title: The changing faces of IgG4-related disease: Clinical manifestations and pathogenesis.
abstract: Since the earliest reports in 2001, immunoglobulin G4 (IgG4)-related disease has been defined as an autoimmune systemic disease characterized by the lymphoplasmacytic infiltration of affected tissues leading to fibrosis and obliterative phlebitis along with elevated serum IgG4 levels. Prior to this unifying hypothesis, a plethora of clinical manifestations were considered as separate entities despite the similar laboratory profile. The pathology can be observed in virtually all organs and may thus be a challenging diagnosis, especially when the adequate clinical suspicion is not present or when obtaining a tissue biopsy is not feasible. Nonetheless, the most frequently involved organs are the pancreas and exocrine glands but these may be spared. Immunosuppressants lead to a prompt clinical response in virtually all cases and prevent histological sequelae and, as a consequence, an early differential diagnosis from other conditions, particularly infections and cancer, as well as an early treatment should be pursued. We describe herein two cases in which atypical disease manifestations were observed, i.e., one with recurrent neck lymph node enlargement and proptosis, and one with jaundice. Our understanding of the pathogenesis of IgG4-related disease is largely incomplete but data support a significant role for Th2 cytokines with the contribution of innate immunity factors such as Toll-like receptors, macrophages and basophils. Further, macrophages activated by IL4 overexpress B cell activating factors and contribute to chronic inflammation and the development of fibrosis. We cannot rule out the possibility that the largely variable disease phenotypes reflect different pathogenetic mechanisms and the tissue microenvironment may then contribute to the organ involvement.
authors.affiliation: Department of Internal Medicine, Division of Rheumatology, Allergy and Clinical Immunology, University of California Davis, School of Medicine, Davis, CA, USA; VA Medical Center Sacramento, Mather, CA, USA.
authors.forename: Arshia Duza
authors.initials: AD
authors.lastname: Islam
authors.affiliation: Division of Rheumatology and Clinical Immunology, Humanitas Research Hospital, Rozzano, Italy; BIOMETRA Department, University of Milan, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Selmi
authors.affiliation: VA Medical Center Sacramento, Mather, CA, USA.
authors.forename: Ananya
authors.initials: A
authors.lastname: Datta-Mitra
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California Davis, School of Medicine, Davis, CA, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Sonu
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California Davis, School of Medicine, Davis, CA, USA.
authors.forename: Mingyi
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Internal Medicine, Division of Rheumatology, Allergy and Clinical Immunology, University of California Davis, School of Medicine, Davis, CA, USA.
authors.forename: M Eric
authors.initials: ME
authors.lastname: Gershwin
authors.affiliation: Department of Internal Medicine, Division of Rheumatology, Allergy and Clinical Immunology, University of California Davis, School of Medicine, Davis, CA, USA; VA Medical Center Sacramento, Mather, CA, USA. Electronic address: sraychaudhuri@ucdavis.edu.
authors.forename: Siba P
authors.initials: SP
authors.lastname: Raychaudhuri
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology*; D002908:Chronic Disease; D006801:Humans; D007113:Immunity, Innate; D007074:Immunoglobulin G / Q000276:immunology*; D012008:Recurrence
chemical_list: D007074:Immunoglobulin G
keywords: Autoimmune disease; Diagnostic criteria; Histology; Lymphoproliferative; Pancreatitis; Plasma cells; Sclerosing fibrosis