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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2000  |  Volume : 11  |  Issue : 2  |  Page : 191-196
Abnormal Aspects of IgA in IgA Nephropathy


Department of Internal Medicine, Nephrology Division, King Hussein Medical Center, Amman, Jordan

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How to cite this article:
Akash N, El-Lozi M. Abnormal Aspects of IgA in IgA Nephropathy . Saudi J Kidney Dis Transpl 2000;11:191-6

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Akash N, El-Lozi M. Abnormal Aspects of IgA in IgA Nephropathy . Saudi J Kidney Dis Transpl [serial online] 2000 [cited 2020 Sep 27];11:191-6. Available from: http://www.sjkdt.org/text.asp?2000/11/2/191/36677

   Introduction Top


IgA nephropathy (IgAN) is defined as glomerulonephritis characterized by the predominance of IgA among glomerular immunoglobulin deposits.

While initially regarded as a benign disease of questionable significance and prevalence, IgAN is now considered the most prevalent form of glomerulonephritis worldwide, and a major cause for end-stage kidney disease. [1],[2],[3],[4]

Approximately 65% of patients are in the second and third decade of life and virtually all studies showed a male predominance of at least 2:1. [5]

The presenting symptoms in more than 75% of patients is painless macroscopic hematuria frequently at the time of infectious illnesses, which are most often pharyngitis, tonsillitis and less often pneumonia, gastroenteritis or urinary tract infection. [6] Hematuria is usually associated with proteinuria, hypertension and/ or azotemia in variable combinations. [5]

The pathological changes are variable. The histopathological classification used by Haas [7] summarizes the wide range of lesions [Table - 1]. The most common appearance of the glomeruli is that of mesangial proliferative glomerulonephritis followed by focal and segmental proliferation and diffuse proliferative glomerulonephritis.

The predominant immunohistochemical finding in the glomeruli is, by definition, IgA deposits, but it is the exclusive immuno­globulin (Ig) in only 15 to 26% of cases. [8],[9],[10] IgG, almost exclusively IgG1 and IgG3, and IgM are co-deposited in 37% and 13% of cases respectively, and 25% of patients have deposits of all three major Ig classes. [11],[12]

Diffuse mesangial deposits is the rule, but they can extend into the sub-endothelial and sub-epithelial spaces of the capillaries. [2],[3],[4] Immune deposits in the extra-glomerular sites are rare. Electron microscopy typically reveals the glomerular dense deposits that generally correlate well with the severity of changes seen on light microscopy. [3] The presence of deposits in the capillaries usually correlates with the presence of proteinuria. [13]

The complement C3 is present in 95%, while complements C1 and C4 are detected in only 12% of the renal biopsies. The finding of properdin and factor B in mesangial areas supports the assumption that complement C3 is activated by the alternate pathway.

Physiological Background

The primary function of the IgA system is to prevent the invasion of the internal milieu by a variety of microbial, food and environmental antigens. [13]

IgA represents 15 to 20% of the human pool of immunoglobulins in serum, [14] but the daily production of IgA (approximately 66 mg/kg/day) exceeds production of all other immunoglobulins combined. [15]

Two distinctive systems produce IgA: the systemic component that includes the bone marrow, lymph nodes, tonsils and spleen; and the secretory or mucosal system, which includes the gut, salivary glands, breast and respiratory tract. In some species these systems display a considerable degree of independence. [16]

In man, two isotope subclasses, IgA1 and IgA2 are recognized together with two allo­types of the IgA2 subclass namely IgA2m1 and IgA2m2. The two subclasses of IgA differ in their resistance to cleavage by proteases of micro-organisms living in the gastrointestinal and respiratory system. [17] IgA2 is more stable than IgA1 and possibly, therefore, is the predominant subclass in secretions, while IgA1 is prevalent in serum. [14]

In serum, most IgA molecules display a typical four-polypeptide chain structure of the basic molecule with two heavy and two light chains. External secretions contain dimeric and tetrameric disulfide-linked heavy chains to form a multimere in addition to a glycoprotein derived from various epithelial cells. Therefore, the assembled molecule of secreted IgA is a product of two entirely different cell types, plasma cells and epithelial cells. [18]

Multimeric IgA also requires a secretory component at the basolateral membrane of epithelial cells, which is necessary for the secretion of IgA across the mucosa. [19]

Upon exposure to certain viral antigens, serum initially produces predominantly polymeric IgA antibodies. Prolonged contact to these antigens results in a shift to the monomeric form. This shift suggests that such antibodies against environmental antigens may be produced initially, at mucosal sites and later in the bone marrow.

Abnormalities of IgA

IgA derived form mesangial deposits has been shown to be remarkably homogenous in the anionic charge, which may be related to its affinity for the mesangium. [21],[22] IgA may be deposited in the mesangium because some of its physiochemical properties trapping it there, bound to a deposited antigen(s) or to an intrinsic mesangial antigen, or it has structural abnormalities.

Initially, both IgA1 and IgA2 were shown to be deposited in IgA-associated nephro­pathy. [22] More recent studies, nevertheless, have shown with the use of specific reagents, that IgA1 subclass was deposited selectively in the mesangium in IgAN. [23],[24],[25],[26],[27]

Structural abnormalities of the IgA1 may play a role in its mesangial deposition. IgA is a glycoprotein that carries both N-linked and O-linked glycans. The IgA molecule contains 5 serine and 4 threonine residues, all of which are potential O-glycosylation sites. [28] The human IgA1 hinge region on the heavy chain is a distinctive feature of the molecule and consists of 18 aminoacids located between the CH1 and CH2 domains. These aminoacids are absent in IgA2. [29]

Recent studies by different assays [30],[31],[32],[33],[34] have indicated differences in the hinge region O-glycans that could have structural and functional implications relevant to the pathogenesis of IgAN. [34]

This O-glycan aggregate is large when compared to other proteins, and has anionic charge secondary to sialyzation of sugars. Series of O-glycans tend to provide an extended structure on the protein domain of the IgA molecule. [35]

The major site of IgA1 catabolism is through hepatic sialogycoprotein receptor, which has high affinity for the O-glycan and it is specific for the terminal galactose residues. Impairment of this process may lead to failure of clearance of IgA1 or IgA­containing immune complexes from the circulation leading to mesangial deposition. [36],[37]

Furthermore, the O-glycosylation hinge region is under the control of the enzyme B1-3-galactosyltransferase. It has been suggested that deficiency of this enzyme may be an important primary cause of IgA1 deposition. [38] The activity of B1-3-galacto­syltransferase was found to be reduced in peripheral blood B cells in IgAN, [39] which could support the above hypothesis. On the other side of the spectrum, some investi­gators have shown that elevated anti-a­galactosyl IgG antibodies in patients with IgA-associated nephropathy is not related to defective galactosylation and these anti­bodies may simply represent some of the many circulating antibodies in IgAN. [40]

To investigate the possibility of point mutations or deletions in the nucleotide sequence which could modify the amino acid sequence, Morag and co-workers [28] compared the IgA1 hinge region DNA nucleotide sequence in IgAN and controls. They also synthesized hinge region cDNA by reverse transcription from mRNA and compared the sizes of these transcripts in IgAN and controls. They did not find any difference in the amino acid sequences nor in the size of transcript in both groups. However, Hiki and colleagues [41] analyzed the IgA1 hinge glycopeptide utilizing a matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and suggested the presence of a defect in the Gal and or the Gal-Nac residues in the IgA1 hinge region in IgAN.

IgA in blacks

Unlike the high frequency of most glomerular diseases in blacks, IgAN is uncommon in blacks whether in the United States or in Africa. [42],[43] The low prevalence of IgAN in blacks has been linked to structural property of IgA2 as the frequency of the A2m (1) allotype is higher in whites than in blacks. [44] Since the A2m (2) allotype is more resistant to cleavage than A2m (1), homozygosites for A2m (2) allele in blacks were thought to protect against IgAN.[45] Others, however, suggested that the presence of A2m (1) allele did not increase the risk for IgAN and the presence of A2m (2) allele or homozygosity for this allele did not protect blacks from the development of IgAN. [46]

Multimeric-Macromolecular IgA

There is evidence of high molecular weight circulating IgA in IgAN. [47] This may be due to immune complex formation,[2],[4] interaction of IgA with fibronectin[48] or the presence of IgA rheumatoid factor.[49],[50]

The multimeric nature of the deposited IgA has been suggested by the presence of J-chain.[51],[52] Since IgM also contains J­ chain, co-deposits of IgM must be carefully excluded before concluding that multimeric IgA is present.


   Conclusion Top


IgA nephropathy (IgAN) is the most common type of glomerulonephritis worldwide and is found more commonly in men. Systemic abnormalities including the incorporation of a variety of antigens and alteration of mucosal and systemic immune responses, possibly modulated by multiple genetic influences and immune complex formation, represent the initial events in its patho­genesis. Growing evidence, however, suggests that structural abnormalities of the IgA molecule coupled with polyclonal stimula­tion of immunoglobulin may play a vital role.

 
   References Top

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28.Morag RG, Jonathan B, Steven JH, Alice CA, John Freehally. The nucleotide sequence of the IgA1 hinge region in IgA nephropathy. Nephrol Dial Transplant 1988;13:1980-83.  Back to cited text no. 28    
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48.Jennette JC, Wieslander J, Tuttle R, Falk RJ. Serum IgA-fibronectin aggregates in patients with IgA nephropathy and Henoch­Schonlein purpura: diagnostic value and pathogenic implications. Am J Kidney Dis 1991;18:466-71.  Back to cited text no. 48  [PUBMED]  
49.Czerkinsky C, Koopman WJ, Jackson S, et al. Circulating immune complexes and immunoglobulin A rheumatoid factor in patients with mesangial immunoglobulin A nephropathies. J Clin Invest 1986;77: 1931-­8.  Back to cited text no. 49  [PUBMED]  [FULLTEXT]
50.Kumatso N, Nagura H, Watanabe K, Nomoto Y, Kobayashi K. Mesangial deposition of J chain-linked polymeric IgA on IgA nephropathy. Nephron 1983;33:61­4.  Back to cited text no. 50    
51.Egido J, Sancho J, Mampaso F, et al. A possible common pathogenesis of the mesangial IgA glomerulonephritis in patients with Burger's disease and Schonlein-Henoch Syndrome. Proc Eur Dial Transplant Assoc 1980;17:660-6.  Back to cited text no. 51  [PUBMED]  
52.Valentijn R, Radl J, Haaijman JJ, et al. Circulating and mesangial secretory component-binding IgA1 in primary IgA nephropathy. Kidney Int 1984;26:760-6.  Back to cited text no. 52    

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Correspondence Address:
Nabil Akash
Department of Nephrology, King Hussein Medical Center, P.O. Box 1362, Amman 11953
Jordan
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