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Mesangial IgA in IgA Nephropathy Arises From the Mucosa
Mesangial IgA in IgA Nephropathy Arises From the Mucosa Marie C. Bene, PharmSciD, and Gilbert C. Faure, MD • Numerous studies have attempted to elucidate the pathogenetic mechanisms of IgA nephropathy, analyzing kidney, serum, lymphocytes, and lymphoid tissue of patients with this glomerulonephritis. Based on studies of the molecular characteristics of the mesangiallgA, clinical features, and immunologic analysis of the mucosal tissue, a wide array of findings suggest that mesangiallgA indeed arises from the mucosa. These three areas of research are discussed, as well as the hypothesis of a systemic origin for the mesangial IgA. © 1988 by the National Kidney Foundation, Inc. INDEX WORDS: IgA nephropathy; mucosae; molecular forms of IgA; origin of mesangial IgA.
I
MMUNOGLOBULIN A (lgA) is a very special isotype representing the major humoral defense mechanism in mammalian mucosae. IgA is also the second most abundant isotype in the blood, composing about 20% of the circulating antibodies. Its discovery in the 1960s unveiled many new areas for immunologic investigation. Despite intensive work over the last 20 years, both its physiologic and immunopathologic features remain surprisingly poorly defined . These shortfalls partially explain the limited understanding of the pathogenesis of IgA nephropathy (IgAN). In this report, we shall review several studies that elucidate the pathogenesis of IgAN and the potential relationships of the disease with the major battleground of IgA: the mucosae. IGA IN IGAN: MOLECULAR ASPECTS
IgA occurs in humans in at least 12 different molecular forms (Table 1), 18 if the coexpression of Am allotypes in the IgA2 subclass is included. Secretory IgA is dime ric , composed of two monomeric subunits, J chain, and secretory component. I The monomeric subunits in a dimer are identical, composed of two (X-heavy chains (either (Xl or (X2 isotype) and two light chains (either x or >-). By varying the isotypes of heavy chains and light chains, IgA dimers may assume four different compositions . In secretory IgA, IgA2 with From the Laboratorie d'lmmunologie, Faculte de Medecine de Nancy, France. Supported in part by a grant from lNSERM (843002) to M. C. B. , and by the Fondation pour la Recherche Medicale. Address reprint requests to Marie C. Bene, PharmSciD, Laboratorie d'lmmunologie , Faculte de Medecine de Nancy, BP 184, 54505 Vandoeuvre les Nancy Cedex, France. © 1988 by the National Kidney Foundation, Inc. 0272-6386/88/1205-0015$3.00/0
406
the (X2 heavy chain is the more abundant subclass 2 and >- may be the predominant light chain isotype. 3 Serum IgA is predominantly IgAlmonomers; x light chains outnumber >- light chains. 2 However, due to their primary structure and extensive glycosylation, IgA monomers tend to spontaneously aggregate, thereby forming noncovalently bound dimers, trimers, or larger polymers. These polymers may be homogeneous or may contain different heavy chain isotypes, further increasing the heterogeneity of serum IgA. A small portion of serum IgA apparently arises from the lamina propria in the mucosa. These molecules are secreted by plasma cells as dimers with J chain, but they have not bound the secretory component. I It is not known which (X heavy chain or light chain isotype predominates in these molecules. This heterogeneity in composition has stimulated many investigators to analyze the composition of IgA in the glomerular mesangium of patients with IgAN. In most instances, mesangial IgA contains J chain and lacks secretory component, but binds secretory component overlaid on tissue sections.4 IgA1 is the subclass usually found, but sometimes IgA2 has also been detected. The wide range in the observed frequencies of the two IgA subclasses may reflect genetic influences because most studies have used the same technique and reagents. 5 In recent investigations of the distribution of the light chain isotypes, >- has appeared predominant. 6 In summary, the in situ analyses of the mesangial deposits in patients with IgAN have suggested that the IgA contains dimers of both subclasses with >- as the predominant light chain isotype. Because IgAN displays several characteristicsof an immune complex-mediated disease, serum IgA and complement protein concentrations have been
American Journal of Kidney Diseases, Vol XII, No 5 (November), 1988: pp 406-409
407
MUCOSAL ORIGIN OF IGA IN IGAN
Table 1.
Molecular Forms of IgA Secretory Dimers
Predominant Other(s)
([a2-A)2kJ-SC ([a2-x )2)2-J-SC ([a,-A)2kJ-SC ([a,-x)2h-J-SC
Serum Monomers
(a,-x)2 (a,-Ah (a2- xh (a2-A)2
Serum Dimers
? ([a2-A)2h-J ([a2-x)2h-J ([a,-A)2h-J ([a,-x)2)2-J
Molecular characteristics of the various types of IgA present in humans. Serum dimers originate from plasma cells in the lamina propria of mucosae and contain a J chain. Serum polymers, made of homogeneous or heterogeneous aggregates of IgA, and containing no J chain, add to the variety of IgA molecular forms.
analyzed. 7 Elevated serum IgA concentrations are a frequent feature of IgAN. Several studies have shown that the polymeric portion of serum IgA concentration is increased. The size of the IgA molecules and the presence of alternative pathway complement proteins within the circulating immune complexes suggested that the IgA in the complexes was dimeric. Such complexes can be isolated by their binding on columns coated with secretory component, suggesting that they contained dimers with J chain. 8 Thus, both mesangial and serum IgA in patients with IgAN had the "serum dimeric" structure and probably arise from the mucosae. MUCOSA IN IGAN: CLINICAL ASPECTS
Idiopathic IgAN (Berger's disease) shares many clinical features with Henoch-Schonlein purpura (HSP).9 The signs of renal disease are usually mild and nonspecific: intermittent microscopic or macroscopic hematuria and variable proteinuria. The macroscopic hematuria often occurs contemporaneously with an infectious illness. Many patients report a history of recurrent infections of the oropharynx, although infections in the gastrointestinal or genitourinary tract also may coincide with episodes of macroscopic hematuria. Macroscopic hematuria may develop with ocular inflammatory conditions such as episcleritis, tonsillectomy, and dental therapy. The striking propensity of these disorders to involve mucosal areas has been proposed as a clue ro their pathogenesis. The pathognomonic skin lesions of HSP fit this hypothesis if the close immunologic relationships between the skin and mucosae are considered.
MUCOSA IN IGAN: IMMUNOLOGIC INVESTIGATIONS
Two major conditions hamper the analysis of mucosal abnormalities in patients with IgAN: (1) ethical limitations for obtaining large samples of mucosal tissue and (2) the physiologic predominance of IgA in most areas of the mucosaeassociated lymphoid tissue (MALT). Because T and B cells from the MALT continuously move between the mucosal compartments, some information may be obtained by analyzing the peripheral blood lymphocytes. Most studies of T cells in peripheral blood 10.11 have shown normal percentages of cells in the CD4 and CD8 subsets. However, the number of functionally active Thelper cells and T cells bearing receptors for the Fc portion of IgA may be increased. B cells from patients with IgAN overproduced IgA in culture; some of this IgAN was dimeric. Analysis of biopsy specimens of the small intestine, where IgA is produced by almost 90 % of the plasma cells, showed no difference in the subclass distribution compared with controls. 12 In the frequently inflammed (and often removed) tonsils of patients with IgAN, we have observed an inverted IgG:IgA ratio of the plasma cells. 13 This finding was due primarily to an increased number of IgAproducing plasma cells (patients: 37% IgG v 56% IgA; normal controls: 65% IgG v 29% IgA). Most of the IgA-producing plasma cells also contained J chain. Furthermore, cultures of tonsillar B cells from patients with IgAN overproduced dimeric
y
A A
A
B
Q2
Q
C
Q;l
5 (I
Y
Q~
K
~
K
Q
e
e
p
e
p
Fig 1. (A) Proportions of IgG h) v IgA (a), (8) x v}.., (e) and a1 v a2 among tonsillar plasma cells in control subjects (e) and patients with IgA nephropathy (P).
These observations are consistent with the composition of mesangial IgA. Except for subclasses partition, these data have been published previously.3.13
408
BENE AND FAURE
IgA.14 Recently we reported the predominance of the }.. isotype of the light chains on the tonsillar plasma cells. 3 Quantitative analysis of the tonsillar IgA-bearing B cells in patients with IgAN showed increased numbers of cells producing either IgA subclass. Although the percentage of a2-bearing cells as compared with normal controls, the a2 cells remained predominant in the patients (unpublished data) (Fig 1). Because IgAI binds to secretory component less efficiently than IgA2, some dimeric IgAI produced in the mucosae may enter the circulation, perhaps within immune complexes, rather than the secretions. These immune complexes might contain common environmental pathogens, food antigens, or even autologous IgG because IgA rheumatoid factor has been recently described. 8 NONMUCOSAL ORIGIN OF IGA in IGAN
The hypothesis for a systemic (eg, bone marrow) origin for the mesangial IgA in patients with IgAN will be discussed at length in the following report, but we shall make a few comments. Valentijn et al l5 have found increased numbers of IgAproducing plasma cells in the bone marrow of patients with IgAN. Perhaps the hyperstimulation of MALT may reflect a more general imbalance including the primary lymphoid organs such as the bone marrow. Nonetheless, although the basis of mucosal abnormalities remains unclear, the assumption of local dysregulation of the IgA immune system appears logical. However, the predominant role of the IgA system in the mucosal defense would more clearly explain the apparent involvement of MALT in IgAN. Reports of familial IgAN are consistent with a genetically influenced imbalance in the IgA immune system. 16 Several observations contradict a proposed systemic origin of the mesangial IgA in IgAN. The contemporaneous relationship between infectious illnesses affecting the mucosae and macroscopic hematuria is very striking and seems irrelevant to a postulated systemic origin. In contrast to a roughly equal distribution of the IgA subclasses in the mucosae and the presence of IgA2 in the mesangial deposits, about 90% of IgA produced by the bone marrow is IgA1.2.17 Deposits of food antigens with mesangial deposits and a portion of dimeric serum IgA of some patients as IgA rheumatoid factor further supports the participa-
tion of MALT in the pathogenesis of IgAN. Nonetheless, the most compelling evidence against the proposed systemic origin of mesangial IgA is the infrequent concurrence of IgAN and IgA monoclonal gammopathy, although the latter is not rare (23 % of patients with multiple myeloma 18). Furthermore, the 2: 1 x:}.. light chain ratio in human serum is shared by the IgA monoclonal gammapathies. 18 The notable lack of association between IgAN and a heavy chain disease suggests that high molecular weight, intact dimers are necessary for mesangial deposition of IgA. The controversy between a mucosal or systemic origin for the mesangial IgA in IgAN could be quieted by a 15-year-old hypothesis, recently quoted by Alley et aP 7: ". . . The idea that cells stimulated in the peripheral lymphoid organ form memory cells, and that upon subsequent challenge the progeny of these memory cells migrate to the bone marrow and become antibody producing cells .... " However, this hypothesis will not explain why IgA deposits in the glomerular mesangium induces hematuria and frequently damages the kidneys so much that renal failure often develops. REFERENCES 1. Brandtzaeg P: The oral immune system under normal and pathological conditions. Pathol Res Pract 179:619-621, 1985 2. Mestecky J, McGhee JR: Immunoglobulin A (IgA): Molecular and cellular interactions involved in IgA biosynthesis and immune response. Adv ImmunoI40:153-245, 1987 3. Bene MC, Faure G: Mucosal immunity and IgA nephropathies. Semin Nephrol 7:297-300, 1987 4. Bene MC, Faure G, Duheille J: IgA nephropathy: Characterization of the polymeric nature of mesangial deposits by in vitro binding of the secretory component. Clin Exp ImmunoI47:527-534, 1982 5. Sakai H: Lymphocyte function in IgA nephropathy, in Clarkson AR (ed): IgA Nephropathy, Topics in Renal Medicine. Boston, Martinus Nijhoff, 1987, pp 176-187 6. Lai KN, Chan KW, Lai FM-M, et al: The immunohistochemical characterization of the light chains in the mesangial IgA deposits in IgA nephropaty. Am J Clin PathoI85:548-551, 1986 7. Coppo R, Basolo B, Martina G, et al: Circulating immune complexes containing IgA, IgG, and IgM in patients with primary IgA nephropathy and with Henoch-Schonlein nephritis. Correlations with clinical and histological signs of activity. Clin Nephrol 18:230-239, 1982 8. D'Amico G: The commonest glomerulonephritis in the world: IgA nephropathy. Q J Med 64:709-727, 1987 9. Clarkson AR: Clinical and laboratory features in IgA nephropathy, in Clarkson AR (ed): IgA Nephropathy, Topics in Renal Medicine. Boston, Martinus Nijhoff, 1987, pp 9-15 10. Faure G, Bene MC, Hurault de Ligny B, et al: Popula-
MUCOSAL ORIGIN OF IGA IN IGAN
tions Iymphocytaires sanguines et nephropathies Ii immunoglobulines A. Presse Med 13:1846,1984 II. Egido J: The role of polymeric IgA in the pathogenesis of IgA nephropathy, in Clarkson AR (ed): IgA Nephropathy, Topics in Renal Medicine, Boston, Martinus Nijhoff, 1987, pp 157-175 12. Westberg NG, BakJien K, Schmekel B, et al: Quantitation of immunoglobulin-producing cells in small intestinal mucosa of patients with IgA nephropathy. Clin Immunol Immunopathol 26:442-445 , 1983 13. Bene MC, Faure G, Hurault de Ligny B, et al: Immunoglobulin A nephropathy. Quantitative immunohistomorphometry of the tonsillar plasma cells evidences an inversion of the immunoglobulin A versus immunoglobulin G secreting cell balance. J Clin Invest 71:1342-1347, 1983 14. Egido J, Blasco R, Lozano L, et al: Immunological ab-
409 normalities in the tonsils of patients with IgA nephropathy: Inversion in the ratio of IgA:IgG bearing lymphocytes and increased polymeric synthesis. Clin Exp Immunol 57:101-106, 1984 IS. van den Wall Bake AWL, Daha MR , Valentijn RM, et al: The bone marrow as a possible origin of the IgA I deposited in the mesangium in IgA nephropathy. Semin Nephrol 7:329-331, 1987 16. Julian BA, Quiggins PA, Thompson JS , et al: Familial IgA nephropathy. Evidence for an inherited mechanism of disease. N Engl J Med 312:202-208 , 1985 17. Alley CD: Synthesis of IgA by mammalian bone marrow. Adv Exp Med Bioi 216B:1175-1183 , 1987 18. Kyle RA: Monoclonal gammopathy of undetermined significance. Natural history in 241 cases. Am J Med 64:814826, 1978
I
MMUNOGLOBULIN A (lgA) is a very special isotype representing the major humoral defense mechanism in mammalian mucosae. IgA is also the second most abundant isotype in the blood, composing about 20% of the circulating antibodies. Its discovery in the 1960s unveiled many new areas for immunologic investigation. Despite intensive work over the last 20 years, both its physiologic and immunopathologic features remain surprisingly poorly defined . These shortfalls partially explain the limited understanding of the pathogenesis of IgA nephropathy (IgAN). In this report, we shall review several studies that elucidate the pathogenesis of IgAN and the potential relationships of the disease with the major battleground of IgA: the mucosae. IGA IN IGAN: MOLECULAR ASPECTS
IgA occurs in humans in at least 12 different molecular forms (Table 1), 18 if the coexpression of Am allotypes in the IgA2 subclass is included. Secretory IgA is dime ric , composed of two monomeric subunits, J chain, and secretory component. I The monomeric subunits in a dimer are identical, composed of two (X-heavy chains (either (Xl or (X2 isotype) and two light chains (either x or >-). By varying the isotypes of heavy chains and light chains, IgA dimers may assume four different compositions . In secretory IgA, IgA2 with From the Laboratorie d'lmmunologie, Faculte de Medecine de Nancy, France. Supported in part by a grant from lNSERM (843002) to M. C. B. , and by the Fondation pour la Recherche Medicale. Address reprint requests to Marie C. Bene, PharmSciD, Laboratorie d'lmmunologie , Faculte de Medecine de Nancy, BP 184, 54505 Vandoeuvre les Nancy Cedex, France. © 1988 by the National Kidney Foundation, Inc. 0272-6386/88/1205-0015$3.00/0
406
the (X2 heavy chain is the more abundant subclass 2 and >- may be the predominant light chain isotype. 3 Serum IgA is predominantly IgAlmonomers; x light chains outnumber >- light chains. 2 However, due to their primary structure and extensive glycosylation, IgA monomers tend to spontaneously aggregate, thereby forming noncovalently bound dimers, trimers, or larger polymers. These polymers may be homogeneous or may contain different heavy chain isotypes, further increasing the heterogeneity of serum IgA. A small portion of serum IgA apparently arises from the lamina propria in the mucosa. These molecules are secreted by plasma cells as dimers with J chain, but they have not bound the secretory component. I It is not known which (X heavy chain or light chain isotype predominates in these molecules. This heterogeneity in composition has stimulated many investigators to analyze the composition of IgA in the glomerular mesangium of patients with IgAN. In most instances, mesangial IgA contains J chain and lacks secretory component, but binds secretory component overlaid on tissue sections.4 IgA1 is the subclass usually found, but sometimes IgA2 has also been detected. The wide range in the observed frequencies of the two IgA subclasses may reflect genetic influences because most studies have used the same technique and reagents. 5 In recent investigations of the distribution of the light chain isotypes, >- has appeared predominant. 6 In summary, the in situ analyses of the mesangial deposits in patients with IgAN have suggested that the IgA contains dimers of both subclasses with >- as the predominant light chain isotype. Because IgAN displays several characteristicsof an immune complex-mediated disease, serum IgA and complement protein concentrations have been
American Journal of Kidney Diseases, Vol XII, No 5 (November), 1988: pp 406-409
407
MUCOSAL ORIGIN OF IGA IN IGAN
Table 1.
Molecular Forms of IgA Secretory Dimers
Predominant Other(s)
([a2-A)2kJ-SC ([a2-x )2)2-J-SC ([a,-A)2kJ-SC ([a,-x)2h-J-SC
Serum Monomers
(a,-x)2 (a,-Ah (a2- xh (a2-A)2
Serum Dimers
? ([a2-A)2h-J ([a2-x)2h-J ([a,-A)2h-J ([a,-x)2)2-J
Molecular characteristics of the various types of IgA present in humans. Serum dimers originate from plasma cells in the lamina propria of mucosae and contain a J chain. Serum polymers, made of homogeneous or heterogeneous aggregates of IgA, and containing no J chain, add to the variety of IgA molecular forms.
analyzed. 7 Elevated serum IgA concentrations are a frequent feature of IgAN. Several studies have shown that the polymeric portion of serum IgA concentration is increased. The size of the IgA molecules and the presence of alternative pathway complement proteins within the circulating immune complexes suggested that the IgA in the complexes was dimeric. Such complexes can be isolated by their binding on columns coated with secretory component, suggesting that they contained dimers with J chain. 8 Thus, both mesangial and serum IgA in patients with IgAN had the "serum dimeric" structure and probably arise from the mucosae. MUCOSA IN IGAN: CLINICAL ASPECTS
Idiopathic IgAN (Berger's disease) shares many clinical features with Henoch-Schonlein purpura (HSP).9 The signs of renal disease are usually mild and nonspecific: intermittent microscopic or macroscopic hematuria and variable proteinuria. The macroscopic hematuria often occurs contemporaneously with an infectious illness. Many patients report a history of recurrent infections of the oropharynx, although infections in the gastrointestinal or genitourinary tract also may coincide with episodes of macroscopic hematuria. Macroscopic hematuria may develop with ocular inflammatory conditions such as episcleritis, tonsillectomy, and dental therapy. The striking propensity of these disorders to involve mucosal areas has been proposed as a clue ro their pathogenesis. The pathognomonic skin lesions of HSP fit this hypothesis if the close immunologic relationships between the skin and mucosae are considered.
MUCOSA IN IGAN: IMMUNOLOGIC INVESTIGATIONS
Two major conditions hamper the analysis of mucosal abnormalities in patients with IgAN: (1) ethical limitations for obtaining large samples of mucosal tissue and (2) the physiologic predominance of IgA in most areas of the mucosaeassociated lymphoid tissue (MALT). Because T and B cells from the MALT continuously move between the mucosal compartments, some information may be obtained by analyzing the peripheral blood lymphocytes. Most studies of T cells in peripheral blood 10.11 have shown normal percentages of cells in the CD4 and CD8 subsets. However, the number of functionally active Thelper cells and T cells bearing receptors for the Fc portion of IgA may be increased. B cells from patients with IgAN overproduced IgA in culture; some of this IgAN was dimeric. Analysis of biopsy specimens of the small intestine, where IgA is produced by almost 90 % of the plasma cells, showed no difference in the subclass distribution compared with controls. 12 In the frequently inflammed (and often removed) tonsils of patients with IgAN, we have observed an inverted IgG:IgA ratio of the plasma cells. 13 This finding was due primarily to an increased number of IgAproducing plasma cells (patients: 37% IgG v 56% IgA; normal controls: 65% IgG v 29% IgA). Most of the IgA-producing plasma cells also contained J chain. Furthermore, cultures of tonsillar B cells from patients with IgAN overproduced dimeric
y
A A
A
B
Q2
Q
C
Q;l
5 (I
Y
Q~
K
~
K
Q
e
e
p
e
p
Fig 1. (A) Proportions of IgG h) v IgA (a), (8) x v}.., (e) and a1 v a2 among tonsillar plasma cells in control subjects (e) and patients with IgA nephropathy (P).
These observations are consistent with the composition of mesangial IgA. Except for subclasses partition, these data have been published previously.3.13
408
BENE AND FAURE
IgA.14 Recently we reported the predominance of the }.. isotype of the light chains on the tonsillar plasma cells. 3 Quantitative analysis of the tonsillar IgA-bearing B cells in patients with IgAN showed increased numbers of cells producing either IgA subclass. Although the percentage of a2-bearing cells as compared with normal controls, the a2 cells remained predominant in the patients (unpublished data) (Fig 1). Because IgAI binds to secretory component less efficiently than IgA2, some dimeric IgAI produced in the mucosae may enter the circulation, perhaps within immune complexes, rather than the secretions. These immune complexes might contain common environmental pathogens, food antigens, or even autologous IgG because IgA rheumatoid factor has been recently described. 8 NONMUCOSAL ORIGIN OF IGA in IGAN
The hypothesis for a systemic (eg, bone marrow) origin for the mesangial IgA in patients with IgAN will be discussed at length in the following report, but we shall make a few comments. Valentijn et al l5 have found increased numbers of IgAproducing plasma cells in the bone marrow of patients with IgAN. Perhaps the hyperstimulation of MALT may reflect a more general imbalance including the primary lymphoid organs such as the bone marrow. Nonetheless, although the basis of mucosal abnormalities remains unclear, the assumption of local dysregulation of the IgA immune system appears logical. However, the predominant role of the IgA system in the mucosal defense would more clearly explain the apparent involvement of MALT in IgAN. Reports of familial IgAN are consistent with a genetically influenced imbalance in the IgA immune system. 16 Several observations contradict a proposed systemic origin of the mesangial IgA in IgAN. The contemporaneous relationship between infectious illnesses affecting the mucosae and macroscopic hematuria is very striking and seems irrelevant to a postulated systemic origin. In contrast to a roughly equal distribution of the IgA subclasses in the mucosae and the presence of IgA2 in the mesangial deposits, about 90% of IgA produced by the bone marrow is IgA1.2.17 Deposits of food antigens with mesangial deposits and a portion of dimeric serum IgA of some patients as IgA rheumatoid factor further supports the participa-
tion of MALT in the pathogenesis of IgAN. Nonetheless, the most compelling evidence against the proposed systemic origin of mesangial IgA is the infrequent concurrence of IgAN and IgA monoclonal gammopathy, although the latter is not rare (23 % of patients with multiple myeloma 18). Furthermore, the 2: 1 x:}.. light chain ratio in human serum is shared by the IgA monoclonal gammapathies. 18 The notable lack of association between IgAN and a heavy chain disease suggests that high molecular weight, intact dimers are necessary for mesangial deposition of IgA. The controversy between a mucosal or systemic origin for the mesangial IgA in IgAN could be quieted by a 15-year-old hypothesis, recently quoted by Alley et aP 7: ". . . The idea that cells stimulated in the peripheral lymphoid organ form memory cells, and that upon subsequent challenge the progeny of these memory cells migrate to the bone marrow and become antibody producing cells .... " However, this hypothesis will not explain why IgA deposits in the glomerular mesangium induces hematuria and frequently damages the kidneys so much that renal failure often develops. REFERENCES 1. Brandtzaeg P: The oral immune system under normal and pathological conditions. Pathol Res Pract 179:619-621, 1985 2. Mestecky J, McGhee JR: Immunoglobulin A (IgA): Molecular and cellular interactions involved in IgA biosynthesis and immune response. Adv ImmunoI40:153-245, 1987 3. Bene MC, Faure G: Mucosal immunity and IgA nephropathies. Semin Nephrol 7:297-300, 1987 4. Bene MC, Faure G, Duheille J: IgA nephropathy: Characterization of the polymeric nature of mesangial deposits by in vitro binding of the secretory component. Clin Exp ImmunoI47:527-534, 1982 5. Sakai H: Lymphocyte function in IgA nephropathy, in Clarkson AR (ed): IgA Nephropathy, Topics in Renal Medicine. Boston, Martinus Nijhoff, 1987, pp 176-187 6. Lai KN, Chan KW, Lai FM-M, et al: The immunohistochemical characterization of the light chains in the mesangial IgA deposits in IgA nephropaty. Am J Clin PathoI85:548-551, 1986 7. Coppo R, Basolo B, Martina G, et al: Circulating immune complexes containing IgA, IgG, and IgM in patients with primary IgA nephropathy and with Henoch-Schonlein nephritis. Correlations with clinical and histological signs of activity. Clin Nephrol 18:230-239, 1982 8. D'Amico G: The commonest glomerulonephritis in the world: IgA nephropathy. Q J Med 64:709-727, 1987 9. Clarkson AR: Clinical and laboratory features in IgA nephropathy, in Clarkson AR (ed): IgA Nephropathy, Topics in Renal Medicine. Boston, Martinus Nijhoff, 1987, pp 9-15 10. Faure G, Bene MC, Hurault de Ligny B, et al: Popula-
MUCOSAL ORIGIN OF IGA IN IGAN
tions Iymphocytaires sanguines et nephropathies Ii immunoglobulines A. Presse Med 13:1846,1984 II. Egido J: The role of polymeric IgA in the pathogenesis of IgA nephropathy, in Clarkson AR (ed): IgA Nephropathy, Topics in Renal Medicine, Boston, Martinus Nijhoff, 1987, pp 157-175 12. Westberg NG, BakJien K, Schmekel B, et al: Quantitation of immunoglobulin-producing cells in small intestinal mucosa of patients with IgA nephropathy. Clin Immunol Immunopathol 26:442-445 , 1983 13. Bene MC, Faure G, Hurault de Ligny B, et al: Immunoglobulin A nephropathy. Quantitative immunohistomorphometry of the tonsillar plasma cells evidences an inversion of the immunoglobulin A versus immunoglobulin G secreting cell balance. J Clin Invest 71:1342-1347, 1983 14. Egido J, Blasco R, Lozano L, et al: Immunological ab-
409 normalities in the tonsils of patients with IgA nephropathy: Inversion in the ratio of IgA:IgG bearing lymphocytes and increased polymeric synthesis. Clin Exp Immunol 57:101-106, 1984 IS. van den Wall Bake AWL, Daha MR , Valentijn RM, et al: The bone marrow as a possible origin of the IgA I deposited in the mesangium in IgA nephropathy. Semin Nephrol 7:329-331, 1987 16. Julian BA, Quiggins PA, Thompson JS , et al: Familial IgA nephropathy. Evidence for an inherited mechanism of disease. N Engl J Med 312:202-208 , 1985 17. Alley CD: Synthesis of IgA by mammalian bone marrow. Adv Exp Med Bioi 216B:1175-1183 , 1987 18. Kyle RA: Monoclonal gammopathy of undetermined significance. Natural history in 241 cases. Am J Med 64:814826, 1978