https://imcjms.com Ibrahim Medical College Journal of Medical Science https://imcjms.com/registration/journal_full_text/387 Tue, 10 Aug 2021 01:17:07 +0000 Abstract Immunoglobulin G4 related disease (IgG4-RD) is a recently perceived fibroinflammatory condition, identified as a systemic illness for the first time in the early 2000. It can involve virtually every organ of the body, commonly presenting as lymphadenopathy, retroperitoneal fibrosis, autoimmune pancreatitis, tubulointerstitial nephritis, parotid or lacrimal gland enlargement. The diagnosis is confirmed by histopathological analysis and is often, but not always accompanied by an increased level of serum IgG4 concentration. In fact, the name addressing this autoimmune fibroinflammatory condition may be considered a misnomer, as the role of the non-inflammatory immunoglobulin IgG4 in the immune mechanism of IgG4-RD remains to be elucidated. IMC J Med Sci 2021; 15(2): 006. DOI: https://doi.org/10.3329/imcjms.v15i2.55878 *Correspondence: Saika Farook, Department of Microbiology, Molecular and Flow Cytometry, DMFR Molecular Lab & Diagnostics BD LTD, Dhaka, Bangladesh. Email: sairana15@yahoo.com   Introduction An International symposium held in 2011 provided a set of guidelines for the diagnosis of IgG4-RD. Even the nomenclature of this newly discovered condition continues to evolve and the term IgG4-related disease has recently been elected in preference to alternatives such as IgG4-related systemic disease, IgG4-related sclerosing disease, and IgG4-related multi-organ lymphoproliferative syndrome [4]. Epidemiology   Since the establishment of the disease entity, several studies have been conducted to elucidate the immunopathogenesis of IgG4-RD. The immunoglobulin IgG4 has restricted ability to bind complement and to interact with activating Fc receptors for which it is considered as a non-inflammatory immunoglobulin [9]. Hence, whether IgG4 play an active role in the autoimmune mechanism of the disease is still questionable. Recent studies claim, interactions among clonally expanded CD4+ cytotoxic T-lymphocytes (CD4+CTL), T follicular helper (TFH) cells, and B cells play a major role in the immunopathogenesis of IgG4-RD [13]. Annexin A11 and galactin-3 have been implicated to be the causative autoantigens [14]. The plasmablasts or activated B cells in patients with IgG4-RD are specific for these autoantigens and are oligoclonally restricted, resulting in clonal expansion of CD4+ CTL in tissue sites [13]. CD4+ CTLs are a unique CD4+ T cells with cytolytic capabilities, especially found associated with chronic viral infections and malignancies [15]. In IgG4-RD, CD4+ CTLs in affected tissues, secrete profibrotic cytokines including interleukin (IL)-1β, transforming growth factor β1 (TGF-β1), and interferon γ (IFN-γ) as well as cytolytic molecules such as perforin and granzymes A and B, responsible for killing target cells. Furthermore, IL-4-secreting TFH cells are also expanded in blood and tissue sites, which are essentially responsible for germinal center formation, affinity maturation, class switching to IgG isotypes including IgG4 and the development of most high affinity memory B cells [13, 16].   Risk factors Several immune mediated mechanisms are thought to play a role in the fibroinflammatory process of IgG4-RD. Since the condition is relatively new, these factors are not well established and further extensive studies are essential to confirm their contributions.   Genetic factors:Genetic studies revealed that the HLA serotypes DRB1*0405 and DQB1*0401 are associated with increased susceptibility to IgG4-related disease in Japanese populations, whereas DQβ1-57 without aspartic acid is related to disease relapse in Korean populations [17, 18].       IgG4-RD can affect any organ of the body and can present with varied clinical features. Presentation is usually subacute; fever and elevation of C-reactive protein levels are unusual. The disorder is often diagnosed incidentally through radiologic findings or unpredictably in pathological specimens [26]. However, patients with multi-organ involvement may suffer from weight loss - about 9 to14 kgs over a period of few weeks to months before reaching the correct diagnosis [26]. IgG4-RD is relatively new in Bangladesh and cases have not been reported widely. Till now, a single case of IgG4-related peri-aortitis has been reported in 2018, suggesting that although the incidence of the disease exists in Bangladesh, cases are not being unmasked extensively [35]. This is possibly due to a lack of awareness as well as adequate diagnostic facilities. Clinicians should remain concerned to the possibility that IgG4-RD often presents with features of malignancy and may mimic some autoimmune rheumatic diseases such as Sjögren's syndrome, systemic lupus erythematosus (SLE), and granulomatosis with polyangiitis [36]. Diagnosis       Although IgG4 level reduces in patients whose serum IgG4 concentration was raised at baseline following treatment with glucocorticoids, they may remain above normal values in certain patients [41]. Interestingly, a study conducted in Japan revealed that IgG4 concentration was not reduced to normal level in 115 out of 182 (63%) patients treated with glucocorticoids [44]. Therefore, the diagnosis of IgG4-RD is determined by the combination of clinical, imaging, serological and histological criteria. A summary diagnostic scheme of IgG4-RD is shown in Figure-1.     Figure-1: Diagnostic scheme of IgG4-RD. Serum IgG4 - normal up to 1.35 g\L. HPF: high power field (400x); +ve: positive.   Treatment 6.     Umehara H, Okazaki K, Masaki Y, Kawano M, Yamamoto M, Saeki T, et al. Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD). Mod Rheumatol. 2012; 22(1): 21-30. 7.     Comai G, Cuna V, Fabbrizio B, Sabattini E, Leone O, Tondolo F, et al. A case report of IgG4-related disease: an insidious path to the diagnosis through kidney, heart and brain. BMC Nephrol. 2019; 20(1): 1-7. 8.     Karim F, Loeffen J, Bramer W, Westenberg L, Verdijk R, van Hagen M, et al. 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