LACC1 Regulates TNF and IL-17 in Mouse Models of Arthritis and Inflammation.

Both common and rare genetic variants of laccase domain-containing 1 (LACC1, previously C13orf31) are associated with inflammatory bowel disease, leprosy, Behcet disease, and systemic juvenile idiopathic arthritis. However, the functional relevance of these variants is unclear. In this study, we use LACC1-deficient mice to gain insight into the role of LACC1 in regulating inflammation. Following oral administration of Citrobacter rodentium, LACC1 knockout (KO) mice had more severe colon lesions compared with wildtype (WT) controls. Immunization with collagen II, a collagen-induced arthritis (CIA) model, resulted in an accelerated onset of arthritis and significantly worse arthritis and inflammation in LACC1 KO mice. Similar results were obtained in a mannan-induced arthritis model. Serum and local TNF in CIA paws and C. rodentium colons were significantly increased in LACC1 KO mice compared with WT controls. The percentage of IL-17A-producing CD4+ T cells was elevated in LACC1 KO mice undergoing CIA as well as aged mice compared with WT controls. Neutralization of IL-17, but not TNF, prevented enhanced mannan-induced arthritis in LACC1 KO mice. These data provide new mechanistic insight into the function of LACC1 in regulating TNF and IL-17 during inflammatory responses. We hypothesize that these effects contribute to immune-driven pathologies observed in individuals carrying LACC1 variants.

Understanding inflammatory bowel disease via immunogenetics.

The major inflammatory bowel diseases, Crohn's disease and ulcerative colitis, are both debilitating disorders of the gastrointestinal tract, characterized by a dysregulated immune response to unknown environmental triggers. Both disorders have an important and overlapping genetic component, and much progress has been made in the last 20 years at elucidating some of the specific factors contributing to disease pathogenesis. Here we review our growing understanding of the immunogenetics of inflammatory bowel disease, from the twin studies that first implicated a role for the genome in disease susceptibility to the latest genome-wide association studies that have identified hundreds of associated loci. We consider the insight this offers into the biological mechanisms of the inflammatory bowel diseases, such as autophagy, barrier defence and T-cell differentiation signalling. We reflect on these findings in the context of other immune-related disorders, both common and rare. These observations include links both obvious, such as to pediatric colitis, and more surprising, such as to leprosy. As a changing picture of the underlying genetic architecture emerges, we turn to future directions for the study of complex human diseases such as these, including the use of next generation sequencing technologies for the identification of rarer risk alleles, and potential approaches for narrowing down associated loci to casual variants. We consider the implications of this work for translation into clinical practice, for example via early therapeutic hypotheses arising from our improved understanding of the biology of inflammatory bowel disease. Finally, we present potential opportunities to better understand environmental risk factors, such as the human microbiota in the context of immunogenetics.

Conference Scene: T-cell subset phenotype and function.

Organized by Euroscicon, this meeting focused on the complex and fast-paced research field of T-cell subset phenotype and function. During the past 20 years, this field has moved on from the simple Th1-Th2 paradigm to the discovery of a range of T-cell subsets, including Tregs and Th17 cells. The meeting brought together a variety of researchers currently exploring this field, to give insight into what we know, what we need to know and the potential implications of this research in the medical setting.

Infection and disease caused by environmental mycobacteria.

Many species of mycobacteria that normally live as environmental saprophytes, the environmental mycobacteria (EM), are opportunist causes of disease in humans and animals. Many, but not all, cases are associated with some form of immune deficiency. An increasing number of species and clinical presentations are being described, and advances are being made in the understanding of the underlying predisposing factors. In recent years, four aspects of EM disease have become particularly relevant to human health: (1) the high prevalence of EM disease in patients with AIDS; (2) the emergence of Buruli ulcer, an ulcerative skin disease caused by Mycobacterium ulcerans, as the third most prevalent mycobacterial disease; (3) the effect of infection by EM on the immune responses to BCG vaccination and on the course and outcome of tuberculosis and leprosy; (4) the controversy over the involvement of mycobacteria, notably M. avium subspecies paratuberculosis, in human inflammatory bowel disease. These aspects change the status of EM from mere curiosities to important direct, indirect, and putative causes of serious and increasingly common human disease.