Immunoglobulin A Glycosylation and Its Role in Disease.

Human IgA is comprised of two subclasses, IgA1 and IgA2. Monomeric IgA (mIgA), polymeric IgA (pIgA), and secretory IgA (SIgA) are the main molecular forms of IgA. The production of IgA rivals all other immunoglobulin isotypes. The large quantities of IgA reflect the fundamental roles it plays in immune defense, protecting vulnerable mucosal surfaces against invading pathogens. SIgA dominates mucosal surfaces, whereas IgA in circulation is predominately monomeric. All forms of IgA are glycosylated, and the glycans significantly influence its various roles, including antigen binding and the antibody effector functions, mediated by the Fab and Fc portions, respectively. In contrast to its protective role, the aberrant glycosylation of IgA1 has been implicated in the pathogenesis of autoimmune diseases, such as IgA nephropathy (IgAN) and IgA vasculitis with nephritis (IgAVN). Furthermore, detailed characterization of IgA glycosylation, including its diverse range of heterogeneity, is of emerging interest. We provide an overview of the glycosylation observed for each subclass and molecular form of IgA as well as the range of heterogeneity for each site of glycosylation. In many ways, the role of IgA glycosylation is in its early stages of being elucidated. This chapter provides an overview of the current knowledge and research directions.

The Multifaceted Nature of Immunoglobulin A and Its Complex Role in HIV.

IgA is the most abundant immunoglobulin in mucosal secretions, and understanding the role of IgA in both protection from HIV acquisition and modulation of HIV disease progression is a field of considerable controversy and renewed research interest. Analysis of the RV144 clinical trial associated plasma HIV envelope-specific monomeric IgA from vaccines with reduced vaccine efficacy. The RV144 trial, however, only assessed for plasma IgA, which was not further subclassed, and the role of mucosal IgA was not addressed as mucosal samples were not collected. On the other hand, several studies have detected envelope-specific IgA in mucosal secretions of highly exposed persistently seronegative cohorts, while recent macaque simian-HIV passive immunization studies have suggested a potentially protective role for mucosal IgA. It is well established that total IgA in serum appears to correlate with HIV disease progression. In contrast, a selective deficit of anti-HIV IgA responses in HIV infection is apparent, with a number of recent studies beginning to elucidate the mechanisms behind these dysfunctional IgA responses. In this review, we highlight the dichotomy that exists in the literature as to whether anti-HIV IgA is protective or harmful to the host. Herein, we emphasize the importance of distinguishing between monomeric, multimeric, and isoforms of IgA and review what is known about the complex and diverse interactions of various molecular forms of IgA with HIV in both the systemic circulation and mucosal compartments.

Role of IgA receptors in the pathogenesis of IgA nephropathy.

Immunoglobulin A nephropathy (IgAN) or Berger's disease is the most common form of primary glomerulonephritis in the world and one of the first causes of end-stage renal failure. IgAN is characterized by the accumulation of immune complexes containing polymeric IgA1 in mesangial areas. The pathogenesis of this disease involves the deposition of polymeric and hypogalactosylated IgA1 (Gd-IgA1) in the mesangium. Quantitative and structural changes of Gd-IgA1 play a key role in the development of the disease due to functional abnormalities of two IgA receptors: the FcαRI (CD89) expressed by blood myeloid cells and the transferrin receptor (CD71) on mesangial cells. Abnormal Gd-IgA1 induces release of soluble CD89, which participates in the formation of circulating IgA1 complexes. These complexes are trapped by CD71 that is overexpressed on mesangial cells in IgAN patients together with the crosslinking enzyme transglutaminase 2 allowing pathogenic IgA complex formation in situ and mesangial cell activation. A humanized mouse model expressing IgA1 and CD89 develops IgAN in a similar manner as patients. In this model, a food antigen, the gliadin, was shown to be crucial for circulating IgA1 complex formation and deposition, which could be prevented by a gluten-free diet. Identification of these new partners opens new therapeutic prospects for IgAN treatment.