A novel concept of Mikulicz’s disease as IgG4-related diseaseTetsuo Himia,*, Kenichi Takanoa, Motohisa Yamamotob,Yasuyoshi Naishirob, Hiroki TakahashibaDepartment of Otolaryngology, Sapporo Medical University School of Medicine, Sapporo, JapanbFirst Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo, JapanReceived 10 December 2010; accepted 28 January 2011Available online 14 May 2011AbstractSince Morgan’s report in 1953, Mikulicz’s disease (MD) has been considered part of primary Sjo¨gren’s syndrome (SS). However, MD hasa unique presentation, including persistent swelling of the lacrimal and salivary glands, and is characterized by good responsiveness toglucocorticoids, leading to recovery of gland function. Recently, it has been revealed that MD patients show elevated serum immunoglobulinG4 (IgG4) levels and prominent infiltration of IgG4-positive plasmacytes. The complications of MD include autoimmune pancreatitis,retroperitoneal fibrosis, tubulointerstitial nephritis, autoimmune hypophysitis, and Riedel’s thyroiditis, all of which show IgG4 involvement intheir pathogenesis. Thus, MD is a systemic ‘‘IgG4-related disease.’’ In addition, recent analyses have revealed that Ku¨ttner’s tumor (KT), achronic sclerosing sialadenitis that presents with asymmetrical firm swelling of the submandibular glands, is also associated with prominentinfiltration of IgG4-positive plasmacytes. MD and KT differ from SS and are thought to be singular systemic IgG4-related plasmacyticdiseases. Here we discuss the results of recent studies and provide an overview of MD as an IgG4-related disease.# 2011 Elsevier Ireland Ltd. All rights reserved.Key words: Mikulicz’s disease; Ku¨ttner’s tumor; Sjo¨gren’s syndrome; IgG4-related disease; Immunoglobulin G4\1. IntroductionIn humans, the serum immunoglobulin G (IgG)subclasses are defined as IgG1, IgG2, IgG3, and IgG4. Inhealthy adults, the mean serum level for IgG4 is lower than5% [1]. Generally, the amount of IgG4 does not vary withsex or age, and the amount of IgG4 as well as the IgG4/totalIgG ratio tends to remain constant [2]. Although thephysiological role of IgG4 remains unclear, several diseases,including Mikulicz’s disease (MD) and Ku¨ttner’s tumor(KT), have recently been reported to be associated withelevated serum IgG4 levels and prominent infiltration ofplasmacytes expressing IgG4 [3–5].MD refers to idiopathic, bilateral, painless, and symme-trical swelling of the lacrimal, parotid, and submandibularglands. Because MD and Sjo¨gren’s syndrome (SS) arehistologically similar, MD is considered as a subtype of SS[6]. However, MD and typical SS differ in some clinicalfeatures. In MD, the enlargement of lacrimal and salivaryglands is persistent and secretory dysfunction is either minoror not detectable. Further, MD shows good responsiveness tosteroids. Serologically, MD patients exhibit normogamma-globulinemia or hypergammaglobulinemia and normocom-plementemia or hypocomplementemia, but they lack anti-SS-A and anti-SS-B antibodies. It has also been confirmedthat MD patients show elevated serum IgG4 levels andinfiltration of IgG4-positive plasmacytes in the lacrimal andsalivary glands [3]. Thus, MD is apparently distinct from SS.Attention has also been paid to the pathological similaritiesbetween MD and autoimmune pancreatitis (AIP), particu-larly to the role of IgG4, and new developments are expectedto clarify the pathogenesis of both diseases.In this review, we summarize the results of recent studiesand provide an overview of MD.www.elsevier.com/locate/anlAuris Nasus Larynx 39 (2012) 9–17* Corresponding author at: South 1, West 16, Sapporo 060-8543, Japan.Tel.: +81 11 611 2111x3491; fax: +81 11 615 5405.E-mail address: himi@sapmed.ac.jp (T. Himi).0385-8146/$ – see front matter # 2011 Elsevier Ireland Ltd. All rights reserved.doi:10.1016/j.anl.2011.01.023
