Pathophysiology of Autoimmune Pancreatitis



Fig. 3.1
Characteristic forms of IgG4. (a) Schematic representation of the generation of bispecific IgG4 antibodies by the exchange of half-molecules (“Fab-arm exchange”) (With permission from the publisher of van der Neut Kolfschoten et al. [27]). IgG4 Fab-arm exchange occurs by the exchange of a heavy chain-light chain pair (half-molecule) of one IgG4 molecule with that of another IgG4 molecule. The IgG4 molecule may thereby acquire two distinct Fab arms and become bispecific. The Fc structure remains essentially unchanged apart from potential changes due to differences in glycosylation or allotype. Fab-arm exchange is proposed to be stochastic and dynamic. (b) On the left: IgG4 Fc interacts with Ig Fc. On the right: IgM RF recognizes IgG in a “classical” Fab-Fc recognition (With permission from Kawa et al. [28])



Another recent data on regulating IgG4 showed that IgG4-related diseases may reflect an excessive production of anti-inflammatory cytokines such as IL-10 that triggers an overwhelming expansion of IgG4-producing plasma cells [3135]. Increased peripheral inducible memory Tregs are positively correlated with serum levels of IgG4 [33]. In addition, prominent infiltration of Tregs upregulated IL-10 in livers of patients with IgG4-SC [31]. These findings suggest that IgG4 do not act as a pathogenic factor nor as an anti-inflammatory factor in IgG4-RD. Further studies are necessary to clarify the precise role of IgG4 in IgG4-RD.



The Complement System


Patients with active stage of AIP occasionally show decreased complement (C3, C4) with elevated circulating immune complex as well as serum levels of IgG4 [36]. Both tubulointerstitial nephritis (TIN) and membranous glomerulonephritis are often observed in IgG4-related kidney disease (IgG4-KD), and deposition of immune complex (IgG and C3) was observed on the tubular basement membrane as well as the glomerular basement membrane [37, 38]. As the complements cannot connect at the Fc portion of IgG4, the classical pathway of complement activation through IgG1 may be involved in the development of AIP rather than mannose-binding lectin or alternative pathways through IgG4 [39]. Moreover, IgG4 bound to other isotype such as IgG1, IgG2, and IgG3 with an Fc-Fc interaction immune complex in patients with AIP [28], and then IgG4 may contribute to the clearance of immune complexes or termination of the inflammatory process by preventing the formation of large immune complexes with blocking Fc-mediated effector functions of IgG1.


Autoantibodies and Candidate of Target Antigens


Patients with type 1 AIP generally show several autoantibodies in addition to increased IgG and IgG4 [8]. Although some patients have nonspecific antibodies such as antinuclear antibody (ANA), there is scarcely association of IgG4-RD and well-known autoimmune diseases such as Sjögren’s syndrome and SLE. From the view of IgG4 function, a big mystery whether IgG4-related disease is autoimmune or allergic disease is addressed. However, occasional coexistence of OOIs leads us the concept that there may be common target antigens in the involved organs such as the pancreas, salivary gland, biliary tract, lung, renal tubules, and so on. Although the disease-specific antibodies have not been identified at this moment, several disease-related antibodies such as anti-lactoferrin (LF) [40, 41], anti-carbonic anhydrase (CA)-II [4043], anti-CA-IV [44], anti-pancreatic secretory trypsin inhibitor (PSTI) [45], anti-amylase-alpha [46], anti-HSP-10 [47], and anti-plasminogen-binding protein (PBP) peptide autoantibodies [20] have been reported. Although the patients show increased serum levels of IgG4, the major subclass of these autoantibody is not necessarily IgG4, but often IgG1 [45]. CA-II, CA-IV, LF, and PSTI are distributed in the ductal cells of several exocrine organs, including the pancreas, salivary gland, biliary duct, lung, and renal tubules [40, 41]. Although all peptides have not been studied, immunization with CA-II or LF-induced systemic lesions such as pancreatitis, sialadenitis, cholangitis, and interstitial nephritis in the mice models similar to human IgG4-related diseases [48, 49]. The high prevalence of these antibodies suggests that these may be the candidates for the target antigens in type 1 AIP. Among the involved organs in IgG4-RD, recent studies suggest an extremely high association of pancreatic and biliary lesions [50]. As both peribiliary glands in the biliary tract and pancreatic duct glands associated with pancreatic ducts in human are intermingled with small amounts of pancreatic exocrine acini [51], and the biliary tree-derived stem cells constitute a pancreatic organogenesis in mice [52], Nakanuma et al. have proposed a new concept of the “biliary diseases with pancreatic counterparts” [53], in which targets of type 1 AIP and IgG4-SC may be periductal glands around the bile and pancreatic ducts.

Diabetes mellitus is complicated with 43 ~ 68 % of the patients with AIP, but autoantibodies against glutamic acid decarboxylase, beta-cell, or tyrosine phosphatase-like protein associated type 1A DM are rarely observed [54]. These findings suggest that islet cells may not be targeted in the development of DM associated with AIP.


Role of B Cells


In addition to steroid and immune modulators, the B-cell depletion by rituximab, which reduces only IgG4, but not IgG1, IgG2, or IgG3, is useful in the therapeutic strategy in IgG4-RD [55, 56]. A recent study showed expansion of IgG4+ B-cell receptor (BCR) clones in blood and tissue of patients with active IgG4-cholangiopathy, and disappearance by corticosteroid treatment [57]. A recent study showed that the increased CD19+CD24highCD38high Bregs may suppress the disease activity of type 1 AIP, whereas the decreased CD19+CD24highCD27+ Bregs might be involved in the development of type 1 AIP [58]. These findings suggest that specific B-cell responses may have a pivotal role in the pathogenesis of IgG4-RD such as type 1 AIP and IgG4-SC.


Th1 and Th2 Immune Balance


The effector cells in IgG4-related diseases have been poorly understood. Presence of autoantibodies; infiltration of CD4+/CD8 + T cells, plasmacytes, and B cells; and expression of HLA-DR antigens in the pancreas [41] suggest that acquired immunity may be involved in the development of AIP. The CD4 + T cells differentiate from naïve T cells (Th0) to Th1, Th2, Th17, and regulatory T cells (Treg). IL-12 induces Thl cells, which produce IL-2, tumor necrosis factor (TNF)-alpha, and IFN-gamma; mediate cellular immunity, macrophage activation, and cytotoxicity; and help in B-cell production of opsonizing and complement-fixing antibodies [54]. IL-4 induces Th2 cells which produce IL-4, IL-5, IL-6, and IL-10 and promote humoral and allergic responses [59]. TGF-beta, IL-6, IL-21, and IL-23 induce Th17 cells, which secret IL-17 and may be involved in the inflammation in mice. In some patients with AIP, Th1 cells but not Th17 cells are predominant over Th2-type cells in the periphery. In the livers of IgG4-SC patients, however, a Th2-type immune reaction [60, 61] is induced in addition to a Th1 response [60, 62]. The discrepancy may be explained by the shift of Th2 cells from the periphery to local tissues or different disease stages. The mouse model with depletion of Tregs by neonatal thymectomy (nTx) [62] and the WBN/Kob model (Sakaguchi et al. 2002) support the hypothesis that Th1 cells mainly act as effectors in the initial early stage. Th2 cytokines may be involved in the progression of the disease process, especially the maturation and proliferation of local B cells and plasmacytes.


Regulatory T Cells


From naïve Th0 cells, TGF-beta can induce CD4+CD25+ regulatory T cells (Tregs), which have potent inhibitory function via the transcription factor Foxp3 to CD4+ T-cell-mediated immune responses such as Th1, Th2, and Th17 [61]. This suppressive function is mediated by transforming growth factor β (TGF-β) and IL-10, and/or cell-to-cell contact via ligation of CTLA-4. Foxp3 is a member of the forkhead/winged-helix family of transcriptional regulators and functions as the master regulator in the development and function of CD4+CD25+ regulatory T cells (Tregs) classified as naturally occurring CD4+CD25+ Tregs (nTregs) originating in the thymus and adaptive Tregs (aTregs) induced in the periphery by different antigens [63]. As Tregs expressing Foxp3 are critical in the transfer of immune tolerance, deficient Tregs induce various autoimmune diseases in animal studies [64]. In type 1 AIP, circulatory naïve (CD45RA+) Tregs are significantly decreased in the peripheral blood, whereas memory (CD45RA-) Tregs are significantly increased [33]. In addition, prominent infiltration of Tregs with upregulation of IL-10 is observed in the liver of type 1 AIP and IgG4-SC patients [31, 32]. Moreover, IL-10 and TGF-beta are secreted from ICOS+ and ICOS- inducible aTregs, respectively. These findings suggest that increased memory Tregs in the periphery and local tissues may be an inhibitory immune response against inflammation, although decreased naïve Tregs may be pathogenic.


Hypothesis for the Pathogenesis of Type 1 AIP


The neonatally thymectomized (nTx)-BALB/c mice models showed that immunization with CA-II or LF can induce pancreatitis, cholangitis, and sialadenitis similar to human IgG4-RD [62]. These findings suggest that depletion of naïve Tregs may induce macrophage/T-cell activation and further proinflammatory reactions may occur during the early stage of the disease as direct cytotoxicity effects through Fas ligand expression. WBN/Kob rat models with congenital decreased peripheral Tregs spontaneously develop sclerotic cholangitis, sialadenitis, thyroiditis, and tubulointerstitial nephritis [65]. These animal models suggest that CD4+/CD8+ T cells play major roles in the development of primary lesions similarly to human IgG4-related diseases; however, the counterpart of IgG4 in mice IgG subclasses has not been identified.

Based on these findings, we proposed the pathogenesis of type 1 AIP [8] (Fig. 3.2). The basic concept is the biphasic mechanism of “induction” and “progression.” An initial response to unknown disease-specific antigens including self-antigens (LF, CA-II, CA-IV, and PSTI) or microorganisms (bacteria or virus) might be induced by decreased naïve Tregs and/or CD19+CD24hiCD38hi Bregs followed by a Th1-type immune response with the release of proinflammatory cytokines (IFN-γ, IL-1beta, IL-2, TNF-α). In progression, Th2-type immune responses producing IgG, IgG4, and autoantibodies may be involved in pathophysiology. Production of IgG4 may be upregulated by increased IL-10 from ICOS+ inducible aTregs and CD19+CD24hiCD27hi Bregs and BAFF from monocytes and/or basophils. Fibrosis may be induced by TGF-beta secreted from ICOS-inducible aTregs.

A323555_1_En_3_Fig2_HTML.gif


Fig. 3.2
Hypothesis for the pathogenesis of type 1 AIP as an IgG4-related disease (With permission from the publisher of Okazaki et al. [8]). In the central tolerance, naïve and natural regulatory T cells (Tregs) derived from the thymus suppress autoreactive CD4 or CD8 cells in the normal state. The basic concept is the biphasic mechanism of “induction” and “progression.” An initial response to unknown disease-specific antigens including self-antigens (LF, CA-II, CA-IV, and PSTI) or microorganisms (bacteria or virus) might be induced by decreased naïve Tregs and/or CD19+CD24hiCD38hi Bregs followed by a Th1-type immune response with the release of proinflammatory cytokines (IFN- γ, IL-1beta, IL-2, TNF-α). In progression, Th2-type immune responses producing IgG, IgG4, and autoantibodies may be involved in pathophysiology. Production of IgG4 may be upregulated by increased IL-10 from ICOS+ inducible aTregs and CD19+CD24hiCD27hi Bregs and BAFF from monocytes and/or basophils. Fibrosis may be induced by TGF-beta secreted from ICOS- inducible aTregs. iTreg inducible memory regulatory T cell, TE effector T cell, nTreg naturally occurring naive regulatory T cell, BAFF B-cell-activating factor family, Breg regulatory B cell, ICOS inhibitory costimulatory molecule


Conclusion


Recent advances support the concept of AIP and subtypes, type 1 and type 2 AIP. Type 1 AIP is a pancreatic manifestation of IgG4-RD. Although the pathogenic mechanism remains unclear, innate and acquired immunity, Tregs, and B cells may be involved in the development of type 1 AIP. Further studies are necessary to clarify the pathogenesis including genetic backgrounds, disease-specific antigens, and the role of IgG4.


Acknowledgment

This study was partially supported by (1) Grant-in-Aid for Scientific Research (C) of the Ministry of Culture and Science of Japan (20590810, 24591020, 12008507), (2) the Research Program on Intractable Diseases, from the Ministry of Labor and Welfare of Japan, and (3) Grants-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, from CREST Japan Science, and Technology Agency.


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Jun 3, 2017 | Posted by in GENERAL SURGERY | Comments Off on Pathophysiology of Autoimmune Pancreatitis
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