br Concluding remarks br Introduction

Concluding remarks
Introduction Hypertrophic pachymeningitis (HP) is a neurologic disorder characterized by diffuse or focal thickening of the intracranial or spinal dura mater, presenting with intracranial hypertension, cranial nerve palsy and spinal cord dysfunction (Kupersmith et al., 2004; Lu et al., 2014). The only nationwide survey on HP conducted in Japan reported the crude prevalence rate of HP as 0.949/100,000 individuals (Yonekawa et al., 2014). Although HP occurs secondary to a variety of conditions, such as autoimmune disease, infectious disease, and granulomatous disorders (Shimojima et al., 2017; Bureta et al., 2018), our previous nationwide survey in Japan disclosed two major causes of HP: immunoglobulin (IgG)4- (8.8%), and anti-neutrophil cytoplasmic antibody (ANCA)-related diseases (34%) (Yonekawa et al., 2014). Among ANCA-associated vasculitis, myeloperoxidase (MPO)-ANCA is preferentially found in microscopic polyangiitis while granulomatosis with polyangiitis is predominantly leukocyte proteinase 3 (PR3)-ANCA-positive (Cornec et al., 2016). In ANCA-related HP, MPO-ANCA was more commonly found compared with PR3-ANCA (33 cases vs 14 cases (Yonekawa et al., 2014) and 17 cases vs 4 cases (Yokoseki et al., 2014)). However, it is often difficult to determine the cause of HP even by dural biopsy, and these cases of unknown etiology are termed “idiopathic HP (IHP)”, which account for most HP cases (44%) (Yonekawa et al., 2014). The mechanism of HP remains to be elucidated, irrespective of idiopathic or secondary type. The HP dura shows infiltration of a variety of inflammatory Methyllycaconitine citrate and interstitial fibrosis (Bosman et al., 2008; Hassan et al., 2011). Because components of the inflammatory process facilitate or attenuate fibroblast growth (Atamas and White, 2003; Wynn, 2008; Chen and Frangogiannis, 2013), cerebrospinal fluid (CSF) cytokine/chemokine and growth factor studies may provide insights into the mechanism of HP. However, because of the extreme rarity of HP, only one report has described the CSF cytokine/chemokine profile in MPO-ANCA-related HP (Yokoseki et al., 2014). They found an increase in interleukin (IL)-6, C-X-C motif ligand (CXCL)8/IL-8, and CXCL10/interferon (IFN)-γ-inducible protein-10 (IP-10). Because IP-10 is a downstream cytokine of IFN-γ (Luster and Ravetch, 1987), type 1 helper T cell (Th1) involvement is assumed in MPO-ANCA-related HP. Indeed, Th1 cells induce transforming growth factor β (TGF-β) production in fibroblasts by an IFN-γ-dependent mechanism and play a critical role in Th1-driven fibrosis (Sumida et al., 2008; Bouros et al., 2006), such as cardiac fibrosis (Nevers et al., 2017), and lung and kidney fibrosis in systemic sclerosis (Corrado, 2014). However, Th2 cytokines, such as IL-4 and IL-13, also exert pro-fibrotic functions related to the excessive migration and proliferation of fibroblasts in pulmonary fibrosis (Jakubzick et al., 2003; Singh et al., 2017), and renal fibrosis (Xing et al., 2011; Liang et al., 2017) under conditions of Th2-driven fibrosis (Chizzolini et al., 2011; Gieseck 3rd et al., 2018; Sciurba et al., 2018). In HP, plasma cells induced to differentiate by Th2 cytokines such as IL-4, IL-10, and IL-13 (Lu et al., 2014; Vazquez et al., 2015; De Virgilio et al., 2017), often heavily infiltrate the IgG4-related HP and IHP dura mater (Kupersmith et al., 2004; Wallace et al., 2013). Recently, we reported the first animal model of IgG4-related HP, in which mice with a mutation (Y136F) in the linker for activation of T cells (LAT) that induces Th2 cell proliferation and IgG1 (IgG4 human equivalent) overexpression showed a massive infiltration of IgG1 (equivalent to human IgG4)-positive plasma cells together with marked storiform fibrosis in the dura mater (Cui et al., 2018). Accordingly, Th2 cytokines also seem to play a crucial role in the pathomechanism of HP; however, the contribution of Th2 cytokines remains to be elucidated in human HP. Yokoseki et al. reported the occurrence of Th1-dominant granulomatous lesions in the dura mater as well as an increase in CXCL10 in the CSF of ANCA-related HP, suggesting CSF cytokine profiles reflect dominant dural pathology in inflammatory dural diseases (Yokoseki et al., 2014). Therefore, in the present study, we aimed to clarify the CSF cytokine/chemokine/growth factor profiles in patients mainly with IHP.