium-modulating cyclophilin ligand interactor and fragment crystallizable portion of immunoglobulin G (IgG), which neutralizes the B lymphocyte stimulator and a proliferation-inducing ligand. We presented our single-center experience of treating IgAN with Telitacicept. Method Six patients with IgAN who received Telitacicept at the First affiliated hospital of Xi'an Jiaotong university between January 2023 and July 2023 were included in this retrospective study. All the patients had proteinuria ≥ 1.0 g/d despite optimal supportive therapy and received subcutaneous telitacicept 160 mg weekly. Clinical and laboratory parameters were evaluated before and after telitacicept treatment. Results Of all patients, there were 4 men and mean age was 35.2 ± 7.9 years. Table 1 shows baseline demographic characteristics of these patients. Before telitacicept administration, the mean serum creatinine was 133.2 ± 40.6 umol/L, median protein excretion was 2.23 (IQR, 2.05–3.54) g/d, and MAP was 97.9 ± 17.5 mmHg. After a median follow-up of 151 ± 91 days after telitacicept therapy, the mean proteinuria reduction percentage was 51.1% from baseline. The eGFR remained stable over time. The detailed laboratory parameters were shown in Table 2. No adverse events were observed during the follow-up. Conclusion Telitacicept treatment led to a clinically meaningful reduction in proteinuria in patients with IgAN. Larger prospective studies are needed to confirm these findings.

#2111 Prediction of ESRD in IgA nephropathy using IgA: C3 ratio at diagnosis. 10 year cohort

Abstract Background and Aims IgA Nephropathy is the commonest glomerular pathology with a wide range of outcomes depending on the severity of the circulating serological pathophysiology and on the resulting inflammatory response in the kidney. Prediction of kidney loss, which results in renal failure in 20-40% of cases -versus very benign disease, has largely used traditional clinical parameters such as proteinuria, hypertension and already established renal decline at the point of diagnosis. There has been variable utility from biopsy severity scoring. Pathogenicity of IgA immune complexes may result from activation of complement via the alternative pathway and assessment of serum IgA and complement C3 has been suggested as a marker of pathogenicity. We examined the utility of IgA to C3 ratio in predicting outcomes in a cohort over 10 years Method We examined all the electronic records of biopsy proven IgA cases from 2010 onwards when serum electrophoresis and serum complement became been widely tested at all new renal presentations. These cases were followed to end stage kidney disease or death. A subset of diagnosed patients also had MEST-C score. Results Of 319 biopsy proven IgA cases between 2010 and 2023, 216 had serum IgA and complement studies at diagnosis, with median PCR 309 and median serum creatinine 177. 56 patients had IgA:C3 >4. Outcome of “death or renal replacement therapy” rather than the surrogate “RRT or doubling serum creatinine” was possible due to the length of follow up. Median follow up was 4.5 years, during which 101 (46%) died or reached ESRD. Among those with IgA:C3 > 4, 35 (61%) median survival 5 years, versus 67(42%) of those < 4 (median survival 10 years). Hazard ratio for IgA:C3 >4 was 1.9 (1.2-3.2) Cox Proportional Hazard show this to be independent from presenting creatinine, proteinuria, but not independent of age. A cohort of 107 biopsy proven IgA cases between 2010 and 2015 had data on CMEST score. 62 of this cohort also had IgA and complement measured. There was no correlation with CMEST score, or occurrence of crescents present on biopsy There were no differences in the treatments used following diagnosis of IgA Nephropathy. Similar proportions receiving steroid, calcineurin or mycophenolate. Conclusion IgA to C3 ratio is readily available result which powerfully predicts IgA outcome independently from pathology score and traditional clinical severity estimates. It may well become a useful indicator to target novel immune/complement therapies.

Risk factors and prognosis of pediatric silent lupus nephritis with class Ⅲ to Ⅴ

To study the risk factors and prognostic characteristics of pediatric silent lupus nephritis (SLN) with class Ⅲ to V. A retrospective study was conducted to collect clinical data from 30 children diagnosed with SLN at the Department of Pediatrics, Second Xiangya Hospital, Central South University, from May 2007 to April 2023. Based on renal pathological classification, the patients were divided into a class Ⅱ group (12 cases) and a class Ⅲ to Ⅴ group (18 cases). The risk factors for the occurrence of class Ⅲ to Ⅴ SLN were analyzed, and the prognostic characteristics were summarized. Among the 30 SLN patients, the median follow-up time was 61.50 months. There were no statistically significant differences in the proportions of patients who discontinued glucocorticoids or achieved low disease activity status, nor in the annual decline rate of estimated glomerular filtration rate (eGFR) between the class Ⅱ and class Ⅲ to V groups (P>0.05). However, three patients in the class Ⅱ group progressed to stage 1 chronic kidney disease (CKD), while eight patients in the class III to V group reached stage 1 CKD, and four patients reached stage 2 CKD. Among the 26 female SLN patients, serum complement C3 levels in the class III to V group were lower than those in the class Ⅱ group (P<0.05). Serum C3 levels in SLN patients, as well as in female SLN patients, were negatively correlated with the fluorescence intensity of IgA, IgG, and C3 immune complexes in the kidneys (P<0.05). Additionally, serum C3 levels in female SLN patients were negatively correlated with the renal pathological activity index (P<0.05). Binary logistic regression analysis indicated that being female and having low serum complement C3 levels were risk factors for the occurrence of class Ⅲ to V SLN in children (P<0.05). Class Ⅲ to V SLN is not uncommon among SLN children, and there remains a risk of long-term renal function progression. Being female and having low serum complement C3 levels are identified as risk factors for class Ⅲ to V SLN in children.

ImmunoglobulinA vasculitis

The immune-mediated small vessel vasculitis is known as Schoenlein-Henoch purpura predominantly from pediatrics and in these cases occurs more frequently after infections of the upper airways. In adults, immunoglobulinA (IgA) vasculitis often proceeds more severely und recurrently with the classical tetrad of skin manifestations in the sense of leukocytoclastic vasculitis, joint affection, gastrointestinal involvement and IgA nephritis, in contrast to the mostly mild and self-limiting course in children. The background of this systemic vasculitis with formation of IgA immune complexes is considered to be an altered glycosylation of IgA, as this causes the exposure of binding sites for autoantibodies so that an immune complex reaction can be elicited. This ultimately leads to perivascular deposition of IgA and afurther activation of neutrophils. Groundbreaking in the diagnostics is the histological detection of leukocytoclastic vasculitis and in cases of renal manifestations akidney biopsy with characteristic deposits of immune complexes, which cannot be clearly differentiated from IgA nephropathy. The treatment is aimed at the respective manifestation and is mostly based on consensus recommendations due to the lack of randomized studies. In addition to immunosuppressive medication, in the presence of achronic kidney disease general nephroprotection is becoming increasingly more important also by inhibition of sodium-glucose transporter2 (SGLT2). The type and extent of kidney involvement and also rare cardiac manifestations are the main determinants of the prognosis. Continuous medical accompaniment of those affected is necessary due to the possible progression of the disease and the risk of recurrence.

Treatment of Patients with IgA Nephropathy: Evaluation of the Safety and Efficacy of Mycophenolate Mofetil.

Immunoglobulin A nephropathy (IgAN), characterized by aberrant IgA immune complex deposition, is the most prevalent primary glomerular disease and the main cause of end-stage renal disease, causing a significant physical and psychological burden on people worldwide. Conventional therapeutic approaches, such as renin-angiotensin-aldosterone system inhibitors and corticosteroids, may not achieve sufficient effectiveness and may produce major side events in the past. The previous data in Asian populations indicated that mycophenolate mofetil (MMF) might significantly advance the development of a new therapy strategy for IgAN. The effectiveness and safety of MMF in patients with IgAN will be investigated in this study. A literature search was conducted on June 30th, 2023, by searching the following databases: PubMed and the Cochrane Library according to predefined criteria. To investigate the renoprotective benefits and safety of MMF, statistical analyses were performed using Cochrane's Review Manager Version 5.3. The meta-analysis included nine randomized controlled studies that fulfilled the inclusion criterion. In the Asian population, the results revealed a substantial difference in remission rates between the MMF group and the control group (OR: 2.53, 95% CI: 1.02, 6.30, P = 0.05). MMF can increase the rate of decrease in proteinuria in IgAN patients when compared with controls in Asians (OR: 7.34, 95% CI: 2.69, 20.08, P = 0.0001), and MMF can reduce the urinary protein in patients with IgAN in Asians (WMD: -0.61, 95% CI: -1.15, -0.08, P = 0.02). Interestingly, these studies on Asians were conducted in China. However, the differences in remission rate, rate of decrease in proteinuria, and urinary protein reduction between the MMF group and control group were not found in overall populations and in the Caucasian population. The differences in complete remission rate, partial remission rate, serum creatinine (SCr) doubling rate, rate of 50% increase in SCr, and rate of need for renal replacement treatment between the MMF group and control group were not found in Asians, Caucasians, and overall populations. The difference in the rate of side effects between the MMF group and the control group was not found. MMF protects renal function and is a safe medication for treating Chinese IgAN patients. MMF might significantly advance the development of a new therapy strategy for IgAN in the Chinese population.

The contribution of a proliferation-inducing ligand (APRIL) and other TNF superfamily members in pathogenesis and progression of IgA nephropathy.

Advances in our understanding of the pathogenesis of immunoglobulin A nephropathy (IgAN) have led to the identification of novel therapeutic targets and potential disease-specific treatments. Specifically, a proliferation-inducing ligand (APRIL) has been implicated in the pathogenesis of IgAN, mediating B-cell dysregulation and overproduction of pathogenic galactose-deficient IgA1 (Gd-IgA1). Animal and clinical studies support the involvement of APRIL in the pathogenesis and progression of IgAN. An elevated level of APRIL is found in IgAN when compared with controls, which correlates with the level of Gd-IgA1 and associates with more severe disease presentation and worse outcomes. Conversely, anti-APRIL therapy reduces pathogenic Gd-IgA1 and IgA immune complex formation and ameliorates the severity of kidney inflammation and injury. Genome-wide association studies in IgAN have identified TNFSF13 and TNFRSF13B, a cytokine ligand-receptor gene pair encoding APRIL and its receptor, respectively, as risk susceptibility loci in IgAN, further supporting the causal role of the APRIL signalling pathway in IgAN. Several novel experimental agents targeting APRIL, including atacicept, telitacicept, zigakibart and sibeprenlimab, are currently under investigation as potential therapies in IgAN. Preliminary results suggest that these agents are well-tolerated, and reduce levels of Gd-IgA1, with corresponding improvement in proteinuria. Further studies are ongoing to confirm the safety and efficacy of anti-APRIL approaches as an effective therapeutic strategy in IgAN.

IgA nephropathy.

IgA nephropathy (IgAN), the most prevalent primary glomerulonephritis worldwide, carries a considerable lifetime risk of kidney failure. Clinical manifestations of IgAN vary from asymptomatic with microscopic or intermittent macroscopic haematuria and stable kidney function to rapidly progressive glomerulonephritis. IgAN has been proposed to develop through a 'four-hit' process, commencing with overproduction and increased systemic presence of poorly O-glycosylated galactose-deficient IgA1 (Gd-IgA1), followed by recognition of Gd-IgA1 by antiglycan autoantibodies, aggregation of Gd-IgA1 and formation of polymeric IgA1 immune complexes and, lastly, deposition of these immune complexes in the glomerular mesangium, leading to kidney inflammation and scarring. IgAN can only be diagnosed by kidney biopsy. Extensive, optimized supportive care is the mainstay of therapy for patients with IgAN. For those at high risk of disease progression, the 2021 KDIGO Clinical Practice Guideline suggests considering a 6-month course of systemic corticosteroid therapy; however, the efficacy of systemic steroid treatment is under debate and serious adverse effects are common. Advances in understanding the pathophysiology of IgAN have led to clinical trials of novel targeted therapies with acceptable safety profiles, including SGLT2 inhibitors, endothelin receptor blockers, targeted-release budesonide, B cell proliferation and differentiation inhibitors, as well as blockade of complement components.

249. SARS-CoV-2 Spike Immune Complexes Induce NETosis in COVID-19

Abstract Background Disease severity in SARS-CoV-2 infection is associated with elevated levels of neutrophil extracellular traps (NETs) and antibodies. We previously demonstrated that plasma from patients with SARS-CoV-2 infection stimulates the release of NETs by healthy donor neutrophils and that this can be reversed by R406, a spleen tyrosine kinase (SYK) inhibitor. Immune complexes, stimulating through Fc receptors, induce robust NETosis through a SYK-mediated pathway. Therefore, we hypothesized that SARS-CoV-2 spike immune complexes can mediate the release of NETs from neutrophils and that this process can be reversed by R406. Methods To test this, we created spike specific immune complexes utilizing an optimized concentration of affixed spike-trimer and SARS-CoV-2 patient plasma and evaluated the ability of these complexes to stimulate NETosis from healthy neutrophils. We quantified both IgG and IgA spike specific immune complex formation by ELISA utilizing HRP conjugated secondary antibodies (Promega Glomax Plate Reader). Healthy donor neutrophils were isolated, added to wells containing the spike immune complexes with and without R406, and live cell imaging (Incucyte S3) was used to visualize and quantify NETs. Results Incubation of COVID-19 patient plasma with spike protein resulted in an average 7-fold and 9-fold increase in the formation of IgA and IgG spike specific immune complexes, respectively, compared to spike alone (Figure 1A). After stimulating healthy donor neutrophils with the spike immune complexes created from six SARS-CoV-2 patient plasma samples, we observed a mean 200% increase in the induction of NETs relative to spike alone (Figure 1B). There were positive correlations between immune complexes formation and NETs formed in cells exposed to those wells (IgA R2= 0.67, p=0.01 and IgG R2= 0.82, p=0.002). Preliminary data suggests that spike-immune complex NET formation can be reduced by R406 (n=3 COVID-19 plasma donors). Figure 1A-B A) Quantification of IgA and IgG spike immune complexes was measured through measurement of absorbance at 405 nm after exposure to ABTS for 15 minutes. Value normalized to the spike alone condition ran on each day, and data represents a fold change from that condition (Ordinary One-way ANOVA: ** indicates p &amp;lt; 0.01; *** indicates p &amp;lt; 0.001; **** indicates p &amp;lt;0.0001). B) Induction of NETs 6 hours after exposure, demonstrating percent increase in NETosis in plasma isolated from COVID-19 patients (n=6) and healthy patients (n=2) in the presence and absence of SARS-CoV-2 spike immune complexes. Area of NETs was quantified by calculating the area (µm2 ) of ecDNA, visualized by Incucyte® Cytotox Green Dye. Area of NETs at T0 was subtracted from all conditions, and the induction of NETs was calculated as percentage increase relative to NETosis induced by SARS-CoV spike alone condition run on each day (Ordinary One-way ANOVA: ** indicates p &amp;lt; 0.01; *** indicates p &amp;lt; 0.001; **** indicates p &amp;lt;0.0001). Conclusion Using our ELISA, we demonstrated that we can reliably generate spike-specific IgG and IgA immune complexes. Stimulation of healthy donor neutrophils by spike immune complexes increased NET-formation compared to spike alone providing evidence of immune complex mediated NET induction in SARS-CoV-2 infection. Disclosures All Authors: No reported disclosures

Abstract 11949: Novel First-Trimester Serum Biomarkers for Early Prediction of Preeclampsia

Background: Preeclampsia (PE) is a leading cause of maternal and perinatal mortality and morbidity worldwide, but effective early prediction remains a challenge due to the lack of reliable biomarkers. Research questions: Could potential imbalances in cytokines and autoimmune antibodies be detectable in the first trimester of pregnancy in women who later develop PE? Goals: Our study aims to discover novel biomarkers within the first trimester and construct an efficient predictive model to enhance early PE screening strategies. Methods: Based on the extensive human biobank of our large-scale assisted reproductive cohort platform, we measured the first-trimester serum levels of 48 cytokines, total immunoglobulins (Igs), anti-phosphatidylserine (aPS) antibodies, and several previously identified PE biomarkers—including placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), and activin A—in 34 women diagnosed with PE and 34 matched normotensive controls. Results: Our analysis revealed that the PE group exhibited significantly elevated first-trimester serum levels of hepatocyte growth factor (HGF), interleukin (IL)-2Rα, IL-9, RANTES, tumor necrosis factor-β (TNF-β), total IgM, and total IgG, and aPS IgG optical density (OD) value, in addition to decreased first-trimester serum levels of PlGF and total IgA and aPS-IgG immune complexes (IC) OD value compared to the control group. The combination of the top five first-trimester serum biomarkers (total IgM, total IgG, PlGF, aPS IgG, and total IgA) achieved superior predictive value [area under the curve (AUC) and 95% confidence interval (CI): 0.983 (0.952-1.000)] for PE development compared to PlGF and PlGF/sFlt-1 independently [AUC and 95% CI: 0.825 (0.726-0.924) and 0.670 (0.539-0.800), respectively]. Conclusion: We identified novel first-trimester serum biomarkers and developed an effective prediction model integrating immune-related factors and PlGF for early PE detection, which could facilitate the development of early diagnostic strategies and provide immunological insight into the further mechanistic exploration of PE.

Mucosal IgA immune complex induces immunomodulatory responses in allergic airway and intestinal TH2 disease

IgA is the most abundant immunoglobulin at the mucosal surface and although its role in regulating mucosal immunity is not fully understood, its presence is associated with protection from developing allergic disease. We sought to determine the role of IgA immune complexes for therapeutic application to mucosal allergic responses. Trinitrophenol (TNP)-specific IgA immune complexes were applied, using TNP-coupled ovalbumin (OVA), to airway and gut mucosal surfaces in systemically sensitized allergic animals to regulate allergen challenge responses. Animals were assessed for both pathologic and immune-mediated responses in the lung and gut, respectively, using established mouse models. The mucosal application of IgA immune complexes in the lung and gut with TNP-OVA regulated TH2-driven allergic response in the lung and gut, reducing TH2 cytokines and mucus (lung) as well as diarrhea and temperature loss (gut), but increasing IL-10 and the number of regulatory T cells. The IgA-OVA immune complex did not alter peanut-induced anaphylaxis, indicating antigen specificity. Using OVA-specific DO.11-green fluorescent protein IL-4 reporter mouse-derived TH2-skewed cells in a transfer model demonstrated that mucosal IgA immune complex treatment reduced TH2-cell expansion and increased the number of regulatory T cells. To address a potential mechanism of action, TGF-β and IL-10 were induced in bone marrow-derived dendritic cells when they were exposed to IgA immune complex, suggesting a regulatory phenotype induced in dendritic cells that also led to an altered primary T-cell-mediated response in invitro OVA-specific assays. These studies highlight one possible mechanism of how allergen-specific IgA may provide a regulatory signal to reduce the development of allergic responses in the lung and gut.

IgA Nephropathy: Current Treatment and New Insights

IgA Nephropathy (IgAN) is the most common cause of primary glomerulonephritis worldwide. Despite the histopathologic hallmark of mesangial IgA deposition, IgAN is a heterogenous autoimmune disease not only in terms of clinical presentation but also in long-term disease progression. The pathogenesis of the disease is complex and includes the generation of circulating IgA immune complexes with chemical and biological characteristics that favor mesangial deposition and reaction to mesangial under-glycosylated IgA1 accumulation, which leads to tissue injury with glomerulosclerosis and interstitial fibrosis. Patients with proteinuria over 1 g, hypertension, and impaired renal function at diagnosis are considered to be at high risk for disease progression and end-stage kidney disease (ESKD). Glucocorticoids have been the mainstay of treatment for these patients for years, but without long-term benefit for renal function and accompanied by several adverse events. A better understanding of the pathophysiology of IgAN in recent years has led to the development of several new therapeutic agents. In this review, we summarize the current therapeutic approach for patients with IgAN as well as all novel investigational agents.

Case Report on Henoch-Schonlein Purpura Vasculitis

Henoch-Schonlein purpura is a type III hypersensitivity leukocytoclastic small vessel vasculitis caused by the IgA-immune complex that primarily affects children and has the potential to escalate to many complications. A female patient of age 17 years came with the complaint of asymptomatic red rashes over their left lower leg since 3 weeks back. It soon involved the other leg within 3-4 days. Also Associated ankle pain. on clinical examination Pulse Rate-86/min, BP-120/80 mm/Hg, RR-20/minute, non-pitting edema and palpable purpura of bilateral lower legs and few over the thighs. skin biopsy was done, also received fresh tissue for IF, which shows 1-granular IgA along upper dermal vessels, she was given Tab. Augmentin 625mg, Tab. Colchicine 500 mcg, Mupimet ointment and other supportive measures for two days. When the patient's condition improved, discharged with medication Tab. Augmentin 625mg, Tab. pantoprazole 40mg, Mupimet ointment each for 4 days and Tab. colchicine 500mcg for 7 days with advice to review in dermatology OPD and rheumatology OPD with prior appointment after one week. Continued collaboration and knowledge-sharing within the medical community will ultimately improve patient outcomes and contribute to the advancement of care for individuals affected by this rare vasculitis disorder.

Immunoglobulin a vasculitis with testicular/epididymal involvement in children: A retrospective study of a ten-year period.

The clinical characteristics and risk factors for testicular/epididymal involvement in 73 children with immunoglobulin A vasculitis (IgAV) who were admitted to our hospital between January 2012 and November 2022 were reviewed. The demographic data, laboratory parameters, and follow-up data of the patients were compared to those of 146 males without testicular/epididymal involvement. A logistic regression analysis was performed to determine the variables associated with testicular/epididymal involvement. The prevalence of testicular/epididymal involvement among male patients with IgAV was 1.3% (73/5,556). Increased blood flow in the testes and/or epididymis on ultrasound was found in 71 patients. The remaining two patients underwent surgical exploration for loss or reduction of testicular blood flow. One patient underwent orchiectomy for intraoperative confirmation of complete right testicular infarction. Pathological findings revealed IgA immune complex deposition in the testis. Patient age (odds ratio [OR] = 0.792; 95% confidence interval [CI]: 0.682-0.919, p = 0.002), platelet count (OR = 1.011; 95% CI: 1.002-1.020, p = 0.013), and immunoglobulin M (IgM) levels (OR = 0.236; 95% CI: 0.091-0.608, p = 0.003) were strongly associated with the occurrence of testicular/epididymal involvement in IgAV. Therefore, young age, increased platelet count, and low IgM levels in patients with IgAV are potential risk factors for testicular/epididymal involvement. Doppler ultrasound can help differentiate IgAV from acute scrotum. Most patients with testicular/epididymal involvement have good prognoses, although serious complications such as testicular infarction may occur.

IgA2 immune complexes selectively promote inflammation by human CD103+ dendritic cells.

While immunoglobulin A (IgA) is well known for its neutralizing and anti-inflammatory function, it is becoming increasingly clear that IgA can also induce human inflammatory responses by various different immune cells. Yet, little is known about the relative role of induction of inflammation by the two IgA subclasses i.e. IgA1, most prominent subclass in circulation, and IgA2, most prominent subclass in the lower intestine. Here, we set out to study the inflammatory function of IgA subclasses on different human myeloid immune cell subsets, including monocytes, and in vitro differentiated macrophages and intestinal CD103+ dendritic cells (DCs). While individual stimulation with IgA immune complexes only induced limited inflammatory responses by human immune cells, both IgA subclasses strongly amplified pro-inflammatory cytokine production upon co-stimulation with Toll-like receptor (TLR) ligands such as Pam3CSK4, PGN, and LPS. Strikingly, while IgA1 induced slightly higher or similar levels of pro-inflammatory cytokines by monocytes and macrophages, respectively, IgA2 induced substantially more inflammation than IgA1 by CD103+ DCs. In addition to pro-inflammatory cytokine proteins, IgA2 also induced higher mRNA expression levels, indicating that amplification of pro-inflammatory cytokine production is at least partially regulated at the level of gene transcription. Interestingly, cytokine amplification by IgA1 was almost completely dependent on Fc alpha receptor I (FcαRI), whilst blocking this receptor only partially reduced cytokine induction by IgA2. In addition, IgA2-induced amplification of pro-inflammatory cytokines was less dependent on signaling through the kinases Syk, PI3K, and TBK1/IKKϵ. Combined, these findings indicate that IgA2 immune complexes, which are most abundantly expressed in the lower intestine, particularly promote inflammation by human CD103+ intestinal DCs. This may serve an important physiological function upon infection, by enabling inflammatory responses by this otherwise tolerogenic DC subset. Since various inflammatory disorders are characterized by disturbances in IgA subclass balance, this may also play a role in the induction or exacerbation of chronic intestinal inflammation.

Relapses or de-novo IgA nephropathy following COVID-19 vaccination; a narrative review

Immunoglobulin A (IgA) nephropathy is the most common type of glomerulonephritis worldwide characterized by excessive serum levels of glycosylated which triggers the generation of glycan-specific IgG and IgA autoantibodies. This pathological condition results in the formation of circulatory IgA immune complexes, which are essential for the development of glomerular inflammation, especially IgA nephropathy. The serum galactosylated IgA1, IgG, and IgA autoantibodies are suggested as the biomarkers of IgA nephropathy since IgA antibodies are early markers for disease activity too. Serum IgA antibodies emerged as the early COVID-19-specific antibody response about two days after initial symptoms of COVID-19 in comparison with IgG and IgM antibody concentrations, which appeared after five days. IgA nephropathy is frequently presented as microscopic or macroscopic hematuria and proteinuria with a male predominance. COVID-19 infection can include several organs aside from the lungs, such as kidneys through different mechanisms. It is demonstrated in most cases that short-lasting symptoms such as gross hematuria resolve either spontaneously or following a short course of steroids. This review summarized the reported cases of relapses or de-novo reported cases of relapses or de-novo IgA nephropathy and IgA vasculitis following COVID-19 vaccination.

Iga Associated Lymphocytic Vasculopathy: an Underrecognized Entity

Immunoglobulin A (IgA) associated lymphocytic vasculopathy is an uncommonly reported entity in which IgA immune complexes evoke a lymphocytic vascular reaction instead of a neutrophilic vasculopathy. We present the clinical, histopathological and immunofluorescence features of IgA associated lymphocytic vasculopathy in a 25 year old male

Immune Complex Glomerulonephritis in a Patient with Myelodysplastic Syndrome with Ring Sideroblasts Treated with Luspatercept

Myelodysplastic syndromes (MDS) are a group of clonal myeloid disorders distinguished by dysplastic bone marrow and peripheral blood cells, ineffective hematopoiesis, and an increased risk of developing acute myeloid leukemia (AML). MDS with ring sideroblasts (MDS-RS) is a favorable outcome subtype with a lower frequency of AML transformation. The FDA recently approved luspatercept for the treatment of patients with very-low-, low-, and intermediate-risk MDS-RS who have failed to correct anemia with an erythropoiesis-stimulating agent (ESA) and require two units of red blood cells over an eight-week period. This drug's pharmacology is based on the critical role of the transforming growth factor-beta (TGF-β) pathway in regulating erythropoiesis. In this case report, we describe for the first time an acute kidney injury caused by membranoproliferative glomerulonephritis (MPGN) in a patient with MDS-RS who was treated with luspatercept. We propose that a multi-hit hypothesis could explain the immunopathogenesis. A first unknown hit may stimulate IgA immune complex production, whereas luspatercept administration acts as a second hit, causing Smad1-5-8 phosphorylation. This intriguing case report on immune-complex-mediated proliferative glomerulonephritis following luspatercept treatment generates hypotheses and stimulates further research in this area.

Gut-kidney axis in IgA nephropathy: Role on mesangial cell metabolism and inflammation.

IgA Nephropathy (IgAN) is the commonest primary glomerular disease around the world and represents a significant cause of end-stage renal disease. IgAN is characterized by mesangial deposition of IgA-immune complexes and mesangial expansion. The pathophysiological process includes an abnormally glycosylated IgA1, which is an antigenic target. Autoantibodies specifically recognize galactose-deficient IgA1 forming immune complexes that are amplified in size by the soluble IgA Fc receptor CD89 leading to deposition in the mesangium through interaction with non-classical IgA receptors. The local production of cytokines promotes local inflammation and complement system activation, besides the stimulation of mesangial proliferation. The spectrum of clinical manifestations is quite variable from asymptomatic microscopic hematuria to rapidly progressive glomerulonephritis. Despite all the advances, the pathophysiology of the disease is still not fully elucidated. The mucosal immune system is quoted to be a factor in triggering IgAN and a "gut-kidney axis" is proposed in its development. Furthermore, many recent studies have demonstrated that food intake interferes directly with disease prognosis. In this review, we will discuss how mucosal immunity, microbiota, and nutritional status could be interfering directly with the activation of intrinsic pathways of the mesangial cells, directly resulting in changes in their function, inflammation and development of IgAN.