Humans have two IgA subclasses, IgA1 and IgA2. IgA1 contains O-glycans attached to Ser or Thr, usually three to six, in the hinge region (HR) of the heavy chains (Fig.1). IgA1 HR has nine Ser and Thr amino-acid residues; those are missing in IgA2 HR and, thus, IgA2 does not have O-glycans (Fig.1). In normal human serum IgA1, HR glycoforms with four and five Glycans are the most common. Each heavy chain of IgA1 also contains two N-glycans, one in the CH2 domain and the second in the tailpiece portion. Normal human circulatory IgA1 usually has core 1 O-glycans consisting of N-acetylgalactosamine (GalNAc) with β1,3-linked Galactose. One or both saccharides can be Sialylated, galactose with α2,3-linked, and GalNAc with α2,6-linked sialic acid. The composition of the O-glycans on normal serum IgA1 is variable; prevailing forms include the GalNAc-galactose Disaccharide and its mono- and di-sialylated forms. Normal serum IgA1 had been thought to contain little or no galactose-deficient O-glycans, but it is now considered that some terminal or sialylated GalNAc is likely to present even in healthy individuals.
IgA nephropathy is a relatively newly recognized disease. In 1968, IgA nephropathy was first described. It is now generally known to be the most common form of primary glomerulonephritis throughout the world. Although primary IgA nephropathy was considered a benign condition for many years, it is now clear that a large number of cases eventually progress to renal failure. Indeed, IgA nephropathy is the main cause of end-stage renal disease in patients with the primary glomerular disease who require renal-replacement therapy.
Primary IgA nephropathy occurs at any age, most commonly with clinical onset in the second and third decades of life. There is a male: female ratio ranging from less than 2:1 in Japan to as high as 6:1 in northern Europe and the United States. In addition, whites and Asians are more prone to IgA nephropathy than blacks from the United States and South Africa. The lower prevalence in blacks is unexplained. The frequency seems to be low in Polynesians from New Zealand and high in native Americans from New Mexico and Australian aborigines.
Fig.1 Hinge-region glycosylation of human IgA1 and comparison of amino-acid sequences of human IgA1 and IgA2. (Lai, 2012)
An important element in the pathogenesis of IgA nephropathy is the formation of IgA1 immune complexes. Fundamental to the formation of immune complexes is the increased synthesis of aberrantly galactosylated IgA1. However, the presence of poorly galactosylated IgA1 O-glycoforms alone is insufficient to cause IgA nephropathy, and a second "hit" or even multiple hits are required. The second hit is the formation of glycan-specific IgG and IgA antibodies that recognize the under-galactosylated IgA1 molecule (Fig.2). These antibodies often have reactivity against antigens from extrinsic microorganisms that form the subsequent hits and can arise following recurrent mucosal infection. Levels of glycan-specific IgG, which has a characteristic variable heavy-chain region that recognizes galactose deficient IgA1, are elevated in patients with IgA nephropathy and correlate with proteinuria.
Fig.2 Proposed pathways involved in the mesangial deposition of IgA1 in IgA nephropathy-a multihit mechanism. (Knoppova, et al., 2016)
In the early stages of the disease, many patients have no obvious symptoms and are unaware of any problems. In these patients, IgA nephropathy may be suspected only during routine screening or investigation of another condition. However, some patients may present with aggressive disease. In general, there are few characteristic clinical signs; however, microscopic hematuria and proteinuria may be persistently or intermittently detected for many years. Patients with IgA nephropathy usually present with one of the following: episodes of macroscopic hematuria (tea-colored urine) that may coincide with an infection of the upper respiratory tract (this presentation usually occurs in patients under 40 years of age, and loin pain often accompanies hematuria), or abnormal sediment in the urine and proteinuria in patients without symptoms (this presentation is usually more common in older patients but is observed in patients of all ages).
Until recently, there was no effective treatment available for patients with IgA nephropathy. Although there remains no cure, treatment options that slow disease progression are becoming available. Since IgA nephropathy may affect up to 1.3 percent of the population there is a need for novel therapeutic agents capable of preserving renal function. For patients with only minor urinary abnormalities who do not have hypertension, the consensus is not to offer specific treatment but to follow such patients prospectively over many years. Up to 23 percent of patients will have complete remission. Substantial progress has been made in the past several years in preventing progressive renal disease in at-risk patients with the use of several modes of treatment that include angiotensin-converting enzyme inhibitors, corticosteroids, and n-3 polyunsaturated fatty acids.
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