An 83-year-old man presented with weight loss, lymphadenopathies, anicteric cholestasis, and a striking hypergammaglobulinemia. He developed renal failure with tubular proteinuria. Investigations revealed pronounced increase of serum polyclonal IgG1, IgG3 and IgG4, and salivary gland and kidney interstitium infiltrates that included B-lymphocytes, T-lymphocytes and IgG3+ and IgG4+ plasma cells. Remarkably, lymph node B-cell follicles germinal centers were invaded by numerous T-cells, mostly CD4+. The diagnosis was IgG4-related systemic disease. Rituximab (375 mg/m²/week for 4 weeks) induced a dramatic and sustained clinical and biological improvement. To date, very little is known on the mechanisms underlying IgG4-related systemic disease. In addition to perfectly illustrate the broad spectrum of this protean condition, the present case provides further insights on its pathophysiology. The efficacy of rituximab suggests a critical role of CD20+ B-cells in the disease clinical expression and progression. The overexpression of IgG1 and IgG3, in addition to IgG4, and the unusual abundance of CD4+ T-cells in germinal centers of the B-cell follicles points to a possible role of B follicular helper T-cells in enhancing a skewed B-cell terminal maturation.