Deposition Of IgA Immune Complexes Research Articles

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</p>.

#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.

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.

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.

ANAESTHETIC MANAGEMENT OF HENOCH SCHOLEIN PURPURA IN ADULT WITH ACUTE ABDOMEN – A CASE REPORT

Henoch-Schonlein Purpura (HSP) is a small vessel vasculitis mediated by IgA-immune complex deposition. It is characterized by non-thrombocytopenic purpura, arthritis or arthralgia, abdominal pain, and nephropathy. HSP has an overall excellent prognosis in children, but very rarely reported in adult. There are hardly any evidence for the anesthetic management of adult patients with HSP. We report a sucessful management of a case of a young adult with HSP who presented with acute abdomen for laparotomy. A 25yr old male with HSP presented with acute abdomen two days after admission. Under general anaesthesia with epidural anagesia, emergency laparotomy and resection anastomosis was done. Patient was stable post op and discharged on 5th post operative day. Bowel ischaemia secondary to HSP is a very rare complication. Monitoring and frequent reassessment with early surgical intervention helps to reduce morbidity, and improves outcome. Epidural analgesia can be safely administered in a patient with HSP as it avoids the use of non steroidal anti inammatory drugs for post operative analgesia.

Guben Tongluo Formula Protects LPS-induced Damage in Lamina Propria B Lymphocytes Through TLR4/MyD88/NF-κB Pathway.

The main pathological feature of immunoglobulin A nephropathy (IgAN), an autoimmune kidney disease, is the deposition of IgA immune complexes, accompanied by mesangial cell proliferation and elevated urine protein. The Guben Tongluo formula (GTF) is a traditional Chinese medicine prescription, which has predominant protective effects on IgAN. However, the therapeutic mechanism of the GTF in IgAN remains elusive. The present study aimed to determine the effects of GTF in treating IgAN via regulating the TLR4/MyD88/NF-κB pathway. In the present study, lamina propria B lymphocytes were treated with different concentrations of lipopolysaccharide (LPS) (0, 1, 5, 10 and 20 ng/mL). Flow cytometry was used to define positive CD86+CD19+ cells. CCK-8 assay was used to examine cell proliferation. RNAi was used to induce TLR4 silencing. qRT-PCR and Western blotting were used to determine gene expression. It was found that the LPS dose-dependently increased the content of IgA and galactose-deficient IgA1 (Gd-IgA), the levels of TLR4, Cosmc, MyD88 and phosphorylated (p)-NF-κB, and the ratio of CD86+CD19+ and IgA-producing B cells. However, the TLR4 knockdown reversed the role of LPS. This suggests that TLR4 mediates the effects of LPS on lamina propria B lymphocytes. Furthermore, the GTF could dose-dependently counteract the effects of LPS and TLR4 overexpression on lamina propria B lymphocytes through the TLR4/MyD88/NF-κB pathway. Collectively, these results demonstrate that the GTF can regulate the TLR4/MyD88/NF-κB pathway to treat IgAN model lamina propria B lymphocytes stimulated by LPS.

Progress in the Treatment of Henoch-Schonlein Purpura in Children

Henoch-Schonlein Purpura (HSP) is the most common leukocyte fragmentary vasculitis with IgA immune complex deposition in childhood, which may affect capillaries, arterioles and venules in various systems of the body. Henoch-Schonlein purpura nephritis (HSPN) can be diagnosed when kidney damage occurs in children with HSP, which is the most severe complication of HSP. However, if the treatment of children with HSPN is delayed or recurrent, more than 20% of these children eventually develop chronic renal failure, seriously affecting the prognosis and quality of life of the children. Therefore, early diagnosis and treatment are crucial to the prognosis of children with HSP. This article reviews the treatment of HSP and HSPN.

Increased proportion of follicular helper T cells is associated with B cell activation and disease severity in IgA nephropathy.

IgA nephropathy (IgAN) is the most common primary glomerulonephritis, characterized by glomerular deposition of IgA immune complexes, mainly produced by B cells under the regulation of CD4+T cells. However, the alterations of specific CD4+T cell subsets and the mechanism of B cells activation in IgAN remain unclear. Therefore, we aimed to investigate the landscape characteristics and role of CD4+T cells in the progression of IgAN. We identified that the proportion of Th2, Th17 and Tfh (follicular helper T) cells in patients with IgAN was significantly higher than that of healthy controls (P < 0.05). Single-cell RNA sequencing of peripheral blood mononuclear cells (PBMCs) showed that Th cells and B cells in patients with IgAN were more activated. Correspondingly, multiplex immunohistochemistry staining of renal biopsy showed increased infiltration of CD4+T and B cells in the kidneys of patients with IgAN. The degree of infiltration was positively correlated with the degree of renal damage. Interestingly, the proportion of Tfh cells in peripheral blood was positively correlated with the severity of proteinuria. Moreover, the proximity position of Tfh cells and B cells suggested that cell-cell interactions between Tfh and B cells were happening in situ. Intercellular communication analysis also showed enhanced interaction between Tfh cells and B cells in IgAN. Our findings suggested that Tfh cells of patients possibly contributed to the progression of IgAN by activating B cells via cell-cell interactions and TNFSF14-TNFRSF14 may be an underlying signaling pathway.

TNF-α-mediated podocyte injury via the apoptotic death receptor pathway in a mouse model of IgA nephropathy

Background IgA nephropathy (IgAN) is the most common primary glomerular disease worldwide and it is characterized by mesangial IgA deposits. Proteinuria is a common clinical feature of IgAN, which has a critical connection to podocyte injury and has been used as a clinical prognostic factor for IgAN. Evidence has shown that TNF-α released from mesangial cells may lead to podocyte apoptosis. Methods Forty male BALB/c mouse were randomly divided into the control group and IgAN group. A mice model of IgAN was developed by oral administration of bovine serum albumin (BSA) combined with Staphylococcus Enterotoxin B (SEB) tail vein injection. Urinary protein concentrations, renal function, renal morphological, IgA deposition, apoptosis situation, and the mRNA and protein expression of nephrin, podocin, TNF-α, TNFR1, caspase-8 and caspase-3, were detected after 12 weeks. Results BSA and SEB can successfully establish an IgAN mouse model, and the main pathological changes are the IgA immune complex deposition in the mesangial area. The gene and protein expression levels of nephrin and podocin were found to be downregulated, and death receptor pathway-related indicators were upregulated, and they were involved in TNF-α-activated podocyte injury and apoptosis in IgAN mice. Conclusion TNF-α may play an important role in the pathogenesis of podocyte apoptosis in IgAN, and its effects may be mediated through the apoptotic death receptor pathway.

Liuwei Dihuang Pills Inhibit Podocyte Injury and Alleviate IgA Nephropathy by Directly Altering Mesangial Cell-Derived Exosome Function and Secretion.

Background: Immunoglobulin A nephropathy (IgAN) is the most common glomerular disease worldwide. Its pathological features include IgA immune complex deposition, accompanied by mesangial cell proliferation and mesangial matrix expansion. This study was conducted to investigate the effects of Liuwei Dihuang pills (LWDHW) on IgAN in mice and human podocytes, as well as to determine their underlying mechanisms of action. Methods: For in vitro experiments, podocytes were exposed to the human mesangial cell culture medium supernatant of glomerular cells treated with aggregated IgA1 (aIgA1) and LWDHW-containing serum. Cell viability and the proportion of positive cells were evaluated using CCK-8 and flow apoptosis kits, respectively. The cells were collected for western blot analysis. Twenty-four mice with IgAN induced by oral bovine serum albumin administration combined with tail vein injection of staphylococcal enterotoxin B were randomly divided into four groups of six mice each: untreated model group, model + LWDHW group, model + rapamycin group, and model + LWDHW + rapamycin group. The normal control group contained six mice. The red blood cell count in the urine, urine protein, blood urea nitrogen, serum creatinine, and IgA deposition were determined, and TUNEL and western blotting were performed in the mouse kidney tissues. Results: In vitro experiments showed that LWDHW promoted autophagy by regulating the PI3K/Akt/mTOR signalling pathway and improved the damage to podocytes caused by the aIgA1-treated mesangial cell supernatant. This study demonstrates the effectiveness of LWDHW for treating IgAN. In the animal experiments, LWDHW significantly reduced the urine red blood cell count, serum creatinine and urea nitrogen contents, and 24 h urinary protein function and improved IgA deposition in the kidney tissues, glomerular volume, glomerular cell proliferation and polysaccharide deposition, and glomerular cell apoptosis. The pills also reversed the changes in the LC3II/I ratio and p62 content in the kidney tissues. The combination of LWDHW and rapamycin showed stronger inhibitory effects compared to those of LWDHW or rapamycin alone. Conclusion: LWDHW may improve regulation of the PI3K-Akt-mTOR pathway and inhibit autophagy in podocytes, as well as alleviate IgA nephropathy by directly altering mesangial cell exosomes.

Bowel angina: Henoch-Schonlein purpura in adult patient based on clinical approach: a case report

The GI involvement of Henoch-Schonlein purpura (HSP) has often been described as self-limiting, with no long term morbidity.GI manifestation is higher in adult patient. HSP is an autoimmune disorder characterized by the deposition of IgA immune complexes in the wall of small to medium size arteries. We present a 41-year-old patient with GI involvement (Bowel angina) in HSP case admitted at Wangaya Regional Hospital Denpasar. The case are treated by steroid and symptomatic treatment. Diagnosis is established through a clinical approach with EULAR criteria. The patient recovered with supportive treatment and had a favourable clinical outcome.

POS-107 LONG-TERM PHASE 2 EFFICACY OF THE MASP-2 INHIBITOR NARSOPLIMAB FOR TREATMENT OF SEVERE IGA NEPHROPATHY

IgA nephropathy (IgAN) is a glomerular disease in which the lectin pathway of complement is activated following mesangial deposition of IgA immune complexes. Narsoplimab (OMS721) inhibits mannan-binding lectin-associated serine protease-2 (MASP-2), the effector enzyme of the lectin pathway.

PUK20 Patient and Healthcare System Value Drivers in Immunoglobulin a Nephropathy (IgAN) in the United States

IgAN is a rare autoimmune proliferative glomerulonephritis, the hallmark of which is IgA immune complex deposition in the glomerular mesangium. The immune complexes derive from autoantibodies binding to circulating immunogenic galactose-deficient IgA1 antibodies produced mainly in the ileum. While the burden of kidney disease overall is well established, we sought to understand the burden of illness (BOI) and summarize value drivers specifically in IgAN as patients progress through stages of chronic kidney disease, with a focus on US studies. Using PRISMA guidelines and PICOS criteria (Population, Intervention, Comparators, Outcomes, Study design), EMBASE, MEDLINE, and Cochrane databases (2010−6/26/2020) and relevant congress abstracts (2017 to 2020) were searched to identify real-world evidence on IgAN. Two systematic literature reviews in IgAN were conducted, covering BOI and epidemiology. Of the extracted studies (11 for BOI; 123 for epidemiology), 8 reported quality of life (QoL) results, 31 reported the rate of transition to end-stage renal disease (ESRD), 16 reported mortality, and 24 described treatment patterns in IgAN. While data on symptom burden were limited, fatigue and pain were identified as the main symptoms impacting QoL. Among 4 US studies, progression to ESRD after 3 to 4 years of follow-up occurred in 12.5% to 45% of patients. In one US study with a mean follow-up of 19 years, over half (53%) of patients ultimately developed ESRD, which necessitates dialysis or transplant; renal survival was 60% at 10 years, declining to 50% at 18 years. Life expectancy among those with IgAN in the same US study was 10.1 years lower vs those without IgAN, with 83% of deaths occurring after progression to ESRD. Over half of patients with IgAN eventually progress to ESRD, with impacts on QoL and reduced life expectancy. Delaying progression to ESRD is a major value driver to IgAN patients and healthcare systems.

Dihydroartemisinin inhibits the proliferation of IgAN mesangial cells through the mTOR signaling pathway

IgA nephropathy (IgAN) is an autoimmune kidney disease and is the most prevalent form of glomerular kidney disease in China and worldwide. IgA immune complex deposition accompanied by mesangial cell proliferation and mesangial matrix expansion is the most basic pathological feature of IgAN. Dihydroartemisinin (DHA), an antimalarial drug, was recently reported to be effective in treating autoimmune diseases. However, its potential therapeutic role in IgAN is relatively unstudied. The aim of this study was to investigate the pharmacological effects and the underlying mechanisms of DHA in the treatment of IgAN. In this study, renal biopsy specimens were collected for immunohistochemistry. In vitro, 25 μg/ml concentrations of aggregated IgA1 (aIgA1) was used to construct the IgAN mesangial cell model. Stimulated human mesangial cells (HMCs) were treated for 24 h with DHA (0–15 μM) and were collected for western blot analyses. Cell proliferation was assessed by Cell Counting Kit 8 (CCK8) and 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay. In vitro, our results showed that DHA could downregulate the mammalian target of rapamycin/ribosomal protein S6 kinase beta-1 (mTOR/S6K1) signaling pathway, promote cell autophagy, and ameliorate cell proliferation in aIgA1-induced HMCs. The results suggested that DHA may represent a novel class of mTOR inhibitor and promote an anti-proliferation effect in IgAN HMCs, which provides an alternative approach for IgAN treatment.

Immune pathogenesis of Henoch-Schönlein purpura in children

Henoch Schonlein purpura (HSP) is a multiple immune mediated systemic immune vasculitis with an immune complex characterized by deposition of small blood vessels in the affected tissue. HSP complex etiology, infection, food and drugs can cause disease. Its exact pathogenesis is still not clear, may be related to abnormal immune functions, IgA immune complex deposition, T lymphocyte dysfunction, abnormal lymphocyte activation, B interleukin (IL) -17, IL-21, IL-6, visfatin, IL-8 secretion, and intestinal mucosal barrier dysfunction and so on. Key words: Henoch-Schonlein purpura; Immunology; Intestinal mucosal barrier function; Pathogenesis

Púrpura de Henoch-Schönlein (Vasculite por IgA) no Adulto

A Púrpura de Henoch-Schönlein é uma vasculite de pequenos vasos com deposição de imunocomplexos IgA. Caracteriza- se por púrpura palpável, artralgias/artrite, envolvimento abdominal e renal. A sua etiologia permanece desconhecida, mas vários estímulos têm sido propostos como possíveis fatores desencadeantes, entre eles, agentes infeciosos, fármacos, antígenos tumorais, havendo possível associação a malignidade e doenças autoimunes. Ocorre maioritariamente em crianças, sendo rara nos adultos. Na população pediátrica a doença é, na maioria das vezes, autolimitada, enquanto nos adultos está associada a um pior prognóstico e a um maior número de complicações. Neste artigo abordam-se os principais aspetos da PHS nos adultos, salientando-se as suas particularidades e especificidades.

A Case of Henoch-Scholein Purpura with Gastrointestinal Involvement and an Atypical Petechial Rash

Case presentation: An 18-year-old male with no previous medical history presented with rash, abdominal pain. The rash began on his thighs and spread to all four extremities. He also reported 1 week history of watery diarrhea and nausea. He was unable to tolerate oral intake and sustained a 12 pound weight loss. He denied fevers, chills, arthralgias, oral ulcers, hematuria, hematochezia, melena, or preceding viral symptoms. He denied non-steroidal anti-inflammatory and alcohol use. On admission, vitals were within normal limits. Physical examination was significant for a non-raised petechial rash over the upper and lower extremities, which involved the feet and palms of his hands (Figure 1). Oropharynx, abdominal, and joint exam did not reveal any abnormalities.Figure 1Upper endoscopy reported moderate to severe active gastritis with ulcerations and mild duodenitis with ulcerations (Figure 2). Gastric and duodenal biopsies were negative for Helicobacter pylori, cytomegalovirus, herpes simplex virus, and adenovirus. A punch biopsy of the skin was performed and showed leukocytoclastic vasculitis with IgA deposits on immunochemical staining suggestive of HSP. Laboratory studies were unremarkable except for evidence of mild leukocytosis.Figure 2The patient was treated with supportive care including proton pump inhibitor therapy. His symptoms improved within several days of hospitalization. Discussion: HSP is a systemic small vessel vasculitis characterized by IgA immune complex deposition in capillaries of the skin, gastrointestinal tract, joints and kidneys. This condition is often self-limited and more commonly observed in children compared to adults. The classic presentation includes abdominal pain, palpable purpura, renal dysfunction and/or arthalgias. Abdominal pain can be secondary to several etiologies with varying clinical presentations. IgA deposition in capillaries of the gastrointestinal tract can cause small vessel thrombosis, leading to mucosal hemorrhage, bowel ischemia and ulcerations. Gastric hemorrhage often leads to epigastric pain. Bleeding into the submucosal space can lead to small bowel hematomas and intussusceptions, and patients can present with symptoms of small bowel obstruction. A high index of suspicion is needed for the diagnosis of HSP in patients that present with atypical signs and symptoms. Our patient presented with a petechial rash that is not classic for HSP but suggestive of a vasculitis. The symptoms of acute onset of abdominal pain in an otherwise healthy young adult suggested the diagnosis. Endoscopy and skin biopsy are often necessary to confirm the diagnosis. Cross-sectional imaging may be warranted if upper endoscopy is unremarkable.

Henoch-Schönlein Purpura Nephritis in Children: A Review

Henoch-Schönlein purpura (HSP) is a systemic disorder which involves multiple organs including kidney. The characteristic pathology is leukocytoclastic vasculitis of the capillaries with deposition of IgA immune complexes. The principal cause of morbidity and mortality in this disease is due to renal involvement. Approximately half of the children with HSP develop nephritis (HSPN) within 4-6 weeks of initial presentation and HSPN is a major cause of end stage renal disease (ESRD) in children. So, it is important to be updated about aetio-pathogensis, clinico-pathological aspects and prognostic factors of nephritis related to Henoch Schonlein purpura. The most important is to identify the appropriate treatment options for HSPN. So, herein review has been done on the different aspects of HSPN including treatment. DOI: http://dx.doi.org/10.3329/bjch.v38i1.20024 Bangladesh J Child Health 2014; VOL 38 (1) : 24-31

IgA Nephropathy Caused by Unusual Polymerization of IgA1 with Aberrant N-Glycosylation in a Patient with Monoclonal Immunoglobulin Deposition Disease

Immunoglobulin A nephropathy (IgAN) is a form of chronic glomerulonephritis characterized by the deposition of IgA immune complexes in the glomerular region. The cause of IgAN is unknown, but multiple mechanisms have been suggested. We previously reported a rare case of mesangioproliferative glomerulonephritis in a patient with monoclonal immunoglobulin deposition disease associated with monoclonal IgA1. In this study, we performed the detailed analyses of serum IgA1 from this patient in comparison with those from patients with mIgA plasma cell disorder without renal involvement and healthy volunteers. We found unusual polymerization of IgA1 with additional N-glycosylation distinctive in this patient, which was different from known etiologies. Glycan profiling of IgA1 by the lectin microarray revealed an intense signal for Wisteria floribunda agglutinin (WFA). This signal was reduced by disrupting the native conformation of IgA1, suggesting that the distinct glycan profile was reflecting the conformational alteration of IgA1, including the glycan conformation detected as additional N-glycans on both the heavy and light chains. This unusually polymerized state of IgA1 would cause an increase of the binding avidity for lectins. WFA specifically recognized highly polymerized and glycosylated IgA1. Our results of analysis in the rare case of a patient with monoclonal immunoglobulin deposition disease suggest that the formation of unusually polymerized IgA1 is caused by divergent mechanisms including multiple structural alterations of glycans, which contributes to IgA1 deposition and mesangium proliferation.

HENOCH-SCH^|^Ouml;NLEIN PURPURA NEPHRITIS IN CHILDHOOD: PATHOGENESIS, PROGNOSTIC FACTORS AND TREATMENT

Henoch-Schönlein purpura (HSP) is a systemic disorder characterized by leukocytoclastic vasculitis involving the capillaries and the deposition of IgA immune complexes. Renal involvement is the principal cause of morbidity and mortality in children with HSP. Thus, it is important to clarify the onset mechanism as well as the prognostic factors of Henoch-Schönlein purpura nephritis (HSPN) and to identify the most appropriate treatment. We herein review the pathogenesis, the prognostic factors and treatment of HSPN. As to the pathogenesis, several studies suggest that galactose-deficient IgA1 (Gd-IgA1) is recognized by anti-glycan antibodies, leading to the formation of circulating immune complexes and their mesangial deposition, thereby inducing renal injury. With regard to the prognostic factors, a number of factors have been suggested including nephrotic syndrome, decreased factor XIII activity, hypertension, severe renal injury, high renal accumulation of activated macrophage, alpha-smooth muscle actin, and high serum myeloid-related protein levels. For the treatment of severe HSPN, aggressive therapies including multiple drug combination therapy and plasmapheresis have been shown to be effective in ameliorating proteinuria and histological severity. Nevertheless, detailed investigation into the pathogenesis of HSPN and double-blind randomized control studies on children with HSPN are still necessary.