AUTOIMMUNITY

IFN-γ is central in inflammatory pathogenesis, response to infection and autoimmune diseases. Here the authors show that MMP12 expression is reduced in patients with SLE and that MMP12 post-translationally truncates IFN-y, inhibiting its function and affecting pathogenesis of mouse models of peritonitis, SLE and rheumatoid arthritis.

Natural autoantibodies form a network that serves to protect the organism from outer and inner danger but also contributes to autoimmune disease. It is our view, that this critical component of the immune system deserves much greater attention than it currently attracts for the benefit of patients and for better understanding how immunity operates. Since the early days of immunology, pioneering work by Landsteiner and his group on haptens showed that immunization is a process that can raise highly specific antibodies. In the same era, Ehrlich put forward the dogma of “horror autotoxicus”, proclaiming the inability of the immune system to recognize self-constituents. Later on, in the 1950s, Burnet build upon these seminal observations and formulated the clonal selection theory which states that “cell clones produce highly specific antibodies for environmental constituents while the immune system is educated during ontogeny not to recognize self-constituents”. Nevertheless, other studies, contradicting the “dogma”, were mostly ignored. These studies showed that circulating antibodies in normal human sera could recognize various substances, including self-antigens, albeit with a low avidity 1. In the following years, additional experiments reinforced the notion of a persistent immune system reactivity against self e.g. in either normal or lupus-prone mice where the genetic background alone drives the immune system to generate IgM-producing cells that secret self-reactin

Lupus is a complex heterogeneous disease characterised by autoantibody production and immune complex deposition followed by damage to target tissues. Animal models of human diseases are an invaluable tool for defining pathogenic mechanisms and testing of novel therapeutic agents. There are perhaps more applicable murine models of lupus than any other human disease. There are spontaneous models of lupus, inducible models of lupus, transgenic-induced lupus, gene knockout induced lupus and humanised mouse models of lupus. These mouse models of lupus have contributed significantly to our knowledge of the pathogenesis of lupus and served as valuable preclinical models for proof of concept for new therapies. Despite their utility, mouse models of lupus have their distinct limitations. Although similar, mouse and human immune systems are different and thus one cannot assume a mechanism for disease in one is translatable to the other. Efficacy and toxicity of compounds can vary significantly between humans and mice, also limiting direct translation. Finally, the heterogeneous aspects of human lupus, both in clinical presentation, underlying pathogenesis and genetics, are not completely represented in current mouse models. Thus, proving a therapy or mechanism of disease in one mouse model is similar to proving a mechanism/therapy in a limited subset of human lupus. These limitations, however, do not marginalise the importance of animal models nor the significant contributions they have made to our understanding of lupus.

Biologics