https://www.nejm.org/doi/pdf/10.1056/NEJMra1104650

IgG4-related disease

High serum IgG4 concentrations in patients with sclerosing pancreatitis

https://gut.bmj.com/content/gutjnl/58/12/1680.full.pdf

Recent advances in autoimmune pancreatitis

Primary Sjogren's syndrome (pSS) is a prototypic autoimmune disorder, management of which has long suffered from a lack of knowledge of the underlying pathophysiological mechanisms; however, over the past decade major advances have been made in understanding the pathogenesis of pSS. The innate immune system has been demonstrated to have an important role at the early stage of the disease, notably through activation of the type I interferon (IFN) system. In addition, mechanisms of B-cell activation in pSS have become clearer, particularly owing to recognition of the involvement of the TNF family cytokine B-cell-activating factor, production of which is highly dependent on expression of type I and type II IFNs. Moreover, key inroads have been made in understanding lymphomagenesis, the most severe complication of pSS. IL-12 production and subsequent T-cell activation, mainly IFN-γ-secreting type 1 T-helper cells, have also been implicated in disease pathogenesis. Furthermore, evidence implicates neuroendocrine system dysfunction in pSS pathogenesis. These pathophysiological advances open new avenues of investigation. Indeed, the increased understanding of pSS pathogenesis has already led to the development of promising novel therapeutic strategies. This article summarizes recent findings regarding the pathogenic mechanisms involved in pSS and their implications.

Advances in understanding the pathogenesis of primary Sjögren's syndrome

Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is an immune-mediated condition that can affect almost any organ and is now being recognized with increasing frequency. IgG4-RD is characterized by a lymphoplasmacytic infiltrate composed of IgG4(+) plasma cells, storiform fibrosis, obliterative phlebitis, and mild to moderate eosinophilia. The diagnosis of IgG4-RD unifies many eponymous fibroinflammatory conditions that had previously been thought to be confined to single organs. IgG4-RD lesions are infiltrated by T helper cells, which likely cause progressive fibrosis and organ damage. IgG4 antibodies are generally regarded as noninflammatory. Although autoreactive IgG4 antibodies are observed in IgG4-RD, there is no evidence that they are directly pathogenic. Rituximab-induced B cell depletion in IgG4-RD leads to rapid clinical and histological improvement accompanied by swift declines in serum IgG4 concentrations. Although IgG autoantibodies against various exocrine gland antigens have been described in IgG4-RD, whether they are members of the IgG4 subclass is unknown. The contribution of autoantibodies to IgG4-RD remains unclear.

IgG4-related disease.

Objective
Mikulicz disease has been considered to be a subtype of Sjogren's syndrome (SS). However, recent studies have suggested that Mikulicz disease is an IgG4-related disease and is distinguishable from SS. In addition, it has been reported that both interleukin-4 (IL-4) and IL-10 induce IgG4 production and inhibit IgE. This study was undertaken to examine the expression of these cytokines in patients with Mikulicz disease and patients with SS.

Methods
Labial salivary gland (LSG) sections from 15 patients with Mikulicz disease and 18 patients with SS were examined for subsets of the infiltrating lymphocytes, expression patterns of messenger RNA (mRNA) for cytokines/chemokines, and relationships between the IgG4:IgG ratio and the expression of mRNA for IL-4 or IL-10.

Results
Immunohistochemical analysis showed lymphocyte infiltration of various subsets in the LSGs of SS patients, and the selective infiltration of IgG4-positive plasma cells and Treg cells in the LSGs of Mikulicz disease patients. The levels of mRNA for both Th1 and Th2 cytokines and chemokines in LSGs from patients with SS were significantly higher than in controls, while the expression of both Th2 and Treg cells was significantly higher in the patients with Mikulicz disease than in controls. Furthermore, the expression of IL-4 or IL-10 in the LSGs was correlated with the IgG4:IgG ratio.

Conclusion
These results suggest that the pathogenesis of Mikulicz disease is different from that of SS. Mikulicz disease is a unique inflammatory disorder characterized by Th2 and regulatory immune reactions that might play key roles in IgG4 production.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/art.33320

Th2 and regulatory immune reactions contribute to IgG4 production and the initiation of Mikulicz disease

Objectives Interleukin (IL)-21 is mainly produced by CD4 T helper (Th) cells including Th2, Th17 and follicular helper T (Tfh) cells. Recent studies have reported that IL-21 is involved in the formation of germinal centres (GCs) and class switching of IgG4. It has been suggested that IgG4-related dacryoadenitis and sialoadenitis (IgG4-DS), so-called Mikulicz9s disease (MD), is distinct from Sjogren9s syndrome (SS) and shows a high frequency of GC formation in salivary glands. In this study the expression of IL-21 in IgG4-DS and SS patients was examined. Methods Twelve patients with IgG4-DS, 15 with SS and 15 healthy subjects were screened for (1) ectopic GC formation in formalin-fixed labial salivary gland (LSG) biopsy samples; (2) expression of IL-21, Th2-, Th17- and Tfh-related molecules (cytokines, chemokine receptors and transcription factors) in LSGs; (3) relationship between IgG4/IgG ratio and mRNA expression of IL-21 in LSGs. Results mRNA expression of IL-21 and Bcl-6 in LSGs from patients with IgG4-DS was significantly higher than in patients with SS and controls. IL-21 and CXCR5 were detected by immunohistochemistry in or around GC in patients with SS and those with IgG4-DS. IL-21 was detected in infiltrating lymphocytes outside GC only in patients with IgG4-DS. Expression of IL-21 was consistent with that of Th2-related molecules while IL-17 was rarely seen in IgG4-DS. Furthermore, the expression of IL-21 in LSGs was correlated with the number of GC formations and the IgG4/IgG ratio in patients with IgG4-DS. Conclusions These results suggest that overexpression of IL-21 by Th2 cells might play a key role in GC formation and IgG4 production in IgG4-DS.

https://ard.bmj.com/content/annrheumdis/71/12/2011.full.pdf

Interleukin-21 contributes to germinal centre formation and immunoglobulin G4 production in IgG4-related dacryoadenitis and sialoadenitis, so-called Mikulicz's disease

The aim of this study was to investigate the initiation and progression of autoimmune damage in the lesions of labial salivary glands (LSGs) from primary Sjogren's syndrome (SS) patients by examining the selective localization of T helper (Th) subsets such as Th1, Th2, Th17 regulatory T cells (Tregs) and follicular T helper cells (Tfh). The expression of cytokines and transcription factors associated with these Th subsets in the LSGs from 54 SS patients and 16 healthy controls was examined using real-time polymerase chain reaction (PCR) and immunostaining. Additionally, infiltrating lymphocytes without germinal centre (GC-) and with GC (GC+) in the LSGs specimens from eight SS patients were extracted selectively by laser capture microdissection (LCM). The mRNA expression of these molecules was compared between the two sample groups of GC- and GC+ by real-time PCR. The mRNA expression of cytokines and transcription factors of all T helper (Th) subsets in the LSGs from the SS patients was increased significantly in comparison with controls. In LSGs from the SS patients, Th2 and Tfh was associated closely with strong lymphocytic infiltration; however, Th1, Th17 and Tregs was not. In the selectively extracted lesions of LSGs, Th1 and Th17-related molecules were detected strongly in the GC-, while Th2 and Tfh-related molecules were detected in the GC+. In contrast, no significant association with strong lymphocytic infiltration was observed in Treg-related molecules. These results indicate that SS has selective localization of Th subsets such as Th1, Th2, Th17 and Tfh in the LSGs, which is associated closely with disease severity and/or status. SS might be initiated by Th1 and Th17 cells, and then progressed by Th2 and Tfh cells via GC formation.

Selective localization of T helper subsets in labial salivary glands from primary Sjögren's syndrome patients

Mikulicz’s disease (MD) was considered to be a subtype of Sjogren’s syndrome (SS), based on histopathological similarities. However, recent studies have indicated that patients with MD show high serum IgG4 concentration, and suggested that MD is one of “IgG4-related disease” and distinguishable from SS. Therefore, we clinically and histopathologically examined the disease states of MD and SS in detail. Twenty patients with Mikulicz’s disease and 18 with SS were comparatively studied to determine clinical characteristics in MD patients. Sialography in MD patients did not show the “apple-tree sign” typically seen in SS. Serologically, high serum IgG4 levels but not anti-SS-A or anti-SS-B antibodies were observed in MD. SS showed lymphocytic infiltration of various subsets with atrophy or severe destruction of the acini, while MD showed selective infiltration of IgG4+ plasma cells with hyperplastic germinal centers and mild acini destruction. Corticosteroid treatment of MD reduced IgG and IgG4 levels and improved salivary function. A negative correlation between disease duration and increasing rate of salivary flow was observed in MD. These results suggested that the pathogenesis of MD might be different from those of SS. Clinical Relevance: early diagnosis and treatment of MD is important for the improvement of salivary function.

Yoshiaki Kubo

Papers

Th2 and regulatory immune reactions contribute to IgG4 production and the initiation of Mikulicz disease

Interleukin-21 contributes to germinal centre formation and immunoglobulin G4 production in IgG4-related dacryoadenitis and sialoadenitis, so-called Mikulicz's disease

Selective localization of T helper subsets in labial salivary glands from primary Sjögren's syndrome patients

Clinical characteristics of Mikulicz's disease as an IgG4-related disease

Syntheses OF 15α- and 15β-carboxymethyltestosterone bovine serum albumin conjugates: Characteristics of the antisera to testosterone☆