Secondary IgA nephropathy

Abstract

IgA nephropathy is the most common primary glomerulonephritis worldwide. Its frequent coexistence with inflammatory, infectious, or malignant processes raises the possibility of a pathologic rather than coincidental association. Major strides have been made to elucidate the underlying pathophysiologic events that culminate in the development of primary IgA nephropathy. Whether secondary forms of the disease share common pathways triggered by underlying disorders or different mechanisms leading to similar pathologic findings remains to be determined. In this article we describe the most frequent etiologies for secondary IgA nephropathy and review the available literature for the pathophysiology.

Keywords: autoimmune diseases; glomerulonephritis; inflammatory bowel disease; liver disease; post-infectious glomerulonephritis.

Figure 1.. Mucosal immune system and circulatory and mucosal IgA.

The mucosal immune system consists of inductive and effector sites. Inductive sites are the tissues where naïve B cells are exposed to antigen. Inductive sites include Peyer’s patches (small and large intestine), bronchus-associated lymphoid tissue, tonsils and adenoids. The interaction of antigens (mucosa-derived) with B cells occurs in the germinal centers (GC) of the inductive sites. T-cell dependent (TCD) and T-cell-independent (TCI) activation of B cells (IgM+, IgD+) can result in isotype class-switch to IgA; the IgA+ plasmablasts (PB) and antibody-secreting cells (ASC) express tissue-specific homing receptors. These activated B cells enter the thoracic duct via the draining lymphatics, and then recirculate to the lamina propria of the intestine and other mucosal epithelium (effector sites). In primary IgAN, the tissue origin of galactose-deficient IgA1 (Gd-IgA1) is still debated, but evidence indicates its mucosal origin: i) Gd-IgA1 in mesangial deposits is polymeric, typical of IgA1 produced in mucosal tissues; ii) macroscopic hematuria frequently manifests during an active respiratory tract and gastrointestinal tract infection; and iii) polymeric IgA1 produced at mucosal sites has higher capacity for binding to a lectin specific for N-acetylgalactosamine (the terminal sugar in galactose-deficient glycans of Gd-IgA1) than does serum IgA1 in healthy individuals.^, In contrast, other studies support the concept that polymeric IgA1 is produced in the bone marrow in patients with IgAN. Thus, it has been postulated that patients with IgAN have IgA1-producing B cells with altered homing receptors when migrating from an inductive site to an effector site in gut mucosa, and therefore mistakenly “home” to the bone marrow. TCD mechanisms involve two pathways: 1) CD40L on activated effector T cells and its interaction with CD40 on B cells and 2) involvement of cytokines, transforming growth factor, and interleukins. TCI mechanisms involve dendritic cells (DC) expressing B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL). IgA plasmablasts destined for the intestinal lamina propria express chemokine receptors CCR9 (small-intestine homing) and CCR10 (large -intestine homing), the cognate ligands of which are expressed by respective intestinal epithelial cells. The IgA plasmablasts mature into IgA-secreting plasma cells in the lamina propria, to secrete polymeric IgA, composed of two or more monomeric units (either IgA1 or IgA2) joined by disulfide bonds between C-terminal tail pieces of each monomer and a single J chain. The polymeric IgA secreted by IgA-producing cells in mucosa can bind to polymeric immunoglobulin receptors (pIgR) on the baso-lateral surface of the mucosal epithelial cells, are internalized and then transcytosed into vesicles to the mucosal apical surface. The extracellular portion of the receptor (the secretory component, SC) is cleaved and remains attached to the pIgA that is secreted as secretory IgA (sIgA). Most of the IgA in serum originates from bone marrow and is monomeric IgA1 (mIgA; IgA1~84%, IgA2 ~16%; monomers >90%, polymers <10%), In contrast, mucosal IgA consists mainly of secretory IgA (>95%) with distribution of the two subclasses differing, depending on the mucosal site. sIgA is present in circulation at low concentrations, possibly due to mucosal retrograde transport.

Figure 2.. Hepatic catabolism of circulatory IgA.

Liver is the major site of catabolism of circulatory IgA. Asialoglycoprotein receptor (ASGP-R) is expressed on the sinusoidal surface of hepatocytes. It binds terminal galactose or N-acetylgalactosamine of glycoproteins without sialic acid. Catabolism of IgA occurs through a series of steps noted in the figure by numbers: 1) Circulatory IgA has to pass through the endothelial fenestration to reach the hepatic sinusoids and enter the space of Disse; 2) IgA binds to ASGP-R on hepatocytes in a calcium-dependent manner; 3) IgA bound to ASGP-R is internalized in vesicles; and 4) vesicles containing IgA (and other asialoglycoproteins) fuse with lysosomes, resulting in IgA catabolic degradation. Although IgA is the most abundantly produced immunoglobulin (66 mg/kg/day), it constitutes only 15% of the total circulatory immunoglobulins due to its short half-life (4-6 days) related the dispersal of IgA polymeric forms into various mucosal secretions and liver catabolism. Notably, immune complexes consisting of IgA are often too large to pass through the liver endothelial fenestrations (~148 ± 38 nm) and are thus not effectively catabolized in the liver.