Immunology of IgG4-related disease

Abstract

SummaryImmunoglobulin G4-related disease (IgG4-RD) is a fibroinflammatory condition that derives its name from the characteristic finding of abundant IgG4 1 plasma cells in affected tissues, as well as the presence of elevated serum IgG4 concentrations in many patients. In contrast to fibrotic disorders, such as systemic sclerosis or idiopathic pulmonary fibrosis in which the tissues fibrosis has remained largely intractable to treatment, many IgG4-RD patients appear to have a condition in which the collagen deposition is reversible. The mechanisms underlying this peculiar feature remain unknown, but the remarkable efficacy of B cell depletion in these patients supports an important pathogenic role of B cell/T cell collaboration. In particular, aberrant T helper type 2 (Th2)/ regulatory T cells sustained by putative autoreactive B cells have been proposed to drive collagen deposition through the production of profibrotic cytokines, but definitive demonstrations of this hypothesis are lacking. Indeed, a number of unsolved questions need to be addressed in order to fully understand the pathogenesis of IgG4-RD. These include the identification of an antigenic trigger(s), the implications (if any) of IgG4 antibodies for pathophysiology and the precise immunological mechanisms leading to fibrosis. Recent investigations have also raised the possibility that innate immunity might precede adaptive immunity, thus further complicating the pathological scenario. Here, we aim to review the most recent insights on the immunology of IgG4-RD, focusing on the relative contribution of innate and adaptive immune responses to the full pathological phenotype of this fibrotic condition. Clinical, histological and therapeutic features are also addressed.

Current Treatment, Emerging Translational Therapies, and New Therapeutic Targets for Autoimmune Myasthenia Gravis

“…Thymic pathology does not commonly occur in association with the disease [24]. The production of IgG4 antibodies in the setting of other immune responses appears to be driven, in part, by Th2 cytokines that mediate allergic responses [25], but T cells in patients with MuSK MG have increased frequencies of Th1 and Th17 cytokines [26]. B-cell immunopathology in MuSK MG includes elevated B-cell activating factor (BAFF) and lower frequencies of interleukin (IL)-10-producing regulatory B cells [27].…”

The Lung in Dysregulated States of Humoral Immunity

“…IgG4-RD immunopathogenesis remains incompletely elucidated. It includes oligoclonal expansion of plasmablasts as well as CD4+ T cytotoxic cells [69,70,71]. Oligoclonal expansion of circulating CD19+CD20-CD27+CD38+ plasmablasts reflects the disease activity [72].…”

“…Oligoclonal expansion of circulating CD19+CD20-CD27+CD38+ plasmablasts reflects the disease activity [72]. The implication of IgG4 is uncertain as they have noninflammatory properties in contrast with other IgG subclasses [69,73]. IgG4 increase might represent an ineffective attempt to downregulate the ongoing primary inflammatory response triggered by still unknown antigens.…”

Intrathecal rituximab for IgG4-related hypertrophic pachymeningitis

“…In addition, despite inducing prolonged depletion of circulating B lymphocytes, systemic rituximab does not affect malignant B cells in CNS lymphomas 2. Hypertrophic pachymeningitis (HP) is the most frequently encountered CNS manifestation of IgG 4 -related disease (IgG 4 -RD), a fibroinflammatory condition of unclear aetiology 3. The intrathecal synthesis of IgG 4 in patients with IgG 4 -related hypertrophic pachymeningitis(RHP) and the clinical improvement after rituximab in patients with systemic involvement, support a pathogenic role of B lymphocytes 4–6.…”

“…Brain and meningeal biopsies showed storiform fibrosis, lymphoplasmacytic infiltration, 100 IgG 4 + plasma cells/HPF, and an IgG 4 +/IgG+ plasma cells ratio >40%, consistent with a diagnosis of IgG 4 -RD (see online supplementary figure e2). 3 The patient was treated with three daily pulses of 1 g intravenous methylprednisolone followed by oral prednisone (1 mg per kg of body weight daily in the first month before tapering). In August 2015, given the bilateral progression of the optic nerve atrophy and the unchanged meningocortical MRI findings, two infusions of 1 g rituximab were administered 15 days apart.…”