Immune Monitoring upon Treatment with Biologics in Sjögren's Syndrome: The What, Where, When, and How

Abstract

Over the years, a wide variety of therapeutic antibodies has been successfully introduced in the auto-immunology clinic, and many more are on the way. Many of these treatments address either a pathogenic circulating molecule or a cell-bound molecule. Whereas addressing the former target results in neutralization of the soluble factor and binding to the latter target either inhibits cellular function or induces selective cell death. If this targeted molecule or cell is part of the immune system, this therapy evokes a state of immunodeficiency with infections as a possible consequence. Therefore, immune monitoring is needed to prevent such adverse side effects of immunotherapy. In this paper, different immunotherapies used in Sjögren's syndrome, as well as different approaches to monitoring the immune system, are discussed.

Keywords: Sjögren’s disease; Sjögren’s syndrome; biologics; immune monitoring.

Figure 1

Simplified overview of the key players in pSS pathogenesis. Environmental and genetic factors may lead to pSS. An example of an environmental trigger may be a virus. This leads to antigen uptake by antigen-presenting cells (e.g., dendritic cells, DC) and subsequent antigen presentation to CD4-positive naïve T-cells. These naïve cells will develop (cytokine-dependent) into different T-helper (Th) cells or into regulatory T-cells (Treg) with different effector functions. The Th2 response can lead to the formation of autoantibodies (e.g., anti-SSA, anti-SSB) and, subsequently, to immune complex (IC) formation.

Figure 2

Potential immune therapy targets for treating pSS symptoms. Compounds (depicted in red) directed against different targets involved in B-cell or T-cell signaling have already been addressed or are currently being addressed in different studies. Some interactions can lead to different effector functions. For instance, BAFF can bind to the BAFFR as well as to TACI. In addition, CD80/86 molecules on B-cells can interact with both CD28 as well as CTLA-4 on T-cells. BAFFR and CD28 binding both lead to an activating signal, while binding to TACI and CTLA-4 both lead to an inhibiting signal. Note: The above figure is a simplified version. It does not depict all potential targets present on or in B- and T-cells. In addition, some target molecules are also present on other immune cells (e.g., IL-1R). BAFF: B-cell activating factor; BCR: B-cell receptor; BTK: Bruton’s tyrosine kinase; CTLA-4: cytotoxic T-lymphocyte antigen 4; ICAM-1: intercellular adhesion molecule 1; ICOS: Inducible T-cell Co-stimulator; ICOSL: Inducible T-cell Co-stimulator ligand; IL: interleukin; JAK1: Janus kinase 1; LFA-1: lymphocyte function-associated antigen 1; LTB-R: lymphotoxin beta receptor; MHC: major histocompatibility complex (also known as HLA, human leukocyte antigen); TACI: transmembrane activator and calcium modulator and cyclophilin ligand (CAML) interactor; TCR: T-cell receptor; TNF tumor necrosis factor; TYK2: tyrosine kinase 2.

Figure 3

Simplified overview of B-cell maturation. B-cell development starts in the bone marrow. During development different B-cell maturation stages are identified, characterized by specific molecules on their surface. After B-cells leave the bone marrow, maturation and differentiation may occur. Differentiation of B-cells is antigen-dependent. Antigen recognition occurs in the lymphoid follicles, where centroblasts develop into centrocytes in the so-called germinal center (GC) reaction. As a result of B-cell activation, immunoglobulins are ultimately secreted by plasma cells. An important feature of adaptive immunity is memory formation, which can lead to a quicker and stronger response when the immune system encounters the same antigen for the second time. Memory cells can be divided into unswitched memory B-cells or switched memory B-cells, depending on IgD expression (positive or negative, respectively).