Chemokines in autoimmunity: from pathology to therapeutics
Section snippets
Introduction to the chemokine system
Chemokines are a large family of small secreted proteins (8–15 kDa) that control the trafficking of specific leukocyte subpopulations both in physiological and pathological processes. In the last few years, it has been demonstrated that these mediators play a role in embryonic development, hematopoiesis, angiogenesis, host defence, inflammation, immunity, AIDS and cancer [1], [2], [3].
According to the arrangement of the cysteine residues near the amino terminus, chemokines are classified into
Inflammatory and lymphoid chemokines
From a functional point of view, chemokines can be broadly classified into two classes: inflammatory and lymphoid. This distinction is not absolute, and some members can be ascribed to both subclasses. The inflammatory chemokines are induced by pathogens and proinflammatory stimuli in both resident tissue cells and leukocytes [1], [4], [5]. Their receptors are expressed on phagocytes such as neutrophils, eosinophils and monocytes, in immature dendritic cells (DC) and in some stages of T cell
The complexity of the chemokine system
The existence of approximately 50 ligands and 18 receptors indicates that the relationship between them are far from being of a single ligand/receptor pair interaction. Redundancy and promiscuity of binding are well-known features of the inflammatory chemokines, with a single chemokine binding to different receptors and a receptor binding to different chemokines. What is the meaning of the redundancy and whether it really operates in vivo is a matter of debate.
The comparison of the properties
Chemokines in autoimmune diseases
The migration and accumulation of leukocytes in the target organs are a critical step in the pathogenesis of autoimmune diseases [15]. The role of chemokines in autoimmunity is based on different lines of evidence provided by studies from humans and animal models.
Chemokines as therapeutic targets
The fact that chemokines act through GPCR stimulated pharmaceutical companies to the search for small molecule receptor antagonists, given the historical success of these targets. The first efforts were mainly focused on CCR1 and CCR2 antagonists as targets for autoimmune diseases, CXCR2 antagonists for neutrophil-mediated disorders, and CCR5 and CXCR4 antagonists for AIDS. Small molecule antagonists with nanomolar potency against several chemokine receptors have been reported both in the
Immune chemokines as therapeutic targets?
Recent evidences suggest that lymphoid chemokines would make interesting targets, although their role in homeosthasis could raise some doubts about the potential toxicity of this approach.
The pairs CCR7/CCL21, CXCR5/CXCL13 and CXCR4/CXCL12 are the main lymphoid ligand/receptor pairs. Perturbation in the expression of CCL21 has been described to alter susceptibility to autoimmunity in a model of experimental diabetes in mice [32]. The transgenic expression of CCL21 in the pancreas induces the
Summary
The field of chemokines is moving fast. Only a decade ago, the role of inflammatory chemokines in innate immunity and acute inflammation was established. In the last 5 years, the studies on chemokines have helped to understand their role in the orchestation of lymphocyte migration during immune responses. In the future, we will learn more about the role of specific chemokines in autoimmune diseases, as current knowledge suggests that blocking chemokine/receptor interaction is a suitable
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