Understanding IgA Vasculitis - Epidemiology, Pathogenesis, and Emerging Biomarkers

IgA vasculitis (IgAV), formerly known as Henoch-Schönlein purpura, is a systemic small-vessel vasculitis characterized by IgA1-dominant immune deposits. Predominantly affecting children, it presents with a spectrum of clinical manifestations, ranging from self-limiting cutaneous lesions to life-threatening renal or gastrointestinal complications. Despite its prevalence, the disease's etiology remains enigmatic, with genetic predisposition, environmental triggers, and dysregulated immune responses contributing to its pathogenesis. This article examines the geographical and seasonal epidemiology of IgAV, explores the molecular mechanisms driving vascular inflammation, and highlights emerging biomarkers that could revolutionize diagnosis and prognosis.

Epidemiological Insights: Geographical Clusters and Seasonal Trends

• Global Incidence and Ethnic Disparities

IgAV exhibits striking geographical variability, with annual incidence rates ranging from 3 to 27 cases per 100,000 children. East Asian populations, particularly in Japan and South Korea, report the highest rates (20–27 cases), followed by European cohorts (10–20 cases), while African and Middle Eastern regions document lower prevalence (3–5 cases). These disparities underscore the role of genetic susceptibility. For instance, HLA-DRB1*01:01 and HLA-B35 alleles are overrepresented in European and North African populations, respectively, suggesting region-specific genetic risk factors.

Seasonal patterns further implicate environmental triggers. Approximately 72% of cases occur in autumn and winter, coinciding with peaks in respiratory infections like streptococcal pharyngitis and influenza. A study noted a 40% decline in IgAV cases during COVID-19 lockdowns, likely due to reduced viral exposure and improved hygiene practices.

• Age, Gender, and Clinical Outcomes

Over 90% of IgAV cases occur in children under 10 years, with a median age of 6.5 years. Males are disproportionately affected (male-to-female ratio: 1.5:1), though the reasons remain unclear. Older children (≥7 years) face a 30% higher risk of renal involvement, while adults account for only 1.4–5.1 cases per 100,000 but experience severe nephritis in 40–50% of cases.

Unraveling Pathogenesis: From Aberrant Glycosylation to Neutrophil Dysregulation

• Galactose-Deficient IgA1: A Central Player

A hallmark of IgAV is elevated serum levels of galactose-deficient IgA1 (Gd-IgA1), an aberrantly glycosylated immunoglobulin missing galactose residues on its hinge region. This defect arises from dysregulated activity of β1,3-galactosyltransferase (C1GALT1) and its chaperone protein, Cosmc, in IgA1-producing plasma cells. Gd-IgA1 evades hepatic clearance due to reduced binding to the asialoglycoprotein receptor, leading to systemic circulation.

These molecules form immune complexes (ICs) by binding IgG or IgA autoantibodies targeting the hinge region. ICs deposit in vascular walls and renal mesangial cells, activating complement via the lectin and alternative pathways. Complement activation generates pro-inflammatory anaphylatoxins (C3a, C5a), recruiting neutrophils and monocytes to sites of deposition.

Fig.1 The production and major regulatory mechanisms of Gd-IgA1.^1,3

• Neutrophil Activation and Vascular Injury

Neutrophils amplify vascular damage through FcαRI (CD89) receptor binding to IgA-containing ICs. This interaction triggers neutrophil degranulation, releasing proteases (e.g., myeloperoxidase) and reactive oxygen species (ROS) that degrade endothelial glycocalyx and basement membranes. Activated neutrophils also extrude neutrophil extracellular traps (NETs), web-like structures composed of DNA and histones that entrap pathogens but exacerbate microthrombosis and endothelial dysfunction.

In renal involvement, persistent IC deposition induces mesangial cell proliferation, podocyte effacement, and glomerulosclerosis. TGF-β1 overexpression by damaged podocytes promotes extracellular matrix accumulation, culminating in progressive fibrosis.

• Genetic Susceptibility and Environmental Triggers

Genome-wide association studies (GWAS) link IgAV to HLA class II alleles (HLA-DRB101:01, HLA-DQB105:01*) and non-HLA loci (IL1RN, MEFV). IL1RN polymorphisms reduce interleukin-1 receptor antagonist (IL-1Ra) production, heightening inflammation, while MEFV mutations predispose individuals to neutrophil-driven vasculitis.

Environmental factors, including streptococcal infections, Helicobacter pylori, and vaccines (e.g., influenza, COVID-19), act as triggers. Streptococcal M proteins mimic human antigens, inducing cross-reactive antibodies that attack vascular endothelium.

Emerging Biomarkers: Bridging Diagnosis and Prognosis

• Gd-IgA1 Quantification and Glycosylation Profiling

Serum Gd-IgA1 levels, measured via enzyme-linked immunosorbent assay (ELISA) or lectin-based assays, correlate with disease severity and renal outcomes. Patients with Gd-IgA1 concentrations >50 U/mL have a 4-fold higher risk of nephritis. Advanced mass spectrometry techniques now enable precise glycosylation profiling, identifying specific glycoforms associated with rapid progression to end-stage renal disease (ESRD).

• Complement Activation Markers

Hypocomplementemia (low C3 and C4 levels) occurs in 20–30% of IgAV nephritis cases, reflecting alternative pathway activation. Elevated plasma C5a and soluble C5b-9 (membrane attack complex) predict treatment resistance, guiding the use of complement inhibitors like eculizumab.

Fig.2 Immunofluorescence showing 2+ IgA deposits (left) and 2+ C3 deposits (right) with granular capillary loop and mesangial staining.^2,3

• Urinary Biomarkers of Renal Injury

Urinary monocyte chemoattractant protein-1 (MCP-1) and neutrophil gelatinase-associated lipocalin (NGAL) are sensitive indicators of early glomerular and tubular damage. NGAL levels >150 ng/mL predict a 60% decline in renal function within 12 months. Recent proteomic studies also highlight urinary CD80 and α1-acid glycoprotein as novel markers of podocyte injury.

• Cytokine Profiling and microRNA Signatures

Elevated serum IL-6 (>15 pg/mL) and TNF-α (>20 pg/mL) correlate with systemic inflammation, while IL-17A levels distinguish IgAV from IgA nephropathy (IgAN). Circulating microRNAs, particularly miR-148b (which suppresses C1GALT1 expression), are promising non-invasive biomarkers. A miR-148b level >2.5-fold above baseline predicts Gd-IgA1 overproduction with 85% accuracy.

Therapeutic Innovations: Targeting Molecular Pathways

• Immune Complex Modulation

Bortezomib, a proteasome inhibitor, reduces plasma cell production of Gd-IgA1 in refractory cases. Anti-CD20 therapy (rituximab) depletes B cells, lowering autoantibody titers, while anti-CD71 antibodies block FcαRI-mediated neutrophil activation.

• Complement Inhibition

Eculizumab, a C5 inhibitor, has shown efficacy in severe nephritis, normalizing renal function in 60% of patients within 12 weeks. Novel lectin pathway inhibitors (e.g., narsoplimab) targeting mannose-binding lectin-associated serine protease-2 (MASP-2) are under clinical evaluation.

• Precision Medicine Approaches

Pharmacogenomic strategies are emerging: anakinra (IL-1Ra) benefits patients with IL1RN variants, while colchicine reduces NETosis in those with MEFV mutations. Future therapies may involve CRISPR-based editing of C1GALT1 or Cosmc to restore normal IgA1 glycosylation.

Conclusion: Toward a Holistic Understanding of IgA Vasculitis

IgAV is a multifactorial disease shaped by intricate interactions between genetic susceptibility, environmental exposures, and immune dysregulation. Advances in biomarker research, particularly in glycosylation profiling and microRNA signatures, are refining diagnostic accuracy and prognostic stratification. Meanwhile, targeted therapies aimed at neutralizing pathogenic immune complexes, modulating complement activation, and silencing pro-inflammatory cytokines herald a new era of personalized treatment. Collaborative efforts integrating multi-omics data—genomics, proteomics, and metabolomics—will unravel the remaining mysteries of this enigmatic vasculitis, ultimately improving outcomes for patients worldwide.

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References

1. Xu, Liyun, Yongzhen Li, and Xiaochuan Wu. "IgA vasculitis update: epidemiology, pathogenesis, and biomarkers." Frontiers in Immunology 13 (2022): 921864. https://doi.org/10.3389/fimmu.2022.921864
2. Chan, Melvin, et al. "Hypocomplementemic atypical IgA vasculitis: a case report." Frontiers in Pediatrics 10 (2022): 886371. https://doi.org/10.3389/fped.2022.886371
3. Distributed under the Open Access license CC BY 4.0, without modification.

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