IgA vasculitis update: Epidemiology, pathogenesis, and biomarkers

Abstract

Immunoglobulin A vasculitis (IgAV), formerly known as Henoch-Schönlein purpura, is the most common systemic vasculitis in children, characterized by diverse clinical manifestations with a wide spectrum ranging from isolated cutaneous vasculitis to systemic involvement. The incidence of IgAV is geographically and ethnically variable, with a prevalence in autumn and winter, suggesting a driving role that genetic and environmental factors play in the disease. Although IgAV has a certain degree of natural remission, it varies widely among individuals. Some patients can suffer from severe renal involvement and even progress to end-stage renal disease. Its pathogenesis is complex and has not been fully elucidated. The formation of galactose-deficient IgA1 (Gd-IgA1) and related immune complexes plays a vital role in promoting the occurrence and development of IgAV nephritis. In addition, neutrophil activation is stimulated through the binding of IgA to the Fc alpha receptor I expressed on its surface, resulting in systemic vascular inflammation and tissue damage. Starting from the epidemiological characteristics, this article will review the role of immunological factors such as Gd-IgA1, autoantibodies, circulating immune complexes, complement system, cellular immunization, and the contributions of environmental and genetic factors in the pathogenesis of IgAV, and conclude with the major biomarkers for IgAV.

Keywords: IgA vasculitis; biomarkers; epidemiology; genetic factors; immunopathogenesis.

Figure 1

Two four-hit pathogenesis models for IgAV: (1) Increased production of circulating galactose-deficient IgA1 (hit1) binds to specific IgA1 autoantibodies (hit2), forming pathogenic circulating immune complexes (hit3), which then deposited in the glomerulus and trigger inflammatory responses (hit4); (2) The first hit is provided by elevated AECA levels of IgA1 isotype, followed by the binding of IgA1-AECA complexes to specific β2 glycoprotein I receptors (β2GPI) on vascular endothelial cells (hit2), inducing excessive production of proinflammatory factors such as IL-8, which in turn stimulates neutrophil recruitment (hit3), and then the activation of causes extensive damage to the vascular endothelium via antibody-dependent cellular cytotoxicity (ADCC), complement-mediated cytotoxicity (CDC), and reactive oxygen species (ROS), ultimately leading to systemic vascular inflammation and permeation (hit 4). The pathogenic processes of IgAV are promoted by immune cells and inflammatory mediators and regulated by multiple factors, including genetics and the environment.

Figure 2

The production and major regulatory mechanisms of Gd-IgA1. (1) B cells in the mucosa differentiate into IgA1-secreting plasma cells and produce IgA1 through class switching in a T-cell-dependent or T-cell-independent manner when stimulated by pathogens, such as bacterium and virus. Then, the abnormal activation of signaling pathways promotes the production of Gd-IgA1 through altering the expression and activity of the key glycosyltransferases. Potential signaling pathways involved are mainly below: IL-6 activates the STAT3 pathway via binding to its gp130 receptor; LIF binds the LIF-R/gp130 receptor and activates the STAT1 pathway; TLRs (TLR7/TLR9) activation induce production of IL-6 and APRIL, which function synergistically to promote the generation of Gd-IgA1; BAFF or APRIL signaling through the BAFF receptors, such as TACI, BAFF-R, BCMA prevents degradation of NF-κB and influence the O-glycosylation of IgA1. (2) The structure and O-glycosylation process of IgA1. IgA1 has O-glycans located in the unique hinge region, with 3 to 6 O-glycosylation sites consisting of serine or threonine residues. The low expression of GALNT2, C1GALT1, and COSMC, and upregulation of ST6GalNac2 can hinder the IgA1 glycosylation process, resulting in the exposure of terminal GalNac residues and overproduction of Gd-IgA1.