© Springer-Verlag Berlin Heidelberg 2015
Hakan Demirci (ed.)Orbital Inflammatory Diseases and Their Differential DiagnosisEssentials in Ophthalmology10.1007/978-3-662-46528-8_33. IgG4-Related Orbital Inflammation
(1)
Department of Ophthalmology and Visual Sciences, W.K. Kellogg Eye Center, University of Michigan, 1000 Wall St, Ann Arbor, MI 48105, USA
3.1 Introduction
IgG4-related inflammations are recently recognized fibro-inflammatory conditions, characterized by tumefactive lesions containing dense lymphoplasmacytic infiltrates rich in IgG4+ plasma cells, storiform fibrosis, and obliterative phlebitis that are associated with elevated serum IgG4 [1, 2]. First described by Hamano et al. [3] in 2001, its incidence in Japan is estimated to be 0.28–1.08 cases per 100,000 people [2]. Hamano et al. [3] reported elevated serum IgG4 levels and infiltration of numerous IgG4+ plasma cells in ureteral and pancreatic lesions associated with retroperitoneal fibrosis in patients with autoimmune pancreatitis. In 2003, Kamisawa et al. [4] observed severe or moderate infiltration of IgG4+ plasma cells associated with CD4+ and CD8+ T lymphocytes in autoimmune pancreatitis lesions and in lesions of the liver, stomach, colon, salivary glands, and bone marrow. They proposed a new clinicopathological entity, IgG4-related systemic disease, in which IgG4+ plasma cells extensively infiltrate organs. Since its original observation, IgG4-related inflammation has been reported in almost every tissue with the pancreas, hepatobiliary tract, salivary glands, lymph nodes, retroperitoneum, and orbit most commonly involved [5, 6]. For each of these tissues, the diagnosis of IgG4-related disease has replaced established clinicopathological diagnoses that were otherwise used for patients meeting the criteria for IgG4-related disease. Meanwhile other patients not meeting the criteria retain the previous clinicopathological diagnoses. Therefore, there are clinicopathological entities with patients divided into those with IgG4-related disease and those that retain the previous established diagnosis for each of the entities. Because this phenomenon affects so many clinicopathological entities, it is likely that the findings used to diagnose IgG4-related disease are really the result of a particular host response rather than a newly recognized disease, a notion that is supported by the strong racial predisposition reported for IgG4-related disease. We therefore prefer to refer the term IgG4-related inflammation to IgG4-related disease.
Orbital and adnexal tissues are the fifth most commonly affected extrapancreatic site and occur in 4–13 % of patients with IgG4-related inflammation [3, 7]. While IgG4-related pancreatitis has a strong male predilection of 2.8–7.5:1, men and women are equally affected with M:F ratio of 1.3:1 in IgG4-related orbital inflammation [5, 7–9]. IgG4-related inflammation has a mean age of onset of 56 years in orbital cases and 58–69 years in pancreatitis cases [8–11]. The frequency of IgG4-related inflammation appears to show racial variations in incidence. For pancreatitis, a review of literature showed that 76 % of cases were from Japan, South Korea, Hong Kong, and Taiwan and only 16 % of cases were Caucasian [10]. Compared to IgG4-related pancreatitis which is more severe in men, orbital involvement shows that the proportion of cases resistant to one or more treatment modalities is evenly distributed between men and women [8, 9].
Similarly, a review of histopathology slides from 1,014 patients with orbital lymphoproliferative disease in Japan resulted in reclassification of 22 % of cases as IgG4-related disease [12, 13]. The same evaluation was performed in 164 patients with ocular adnexal lymphoproliferative disease in the United States, and only 5 % of them were reclassified as IgG4-related disease [14].
3.2 Clinical Presentation
IgG4-related inflammation can affect any tissue in the orbit including the lacrimal gland, extraocular muscle, sclera, optic nerve, nasolacrimal sac and duct, sensory nerves, eyelid, and rarely conjunctiva [9, 12, 15–21]. A recent review of 65 patients with IgG4-related orbital inflammation showed that lacrimal gland enlargement (88 %) was the most common, followed by trigeminal nerve branch enlargement (39 %), extraocular muscle enlargement (25 %), diffuse infiltration of orbital fat (23 %), orbital mass lesions (17 %), eyelid mass lesions (12 %), and nasolacrimal duct obstructive lesions (2 %) [22]. In up to 52 % of patients, more than one orbital tissue were involved. Patients usually present with a mass or mass-related symptoms including painless eyelid swelling, proptosis with or without diplopia, and mild or no signs of inflammation [9, 15, 16]. A review of literature showed bilateral involvement in 62 % of patients [23]. Visual acuity is usually unaffected, and some patients are asymptomatic with lesions found incidentally on physical examination or imaging studies [9, 15, 16]. On magnetic resonance imaging, orbital lesions are hyperintense on T1-weighted images and hypointense on T2-weighted images. They usually show homogenous enhancement with gadolinium and no destructive bony involvement [17]. Reported is a single case of IgG4-related inflammation with osteo-destructive lesions that affected the orbital bones and involved the orbital apex, cavernous sinus, palate, nasal septum, turbinates, and paranasal sinuses [15]. A recent study showed that infraorbital nerve involvement associated with enlargement of bony canal strongly suggests IgG4-related inflammation [24].
Orbital cases may be associated with extra-orbital inflammatory lesions, most commonly involving salivary glands and lymph nodes [9, 16, 18–20]. FDG-PET is a useful imaging modality for systemic evaluation of IgG4-related inflammation and shows distant and silent sites of involvement [25]. There is a current trend to reclassify the majority of cases of Mikulicz’s disease as IgG4-related disease. These individuals demonstrate simultaneous bilateral involvement of the lacrimal glands, submandibular glands, or parotid glands and are considered to be affected by a clinical subtype of IgG4-related disease. Matsui et al. [26] reviewed 25 cases of IgG4-related Mikulicz’s disease and found that 44 % of them had asthma and allergic rhinitis, in comparison to allergic rhinitis prevalence of 8–25 % in general Japanese population.
3.3 Diagnosis
Based on two IgG4-related disease study groups organized by the Ministry of Health, Labor and Welfare of Japan, comprehensive clinical diagnostic criteria for IgG4-related disease include (1) clinical examination showing characteristic diffuse/localized swelling or masses in single or multiple organs, (2) hematological evaluation showing elevated serum IgG4 concentrations (≥135 mg/dL), and (3) histopathological examination showing marked lymphocyte and plasma cell infiltration and fibrosis, with IgG4+ plasma cells comprising more than 40 % of the total plasma cell population and with at least 10 IgG4+ plasma cells per high-power microscopic field [2]. However, in some tissues, greater numbers of IgG4+ plasma cells are required for the diagnosis. In lacrimal gland lesions, more than 100 IgG4+ plasma cells/hpf are required [27]. If all three criteria are present, it is classified as definite IgG4-related disease. If the first and third criteria are present, it is probable for IgG4-related disease, and if the first and second criteria are present, it is possible for IgG4-related disease [2]. The presence of IgG4+ plasma cells alone in a biopsy specimen is not specific for IgG4-related disease. Both increased absolute number and proportion of IgG4+ plasma cells are required for the diagnosis. When counting IgG4+ cells, maximum IgG4+ staining areas should be selected and at least three high-power microscopic fields should be averaged [5, 27]. It should be kept in mind that the size of high-power field may change from one microscope to another, but it is generally performed with 40× objective and 10× ocular lenses [9].
Serum IgG4 level varies among the patients who have orbital vs extra-orbital inflammation and unilateral vs bilateral involvement. A review of 27 patients showed that serum IgG4 levels averaged 809 mg/dL in patients with extra-orbital inflammation compared to 235 mg/dL in patients without extra-orbital inflammation and 636 mg/dL in patients with bilateral inflammation compared to 111 mg/dL in patients with unilateral probable disease [15]. The patients with hilar lymphadenopathy or lacrimal and salivary gland lesions were found to have significantly higher IgG4 levels than those without [28]. Elevated serum IgG4 level (>135 mg/dL) is a useful diagnostic tool and has a sensitivity of 97 % and specificity of 79.6 % in diagnosing IgG4-related disease [29]. Serum IgG4 level can be elevated in Churg-Strauss syndrome, multicentric Castleman’s disease, eosinophilic disorders, and in some patients with rheumatoid arthritis, systemic sclerosis, chronic hepatitis, and liver cirrhosis [30]. Additionally, 30 % of patients diagnosed with probable IgG4-related disease may have a normal serum IgG4 level [31].
In the setting of proven IgG4-related inflammation elsewhere in the body, ophthalmic inflammatory lesions may present another manifestation of the condition and not require biopsy. Similarly, in the patients with involvement of orbital structures that are difficult to biopsy, such as extraocular muscles, concurrent inflammatory lesions at the non-ocular sites may represent opportunity for biopsy with low morbidity.
3.4 Histopathological Features
The main histopathological features used to diagnose IgG4-related disease are lymphoplasmacytic infiltration, lymphoid follicle formation, obliterative phlebitis, and storiform fibrosis which are accompanied by atrophy and loss of structures within involved tissue [27, 32]. These features vary depending on the tissue and the age of the lesion. The lymphoplasmacytic infiltrate is more intense in early lesions and consists of polyclonal T lymphocytes, IgG4+ plasma cells, and scattered eosinophils. Fibrosis often develops as lesions mature and is accompanied by atrophy. However, some lesions start as a primary sclerosing inflammation [5, 16]. The lack of lymphoplasmacytic infiltrate and predominance of sclerosis or fibrosis often create challenges in histopathological diagnosis because of the paucity of infiltrating leukocytes, including IgG4+ plasma cells. Based on the relative predominance of the lymphoplasmacytic and sclerotic components, IgG4-related disease is subclassified in three categories: pseudolymphomatous, mixed, and sclerotic [33]. In patients with orbital involvement, the mixed pattern is the most common, followed by the sclerotic and pseudolymphomatous which occur with almost equal frequency. Histopathologically, IgG4-related inflammation differs in the orbit and lacrimal gland compared to other tissues with two exceptions. First, the fibrosis within the orbit rarely forms storiform patterns as it does in extra-orbital tissues [27]. Second, obliterative phlebitis is uncommon in the orbit, while it is invariably seen in the pancreatic lesions [1, 11, 12, 32].
3.5 Pathogenesis
The underlying immune mechanisms of IgG4-related inflammation remain unknown. Several studies have been performed to evaluate autoimmunity as a possible cause [34]. Nonspecific antinuclear antibodies have been identified in more than half of patients with IgG4-related inflammation [34]. Antibodies specific for lactoferrin and carbonic anhydrase (CA)-II are the most frequently detected autoantibodies in autoimmune pancreatitis, affecting 73 and 54 % of patients, respectively [35], with a strong correlation between increased serum IgG4 and anti-CA-II antibody levels [35]. Pancreatic secretory trypsin inhibitor is another potential autoantigen which was detected in 30–40 % of patients with IgG4-related autoimmune pancreatitis [34]. Because of the difference in the clinical presentation of IgG4-related pancreatitis and orbital inflammation, it is suggested that the orbital inflammations might be caused by an antigen of the upper respiratory or digestive tracts that affects men and women equally, while the pancreatitis might be caused by an antigen of the lower respiratory or digestive tracts that affects mainly men [9]. Frulloni et al. [36] found that Helicobacter pylori surface protein was present in 95 % of patients with autoimmune pancreatitis, suggesting that this antigen might play a role in the pathogenesis of IgG4-related pancreatitis. In a proteomics study, Yamamoto et al. [37] found a 13.1 kDa protein autoantigen in all patients with IgG4-related inflammation, regardless of the organ(s) affected. Taken together, these studies suggest that multiple antigens, including a key autoantigen, may be an initiating factor for IgG4-related inflammation.
Analysis of cytokines expressed in patients with IgG4-related inflammation provided important insights into the pathogenesis of the disorder. Real-time polymerase chain reaction (RT-PCR) shows that significantly increased levels of Th-2 cytokines, namely, IL-4, IL-5, IL-10, and IL-13, as well as a secondary pro-fibrotic cytokines, transforming growth factor (TGF)-beta, and connective tissue growth factor (CTGF) in IgG4-related inflammation of the pancreas [38]. The expression of Foxp3 messenger RNA, a transcription factor specific for naturally arising CD4(+)CD25(+) regulatory T lymphocytes, is also significantly increased in IgG4-related inflammation including orbital inflammatory pseudotumor [20, 38, 39]. A similar study of patients with IgG4-related dacryoadenitis showed that IL-4, IL-5, IL-10, IL-13, and TGF-β, but not Th-1 cytokines, as well as a master upregulator of Th-2 responses, GATA3, were significantly elevated in peripheral blood CD4+ T lymphocytes [40].
Th-2 cells play a role in antibody-mediated immunity, parasitic infections, asthma, and allergy. Treg cells are important in immune tolerance, lymphocyte homeostasis, and downregulation of immune responses. In autoimmune inflammation, Treg cells suppress inflammation via cell-cell contact and secretion of immunosuppressive cytokines, IL-10 and TGF-β, while promoting fibrosis [41, 42]. Th-2 cytokines IL-4, IL-5, IL-6, and IL-13 transform B lymphocytes into plasma cells which produce antibodies, including autoantibodies. These cytokines in conjunction with TGF-beta, CTGF, and IGF-2 stimulate fibroblast proliferation, differentiation, and collagen production necessary for fibrosis. In particular, IL-13 induces TGF-β gene expression via IL-13Rα2 in macrophages, enhancing fibrosis [9]. Th-2 cytokines also stimulate B lymphocytes to produce IL-6 which promotes aforementioned fibroblast activities and is a potent stimulator of plasma cell differentiation and proliferation. Treg cells secrete IL-10 and TGF-beta which promote proliferation and differentiation of B lymphocytes into plasma cells to secrete IgG4 isotype and switching plasma cell secretion from IgE, promoted by Th-2 cytokines, IL-4 and IL-13, to IgG4. Treg cells also regulate other activities of Th-2 cells. Treg secretion of IL-10 and TGF-beta suppresses Th-2 cytokines IL-3, IL-4, and IL-5 which are required for the differentiation, survival, and activity of mast cells, basophils, and eosinophils as well as for homing of Th2 cells. Thus, there is a delicate balance between Th-2 and Treg cells in the evolving inflammatory responses in which eosinophilia, fibrosis, and IgG4 secretion may dominate.
IgG4 constitutes less than 5 % of total IgG and has unique anti-inflammatory properties that may affect all of the various types of immune inflammatory responses [29]. Classically produced in response to parasites and allergens, IgG4 is generated against protein targets but lacks the ability to activate complement and participate in complement mediated lysis and lacks the ability to promote antibody-dependent cell-mediated toxicity or form immune complexes. It also has low affinity for type I (CD64) Fc receptors and no affinity for type II (CD32) or III (CD16) Fc receptors. Furthermore, it has the ability to displace proinflammatory IgG1, IgG3, or IgE antibodies from antigen-binding sites. IgG4 titers increase with the development of antigenic tolerance [1, 43, 44, 45], an effect that is utilized therapeutically as the basis of desensitization of patients to external antigens including peanut, egg, and milk protein antigens who exhibit increase in serum IgG4 level with therapy [46]. These features suggest that IgG4 is a surrogate marker of a particular type of pro-fibrotic inflammatory process in which it serves to mitigate inflammatory responses [9].
In a study of IgG4-related Mikulicz’s disease, Yamada et al. [47] demonstrated the effects of Th-2 cytokines in human disease. They found an admixture of polyclonal IgG4+ plasma cells infiltrating lacrimal glands, which they attributed to antigenic responses in which IgE+ and IgG4+ plasma cells undergo Th-2 cytokine-induced class switching thereby retaining overlap of antigen specificity of the generated IgE and IgG4 antibodies. Yamada et al. [47] thought that this was the reason for high incidence of asthma and allergic rhinitis in patients with IgG4-related inflammation. Because they also found genetically related B cells and plasma cells in the lacrimal glands and peripheral blood, Yamada et al. [47] suggested that memory B cells or long-lived plasma cells migrate from lacrimal or salivary glands to the bone marrow or directly to other target organs, causing multiorgan involvement in IgG4-related inflammation.
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