Pathogenesis of IgG4-RD and iMCD

Lymph nodes are frequently involved in patients with IgG4-RD or iMCD and they are the main sources of IgG4 and IgG4⁺ cells. However, the process by which IgG4 and IgG4⁺ cells are generated differs between the two diseases. (a) Tfh2 cells migrate into GCs and Tfh2-derived IL-4 and IL-21 promote the differentiation of IgG4⁺ plasmablasts/plasma cells. IL-21 supports GC expansion and CD8⁺ CTL cytotoxic function. Infiltration of eosinophils is also a unique pathological observation in IgG4-RD. (b) In iMCD, dysregulation of IL-6 production facilitates the development of CD5⁺ B cells in the non-GC area, resulting in the expansion of the non-GC area and regression of the GC area. CD5 on B cells activates the pathway downstream of IL-6, even without the IL-6 receptor, through direct binding of CD5 to IL-6. IL-6-stimulated B cells differentiate into IgG4⁺ plasma cells, IgA⁺ plasma cells and IgM⁺ plasma cells. Sheet-like mature plasma cell proliferation is also a specific pathological finding in iMCD.