Profiles of immunoregulatory cytokine production in vitro in patients with IgA nephropathy and their kindred

Abstract

SUMMARYWe hypothesized that the altered immunoglobulin synthesis and/or lymphocyte ("unciion apparent in patients with IgA nephropathy (IgAN) is due to a primary defeet in lymphokine regulation. In addition, we reasoned that such changes in lymphokine production might be, at least partially, genetically determined. To assess the extent ot'lymphocyte abnormalities, we investigated lhe profile of cytokine production from peripheral blood mononuclear cells (PBMC) in .14 IgAN piilicmsand44 of their first degree relatives, 10 of whom had persistent mierohaematuria. Compared wilh healthy volunteers (o = 34), PBMC from patients showed increased IL-2 production both spontaneously or after phytohaemagglutinin (PHA) (20 /ig/ml) stimulation, whereas lL-4 and interferon-gamma (IFN-y) production were significantly higher only after stimulation. Mierohaemaluric relatives liad a similar pattern of eytokine production, whereas non-microhaematuric relatives showed no significant diflerence versus normals. The altered pattern of cytokine production appeared to be quite specific to IgAN patients and their microhaematuric relatives, because patients with other forms of primary glomerulonephritis (n= 17) did not differ from normal individuals. Patients and relatives that hyperproduced IL-4 were also hyperproducers of IL-2. No such congruence was seen in any other group or with any other pairing of eytokines. We propose that a subpopulation of IgAN patients bear lymphocytes intrinsically hyper responsive. Among those individuals such hyperresponsiveness may be causally related to the pathogenesis and/or character of IgAN.

Down-regulation of core 1 1,3-galactosyltransferase and Cosmc by Th2 cytokine alters O-glycosylation of IgA1

“…Lymphocyte functions, including cytokine profiles, have been investigated extensively in IgAN patients, and several abnormalities were identified [ 39 ]. It is noteworthy that T-cell cytokines known to be synthesized excessively in IgAN are closely related not only to immunoglobulin class switching and production but also to renal insufficiency [ 40–43 ]. Furthermore, it has been suggested that IgAN is a glomerular disease that is likely Th2 dependent [ 30 ].…”

Pathogenesis of Immunoglobulin A Nephropathy: Recent Insight from Genetic Studies

“…Prior studies have demonstrated a range of immunologic defects in asymptomatic family members of IgAN patients, including increased production of IgA1, IgM, and cytokines at baseline and after antigenic stimulation (32, 33). More recently, systematic family studies have shown that elevated Gd-IgA1 levels are heritable, with 25%--33% of asymptomatic family members displaying levels that are just as elevated as the patients’ (34, 35).…”

SLAM‐Associated Protein Solves a Mystery of Autoimmunity

“…These findings strongly suggest that abnormalities of lymphocyte function are involved in the pathogenesis of IgA nephropathy. Also, there is evidence of increased T cell activity in patients with IgA nephropathy 6–12 . Most IgA nephropathy patients have increased serum IgA levels and IgA‐containing circulating immune complexes 13,14 .…”