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Decreased cytokine-induced IgA subclass production by CD40-ligated circulating B cells in primary IgA nephropathy

J W de Fijter, N I van Nisselrooij, W E Schroeijers, M R Daha, L A van Es, C van Kooten
Nephrology, Dialysis, Transplantation 1998, 13 (2): 285-92
9509436

BACKGROUND: In IgA nephropathy (IgAN), the abnormalities in the IgA immune system are apparently restricted to the IgA1 subclass in the systemic compartment, as evidenced by the antigen-specific responses to recall antigens. Since precursors of IgA producing B cells in human peripheral blood belong predominantly to the mucosal compartment, we took the opportunity to assess the capacity of circulating B cells in peripheral blood (PBMC) of 20 IgAN patients and matched controls to produce IgA, IgA1, and IgA2.

METHODS: Supernatants from T cell- (immobilized anti-CD3) and B cell-specific (CD40 ligation) activated cultures were assessed for immunoglobulin isotypes by ELISA. In addition, we compared the sensitivity of T and B cells to various cytokines (IL-2, IL-10, TGF-beta) in both culture systems.

RESULTS: In contrast to significantly higher plasma IgA1 levels (P < 0.01), no significant differences in salivary IgA1 (P = 0.73) and IgA2 (P = 0.96) levels or ratios (P = 0.91) were found. In the absence of exogenous cytokines, none of the different culture systems led to significant differences in IgA or IgA subclass synthesis by PBMCs of patients and controls. However, in IgAN patients, the addition of IL-2 did not enhance the production of the IgA subclasses as was found in controls. Furthermore IL-10 led to significantly (P < 0.05) lower IgA1 and IgA2 synthesis in patients than in controls. TGF-beta induced suppression of all isotypes in patients and controls. None of the different conditions resulted in a selectively enhanced production of any one of the IgA subclasses. When both IL-10 and TGF-beta were added to the cultures, IgM was the predominant immunoglobulin synthesized both in patients and controls with a significantly (P < 0.05) lower synthesis of IgM, IgG, IgA1, and IgA2 in patients.

CONCLUSION: These in vitro data suggest that PBMCs from patients contain more mature and further differentiated B cells. However, there was no selective IgA or IgA1 dysregulation of circulating B cells in IgAN. These results do not confirm the widely believed paradigm that patients with IgAN are primary hyperresponders.

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