Immunoglobulin G4 in primary Sjögren's syndrome and IgG4-related disease - connections and dissimilarities

Abstract

Primary Sjögren's syndrome (pSS) is an autoimmune disease, with B cell hyperactivation and autoantibody production as its immunological hallmarks. Although the distinction between immunoglobulin G4-related disease (IgG4-RD) and pSS, based on the presence or absence of certain autoantibodies, seems easy to make, possibility of elevated serum IgG4 concentration and often similar organ involvement may lead to a misdiagnosis. The increased serum concentration of IgG4 in IgG4-RD is not clearly linked to the pathogenesis of IgG-RD and it has been suggested that it may constitute just an epiphenomenon. The aim of this article is to discuss the presence of IgG4 in pSS and IgG4-RD and its potential significance for these two diseases.

Keywords: IgG4-related disease; Sjögren’s syndrome; autoimmunity; immunoglobulin G4; lymphomas.

Figure 1

The outline of Sjögren’s syndrome pathogenesis (Created with BioRender.com). Genetic susceptibility, environmental factors such as mainly viral infections, but also bacterial infections, dysbiosis (microbiome disbalance), endogenous retroviral elements, hormonal disbalance (estrogen deficiency), and ultraviolet radiation (UV) are involved in epithelial cell damage and apoptosis. The endothelial cell damage and release of autoantigens stimulate innate and acquired immunity. The first-line immune response leads to the activation of dendritic cells (DC), especially of a type I signature of the IFN pathway, which releases interferons (IFNs). Subsequently, cross-talk between DC and T cells and their production of B cell stimulating factors (e.g., IFNγ, B cell activating factor (BAFF), a proliferation-inducing ligand (APRIL), and interleukin-21 (IL-21)) cause the activation of B cells and their hyperreactivity. Newly formed plasma cells produce autoantibodies, to ribonucleoproteins in particular, such as anti-Ro/anti-La antibodies and rheumatoid factors (RF) in various classes of immunoglobulins. In target organs (primarily salivary glands), cell infiltrates are formed, consisting of mononuclear cells such as dendritic cells (mainly CD21), T lymphocytes (CD4+, CD3+), CD20 B lymphocytes, and plasma cells. Under the influence of chronic and intense stimulation, tertiary lymphatic structures may be formed—germinal centers (GC), and activation of B cells beyond the control of T lymphocytes may occur. Such stimulation carries the risk of developing a lymphoproliferative process in pSS.

Figure 2

A craniofacial magnetic resonance image of a patient with pSS. The left parotid gland is bulging outwards. The right parotid gland is not enlarged. Altered vesicular structure of the parotid and submandibular glands. In the left parotid gland in the deep lobe, cystic lesions are visible. A group of cystic structures is visible in the central part of the left parotid gland. After i. v. contrast administration, no significant signal amplification was observed. Currently, the salivary ducts are not dilated. There are numerous lymphatic nodules in the parotid glands (approx. 6 mm). In the submandibular area, there are single lymph nodes up to 11 mm long. There are numerous lymph nodes in the neck, measuring up to 15 mm.