Since immunoglobulin A nephropathy (IgAN) was first described in the seminal papers by Berger [1, 2], we have learned much descriptively about its epidemiology, associations, natural history, and pathology, but the pathogenetic mechanisms remain largely uncertain. Although the histopathologic criterion for IgAN—the dominance or codominance of IgA deposition in the mesangium—suggests a single entity, it may as well characterize a group of diseases or" IgA-associated nephropathies," a concept that better suits this discussion. From the outset [2], Henoch-Schönlein purpura (HSP), clearly a systemic illness, has been closely linked to IgAN, which is defined by the absence of systemic features. Indeed, in some studies investigators include HSP as part of the spectrum of IgAN. This view is justified by several linkages between these two disease entities. Other considerations in the spectrum of glomerulopathies characterized by IgA deposition, such as nephritis associated with systemic lupus erythematosus (SLE) and hepatic glomerulosclerosis, are clinically distinct and will be mentioned only as they relate to the differential diagnosis.

The IgA system The primary function of the IgA system is to prevent the invasion of the internal milieu by a vast array of microbial, food, and environmental antigens [3]. Familiarity with some basic features of IgA biology provides a helpful foundation for understanding the significance of some clinical and pathogenetic obser-vations: More IgA is produced daily—about 66 mg/kg body weight—than all other immunoglobulin isotypes combined [4]. Two distinctive systems produce IgA: the systemic compartment, which includes the bone marrow, lymph nodes, tonsils, and spleen; and the mucosal or secretory system, which includes the gut, salivary glands, respiratory tract, and breast. These systems ap-pear to function for the most part independently of each other [5]. In humans, two isotype subclasses, IgAl and IgA2, are recognized along with two allotypes of the IgA2 subclass, A2m (1) and A2m (2). Since the A2m (1) allotype, unlike A2m (2), is not con-nected by interchain disulfide bonds, it is more readily cleaved by IgA bacterial proteases [6]. IgA2 is produced predominately in the mucosal compartment; its production in the systemic compart-ment is less than 10% of the total. In the systemic compartment, monomers predominate whereas multimers do in the secretory compartment. Multimeric IgA—as well as 1gM—contains J-chain, a component that is linked to the heavy chain in the formation of multimers. Multimeric IgA also acquires secretory component at the basolateral membrane of epithelial cells; secretory component is necessary for the secretion of IgA across the mucosa [7].