Home About us Current issue Back issues Submission Instructions Advertise Contact Login   

Search Article 
Advanced search 
Saudi Journal of Kidney Diseases and Transplantation
Users online: 1006 Home Bookmark this page Print this page Email this page Small font sizeDefault font size Increase font size 

REVIEW ARTICLE Table of Contents   
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

Click here for correspondence address and email

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

How to cite this URL:
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

1.Julian BA, Waldo FB, Rifai A, Mestecky J. IgA Nephropathy, the most common glo­merulonephritis world wise. A neglected disease in the United States? Am J Med 1988;84:129-32.  Back to cited text no. 1    
2.Van Es LA. Pathogenesis of IgA nephro­pathy. Kidney Int 1992;41:1720-9.  Back to cited text no. 2  [PUBMED]  
3.Emancipator SN. IgA nephropathy: morpho­logic expression and pathogenesis. Am J Kidney Dis 1994;23:451-62.  Back to cited text no. 3  [PUBMED]  
4.Galla JH. IgA nephropathy. Kidney Int 1995;47:377-87.  Back to cited text no. 4  [PUBMED]  
5.Schena FP. A retrospective analysis of the natural history of primary IgA nephropathy worldwide. Am J Med 1990;89;209-15.  Back to cited text no. 5    
6.Clarkson AR, Seymour AE, Thompson AJ, Haynes WD, Chan YL, Jackson B. IgA nephropathy: a syndrome of uniform morphology, diverse clinical features and uncertain prognosis. Clin Nephrol 1977; 8:459-71.  Back to cited text no. 6  [PUBMED]  
7.Haas M. Histologic subclassification of IgA nephropathy: a clinicopathologic study of 244 cases. Am J Kidney Dis 1997;(6): 829-42.  Back to cited text no. 7    
8.Ueda Y, Sakai O, Yamagata M, Kitajima T, Kawamura K. IgA glomerulonephritis in Japan. Contrib Nephrol 1977;4:36-47.  Back to cited text no. 8    
9.Sissons JG, Woodrow DF, Curtis JR, et al. Isolated glomerulonephritis with mesangial IgA deposits. Br Med J 1975;3:611-4.  Back to cited text no. 9  [PUBMED]  [FULLTEXT]
10.Jennette JC. The immunohistology of IgA nephropathy. Am J Kidney Dis 1988; 12:348-52.  Back to cited text no. 10  [PUBMED]  
11.Levy M, Lesavre P. Genetic factors in IgA nephropathy. Adv Nephrol Necker Hosp 1992;21:23-51.  Back to cited text no. 11    
12.Emancipator SN. Primary and secondary forms of IgA nephritis, Henoch-Schonlein syndrome: Pathology of the kidney, 4 th edition, Vol, ed. By R.H. Heptinstall. Little, brown and company, Boston, Toronto, London 1992;389-476.  Back to cited text no. 12    
13.Mestecky J. The common mucosal immune system and current strategies for induction of immune responses in external secretions. J Clin Immunol 1987(7):265-76.  Back to cited text no. 13  [PUBMED]  
14.Turner M. Molekule, die Antigene erkennen in Kurzes Lehrbuch der immu­nolgoie, ed. By I.M. Roitt, J Brostoff, D.K. Male, George Thieme, Stuttgart, New York 1991;45-65.  Back to cited text no. 14    
15.Mestecky J. Immunobiology of IgA. Am J Kidney Dis 1988;12:378-83.  Back to cited text no. 15  [PUBMED]  
16.Mestecky J, Russell MW, Jackson S, Brown TA. The human IgA system: a reassessment. Clin Immunol Immunopathol 1986; 40:105-14.  Back to cited text no. 16  [PUBMED]  
17.Kilian M. Degradation of immuno­globulins A1, A2 and G by suspected principal periodontal pathogens. Infect Immun 1981;34:757-65.  Back to cited text no. 17  [PUBMED]  [FULLTEXT]
18.Mestecky J, McGee J. Immunoglobulin A: molecular and cellular interactions involved in IgA biosynthesis and immune response. Adv Immunol 1988;42:153-245.  Back to cited text no. 18    
19.Lamm ME. The IgA mucosal immune system. Am J Kidney Dis 1988;12:384-7.  Back to cited text no. 19  [PUBMED]  
20.Chen HC, Tomino Y, Yaguchi Y, Fukui M, Koide H. Detection of polymorpho-nuclear cells, superoxid dismutease and poly C9 in glomeruli of patients with IgA nephropathy. Nephron 1991;(59)338.  Back to cited text no. 20    
21.Monteiro RC, Halbwachs-Mercarelli L, Roque-Barreiera MC, Noel LH, Gerger J, Lesavre P. Charge and size of mesangial IgA in IgA nephropathy. Kidney Int 1985; 28:666-71.  Back to cited text no. 21    
22.Andre C, Berthoux FC, Andre F, Gillon J, Genin C, Sabatier JC. Prevalence of IgA2 deposits in IgA nephropathies: a clue to their pathogenesis, N Engl J Med 1980; 303:1343-6.  Back to cited text no. 22    
23.Conley ME, Cooper MD, Michael AF. Selective deposition of immunoglobulin A1 in immunoglobulin A nephropathy, anaphylactoid purpura nephritis and systemic lupus erythematosus. J Clin Invest 1980;66:1432-6.  Back to cited text no. 23  [PUBMED]  [FULLTEXT]
24.Russell MW, Mestecky J, Julian BA, Galla JH. IgA associated renal diseases: Antibodies to environmental antigens in sera and deposition of immunoglobulins and antigens in glomeruli. J Clin Immunol 1986;6:74-86.  Back to cited text no. 24  [PUBMED]  
25.Tomino Y, Endoh M, Nomoto Y, Sakai H. Immunoglobulin A1 in IgA nephropathy. N Engl J Med 1981;305:1159-60.  Back to cited text no. 25  [PUBMED]  
26.Lomax-Smith JD, Zabrowarny LA, Howarth GS, Seymour AE, Woodroffe AJ. The immunochemical characterization of mesangial IgA deposits. Am J Pathol 1983;113:359-64.  Back to cited text no. 26  [PUBMED]  [FULLTEXT]
27.Rajaraman S, Goldblum RM, Cavallo T. IgA associated glomerulonephritides: a study with monoclonal antibodies. Clin Immunol Immunopathol 1986;39:514-22.  Back to cited text no. 27  [PUBMED]  
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    
29.Kerr MA. The structure and function of human IgA. Biochem J 1990;271:285-96.  Back to cited text no. 29  [PUBMED]  [FULLTEXT]
30.Allen AC, Harper SJ, Freehally J. Galacto­sylation of N- and O-linked carbohydrate moieties of IgA1 and IgA in IgG nephro­pathy. Clin Exp Immunol 1995;100:470-4.  Back to cited text no. 30    
31.Hiki Y, Iwase H, Saitoh M, Horii Y, Hotta K, Kobayashi Y. Reactivity of glomerular and serum IgA1 to jacalin in IgA nephropathy. Nephrol 1996;72:429-35.  Back to cited text no. 31    
32.Tomana M, Matousovic K, Julian BA, Radl J, Konecny K, Mestecky J. Galactose deficient IgA1 in sera of IgA nephropathy patients is present in complexes with IgA. Kidney Int 1997;52:509-16.  Back to cited text no. 32  [PUBMED]  
33.Hiki Y, Tanaka A, Kokoba T, et al. TOFMS analysis of O-glycans on IgA1 hinge in IgA nephropathy. J Am Soc Nephrol 1996;7:1703.  Back to cited text no. 33    
34.Allen AC. Abnormal glycosylation of IgA: is it related to the pathogenesis of IgA nephropathy? Nephrol Dial Transplant 1995;10:1121-4.  Back to cited text no. 34  [PUBMED]  [FULLTEXT]
35.Jentoft N. Why are proteins O-glycosy­lated? Trend Biochem Sci 1990;15:291-4.  Back to cited text no. 35  [PUBMED]  [FULLTEXT]
36.Tomana M, Kulhavy R, Mestecky J. Receptor-mediated bindings and uptake of immunoglobulin A by human liver. Gastroenterology 1988;94:762-70.  Back to cited text no. 36  [PUBMED]  
37.Stockert RJ, Kressner MS, Collins JC, Sternlied I, Morell AG. IgA interaction with the asialoglycoprotein receptor. Proc Natl Acad Sci USA 1982;79:6229-31.  Back to cited text no. 37    
38.Mestecky J, Tomana M, Crowley-Nowick PA, Moldoveanu Z, Julian BA, Jackson S. Defective galactosylation and clearance of IgA1 molecule as a possible etiopatho­genic factor in IgA nephropathy. Contrib Nephrol 1993;104:172-82.  Back to cited text no. 38  [PUBMED]  
39.Allen AC, Topham PS, Harper SJ, Freehally J. Leukocyte beta 1,3 galactosyl transferase activity in IgA nephropathy. Nephrol Dial Transplant 1997;12:701-6.  Back to cited text no. 39    
40.Davin JC, Malaise M, Foidart J, Mahieu P. Anti-alpha-galactosyl antibodies and immune complexes in children with Henoch­Schonlein purpura of IgA nephropathy. Kidney Int 1987;31:1132-9.  Back to cited text no. 40  [PUBMED]  
41.Hiki Y, Tanaka A, Kokubo T, et al. Analysis of IgA hinge glycopeptide in IgA nephropathy by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. J Am Soc Nephrol 1998; (4):577-82.  Back to cited text no. 41    
42.Galla GH, Kohaut EC, Alexander RC, Mestecky J. Racial differences in the prevalence of IgA-associated nephropathies. Lancet 1985;2:522.  Back to cited text no. 42    
43.Jennette JC, Wall SD, Wilkman AS. Low incidence of IgA in blacks. Kidney Int 1985;28:944-50.  Back to cited text no. 43    
44.Wang AC, Fudenberg HH. Genetics and evolution of human immunoglobulin A. Adv Exp Med Biol 1974;45:161-5.  Back to cited text no. 44  [PUBMED]  
45.Neelakantappa K, Gallo GR, Baldwin DS. Immunoglobulin A nephropathy in blacks and homozygosity for the genetic marker A2m. Ann Intern Med 1986;104:287-8.  Back to cited text no. 45    
46.Crowley-Nowick PA, Julian BA, Wyatt RJ, et al. IgA nephropathy in blacks: studies of IgA2 allotypes and clinical course. Kidney Int 1991;39(6):1218-24.  Back to cited text no. 46    
47.Ebihara I, Nakamura T, Suzuki S, Tomino Y, Koide H. Proto-oncogene expression in peripheral blood mononuclear cells in IgA nephropathy. Kidney Int 1991;39:946-53.  Back to cited text no. 47  [PUBMED]  
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    

Correspondence Address:
Nabil Akash
Department of Nephrology, King Hussein Medical Center, P.O. Box 1362, Amman 11953
Login to access the Email id

PMID: 18209313

Rights and Permissions


  [Table - 1]


    Similar in PUBMED
    Search Pubmed for
    Search in Google Scholar for
    Email Alert *
    Add to My List *
* Registration required (free)  

    Article Tables

 Article Access Statistics
    PDF Downloaded350    
    Comments [Add]    

Recommend this journal