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The first dimension of chemokine heterogeneity is reflected by their discovery and purification as natural proteins. Each of those chemokines attracted a specific inflammatory leukocyte type. With the introduction of genomic technologies, a second wave of chemokine heterogeneity was established by the discovery of putative chemokine-like sequences and by demonstrating chemotactic activity of the gene products in physiological leukocyte homing. In the postgenomic era, the third dimension of chemokine heterogeneity is the description of posttranslational modifications on most chemokines. Proteolysis of chemokines, for instance by dipeptidyl peptidase IV (DPP IV/CD26) and by matrix metalloproteinases (MMPs) is already well established as a biological control mechanism to activate, potentiate, dampen or abrogate chemokine activities. Other posttranslational modifications are less known. Theoretical N-linked and O-linked attachment sites for chemokine glycosylation were searched with bio-informatic tools and it was found that most chemokines are not glycosylated. These findings are corroborated with a low number of experimental studies demonstrating N- or O-glycosylation of natural chemokine ligands. Because attached oligosaccharides protect proteins against proteolytic degradation, their absence may explain the fast turnover of chemokines in the protease-rich environments of infection and inflammation. All chemokines interact with G protein-coupled receptors (GPCRs) and glycosaminoglycans (GAGs). Whether lectin-like GAG-binding induces cellular signaling is not clear, but these interactions are important for leukocyte migration and have already been exploited to reduce inflammation. In addition to selective proteolysis, citrullination and nitration/nitrosylation are being added as biologically relevant modifications contributing to functional chemokine heterogeneity. Resulting chemokine isoforms with reduced affinity for GPCRs reduce leukocyte migration in various models of inflammation. Here, these third dimension modifications are compared, with reflections on the biological and pathological contexts in which these posttranslational modifications take place and contribute to the repertoire of chemokine functions and with an emphasis on autoimmune diseases. ispartof: Journal of Autoimmunity vol:85 pages:45-57 ispartof: location:England status: published