Immunology of IgG4-related disease

Abstract

Immunoglobulin G4-related disease (IgG4-RD) is a fibroinflammatory condition that derives its name from the characteristic finding of abundant IgG4(+) 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.

Keywords: IgG4; IgG4-related disease; immunology; pathogenesis; review.

Figure 1

Clinical and radiological presentation of IgG4-related disease (IgG4-RD). (a) IgG4-related autoimmune pancreatitis: computed tomography scan showing a ‘sausage-like’-shaped pancreas with a surrounding rim of hypodense tissue (asterisks). (b) Retroperitoneal fibrosis with periaortic involvement (circle). (c) Inflammatory aneurism of the thoracic aorta showing ¹⁸fluoro-deoxyglucose uptake on positron emission tomography (arrowhead). (d) Magnetic resonance showing bilateral parotid enlargement due to IgG4-RD (asterisks). (e,f) Clinical and radiological appearance of IgG4-related orbital pseudotumour (asterisk).

Figure 2

Pathological features of immunoglobulin (Ig)G4-related disease. (a) Pancreatic ducts are not affected by the fibroinflammatory infiltrate in IgG4-related autoimmune pancreatitis (arrowhead; haematoxylin and eosin, magnification ×100). (b,c) Areas of storiform fibrosis in IgG4-related autoimmune pancreatitis [asterisks; haematoxylin and eosin, magnification ×40 (b) and ×100 (c)]. (d) Obliterative phlebitis: an obliterated vein surrounded by an inflammatory nodule (arrowhead), next to an intact artery (arrow) (haematoxylin and eosin, magnification ×200). (e,f) Immunohistochemistry for IgG (e) and IgG4 (e) on sequential sections shows an IgG4/IgG ratio > 40% (magnification ×40).

Figure 3

Inflammatory infiltrate in IgG4-related disease. Immunohistochemistry reveals CD20⁺ B lymphocytes organized in follicular structures (a), CD3⁺ T lymphocytes (b), and CD163⁺ M2 macrophages (c) spread throughout the fibrotic tissue (magnification ×100).

Figure 4

Molecular basis of the ‘Fab-arm’ exchange and physiopathological properties of immunoglobulin (Ig)G4 antibodies.

Figure 5

Pathogenic model for immunoglobulin (Ig)G4-related disease. Antigen presentation, T cell and B cell activation presumably occur in lymph nodes or tertiary lymphoid structures originating in inflamed tissues (1). Dendritic and naive/memory B cells might present antigens to CD4⁺ T lymphocytes triggering their activation (2). Local signals from the innate immune system might determine T helper cell polarization and differentiation into effector or memory T cells. Activated naive B cells migrate to the germinal centre where they undergo somatic hypermutation and affinity maturation, and differentiate into memory B cells or plasmablasts (3). IgG4/IgE class-switch probably occurs under the influence of cytokines produced by activated CD4⁺ Th2 or T regulatory cells. Effector CD4⁺ T cells migrate to inflamed tissues, where they are thought to drive the fibroinflammatory process by producing a variety of profibrotic cytokines [such as interleukin (IL)-4, IL-10, IL-13, transforming growth factor (TGF)-β], and by inducing M2 macrophages differentiation and eosinophil activation (4). IgG4 antibodies might have an antinflammatory role but, together with IgE, they might also facilitate antigen capture by innate immune cells through Fc receptor binding and presentation to T cells. In theory, IgG4⁺ plasma cells in the tissue might also have a profibrotic role through the production of IL-6 (4). All these concomitant events lead ultimately to fibroblast activation, generation of myofibroblasts and extracellular matrix deposition. Whether the fibroinflammatory infiltrate that occurs in IgG4-RD lesions also causes tissue damage and further generation of self-antigens is not known (4). By depleting CD20⁺ precursors, rituximab might eliminate both short-lived plasma cells and a major B cell type required for antigen presentation to T cells. This, in turn, leads to loss of activated T cells and profibrotic cytokines, and to a reduction in fibroblast activation. Disease relapse corresponds to a new plasmablast expansion, and to a renewed extracellular matrix deposition. Whether re-emerging plasmablasts observed at disease relapse differentiate de novo from naive B cells or from CD20^- memory B cells that survive rituximab therapy is not known (5). Indeed memory B cells might de-novo present antigens to pathogenic naive T cells, sustaining disease recurrence (5).