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Abstract
Immunoglobulin G4-related disease (IgG4-RD) is an emerging immunemediated fibro-inflammatory disorder which can involve any organ. The main characteristics of IgG4-RD are increased serum IgG4 concentration, abundant IgG4+ plasma cells in affected tissues, and painless swollen organs often without general symptoms. Typical pathology features of IgG4-RD are lymphoplasmacytic infiltration, dense storiform fibrosis, and obliterative pheblitis. The pathogenesis of IgG4-RD remains elu-sive, but involvement of excess production of type 2 T helper cells, regulatory T-cell cytokines, and B-cell activating factor in the development of IgG4-RD has been suggested. Diagnosis of IgG4-RD can be made on the basis of serological, imaging, particularly histopathological findings. Glucocorticoid is the first-line therapy for patients with multiple organ dysfunction and clinical symptoms. Drugs such as azathioprine, mycophenolate mofetil, methotrexate, and cyclophosphamide can be used as ste-roid-sparing agents. Rituximab is reported to be an effective therapy for treatment of IgG4-RD, even without concomitant glucocorticoid therapy. This review summarizes current concepts on pathophysiology, clinical manifestations, and treatment of IgG4-RD.
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Figure 1.
immunoglobulin G (IgG)4 Fab-arm exchange makes bispecific antibodies. The heavy chains of IgG are bound to each other by interchain disulfide bridge. As the disulfide bonds between heavy chains of IgG4 are unstable, IgG4 easily forms intrachain disulfide bonds in the hinge region. Intrachain disulfide bond of IgG4 is linked by noncovalent interaction. When the non-con-valent bonds dissociate, half of one IgG4 molecule (a heavy chain-light chain pair) and half of another IgG4 molecule exchange randomly, forming a Fab-arm exchange. Through such processes, the IgG4 molecule becomes bispecific by acquiring two Fab-arms with different epitope specificity. This bispecific IgG4 molecule, however, loses its ability to form immune complexes as the molecules cannot crosslink antigens.
Figure 2.
Histological and immunohistochemical findings of biopsy specimens of the lymph node (A) and submandibular gland (B∼E). (A) The germinal centersare predominantly composed of small lymphocytes, centrocytes, centroblasts, and numerous mature plasma cells (H&E, ×200). (B) The storiform pattern of fibrosis is present, indicating dense fibrosis within which lymphocytes, plasma cells, and occasional eosinophils are embedded (H&E, ×100). (C) Veins occluded by inflammatory infiltrate composed of lymphocytes and plasma cells are noted (arrowheads) (H&E, ×200). (D, E) The IgG4+/IgG+ plasma cell ratio is estimated at 90%. D: Immunoglobulin (Ig) G-immunohistochemical stain, E: IgG4-immunohistochemical stain; ×100.
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