Cytokines, Chemokines, and the Innate Immune System in Sjögren’s Syndrome

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Introduction

Cytokines are the mediators of the immune system. They are small proteins of around 25 kD that are produced in response to a stimulus (ie, invading microbes) by numerous cell types. They mediate and regulate immune responses, inflammatory reactions, wound healing, hematopoiesis, and chemotaxis, and can be divided into being proinflammatory or antiinflammatory. Their mechanism of action is via specific receptors and can either be autocrine (ie, on themselves), paracrine (ie, on cells in the vicinity), or endocrine (ie, spread via circulation to distant sites). Originally, they were named according to their functionality after either the cell type producing them (monokine and lymphokine) or the cell they acted upon [interleukin (IL): acting on leukocytes]. Cytokines can be divided into chemokines, interferons (IFNs), ILs, some colony-stimulating factors, and tumor necrosis factor (TNF). Chemokines are a certain subclass of cytokines. Approximately 50 different chemokines have been described so far, and they function as chemo-attractants, inducing cells recognizing them to migrate along the chemokine gradient. They determine, for example, the specific localization of lymphocytes and dendritic cells (DCs) in peripheral lymphoid organs. Chemokines can be divided into two different subclasses: CC chemokines with two neighboring cysteine residues close to the amino terminus, and CXC chemokines with two cysteine residues separated by another amino acid. CC chemokines are recognized by CC receptors (CCRs), whereas CXC chemokines are recognized by CXC receptor (CXCR) molecules.

In contrast to hormones, which are present at very low concentrations and are produced by specific cells, cytokines are present at higher (some even picomolar) concentrations that can under certain circumstances increase dramatically. Moreover, a given cytokine can be secreted by several different cells, and several cytokines may act in similar ways, resulting in a certain redundancy of the system. In addition, one cytokine may affect different cell types in different ways (pleiotropy).

In most cases, there is not a single cytokine present, but multiple different ones acting either additively, synergistically or antagonistically to each other, leading to a complexity in the system that is difficult to analyze in in vitro systems.

The innate immune system is considered to be fast but rather nonspecific. It comprises physical barriers, such as epithelia, soluble molecules such as complement, and cellular components, such as leukocytes. Besides neutrophils, macrophages, DCs and natural killer (NK) cells, also the recently identified innate lymphoid cells (ILCs) possess important regulatory and effector functions in immunity and homeostasis. Pathogens and tissue damage are detected by innate immune cells via pattern recognition receptors (PRRs). The first ones discovered and best characterized are Toll-like receptors (TLRs), which are present both on the cell surface and in endosomes. Moreover, additional PRRs are present on the cell surface, such as C-type lectin receptors, and the cytosol, such as nonobese diabetic (NOD)-like receptors, and RIG-I–like receptors.

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Cytokines of the Innate Immune System in Primary Sjögren’s Syndrome

The production of cytokines and chemokines and their interplay are central parts of the regulation of immune responses. An imbalance of the cytokine network is commonly observed in patients with primary Sjögren’s syndrome (pSS) and contributes to local as well as systemic aberrations of this disease. One prominent pathway that has emerged in recent years as a result of expression profiling of salivary glands and peripheral blood cells from pSS patients as well as genome-wide association studies is the type I IFN pathway.