T cell cytokines determine the severity of experimental IgA nephropathy by regulating IgA glycosylation.
Hyperfunction of Th2 cells and aberrant glycosylation of IgA have been proposed independently as factors in the pathogenesis of IgA nephropathy (IgAN), the most common form of glomerulonephritis. To investigate the relationship between Th2 cytokines and IgA glycosylation in the genesis of IgAN, we induced IgAN in C3HeB and BALB/c mice by oral immunization and intranasal challenge with Sendai virus. Although both strains of mice developed microhaematuria and glomerular IgA immune deposits to similar degrees, only BALB/c mice developed significant renal insufficiency. More profound reductions of terminal galactosylation and sialylation occurred in Sendai virus-specific IgA from BALB/c versus C3HeB mice, and splenocytes from immunized BALB/c mice produced more Th2 and less Th1 cytokines compared to C3HeB mice when stimulated with antigen in vitro. Furthermore, the decreased glycosylation of IgA elicited by Th2 cytokines in vitro was blunted by the addition of IFN-gamma. We conclude that increased production of Th2 cytokines can lead to abnormalities in IgA glycosylation, which in turn promote heightened phlogistic responses to IgA immune complexes lodging in the glomerulus. We suggest that a relative or absolute increase in Th2 cytokine production in response to mucosal infection is a significant pathogenic factor in human IgAN.
Chintalacharuvu
S R
SR
Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
Nagy
N U
NU
Sigmund
N
N
Nedrud
J G
JG
Amm
M E
ME
Emancipator
S N
SN
D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D000936:Antigen-Antibody Complex / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis*; D005260:Female; D005922:Glomerulonephritis, IGA / Q000276:immunology*; D006031:Glycosylation; D007070:Immunoglobulin A / Q000097:blood / Q000737:chemistry*; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D015848:Interleukin-5 / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D029082:Sendai virus / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
D000914:Antibodies, Viral; D000936:Antigen-Antibody Complex; D016207:Cytokines; D007070:Immunoglobulin A; D007376:Interleukin-2; D015848:Interleukin-5; D015847:Interleukin-4; D007371:Interferon-gamma