Fine-mapping the MHC locus in juvenile idiopathic arthritis (JIA) reveals genetic heterogeneity corresponding to distinct adult inflammatory arthritic diseases.

OBJECTIVES: Juvenile idiopathic arthritis (JIA) is a heterogeneous group of diseases, comprising seven categories. Genetic data could potentially be used to help redefine JIA categories and improve the current classification system. The human leucocyte antigen (HLA) region is strongly associated with JIA. Fine-mapping of the region was performed to look for similarities and differences in HLA associations between the JIA categories and define correspondences with adult inflammatory arthritides. METHODS: Dense genotype data from the HLA region, from the Immunochip array for 5043 JIA cases and 14 390 controls, were used to impute single-nucleotide polymorphisms, HLA classical alleles and amino acids. Bivariate analysis was performed to investigate genetic correlation between the JIA categories. Conditional analysis was used to identify additional effects within the region. Comparison of the findings with those in adult inflammatory arthritic diseases was performed. RESULTS: We identified category-specific associations and have demonstrated for the first time that rheumatoid factor (RF)-negative polyarticular JIA and oligoarticular JIA are genetically similar in their HLA associations. We also observe that each JIA category potentially has an adult counterpart. The RF-positive polyarthritis association at HLA-DRB1 amino acid at position 13 mirrors the association in adult seropositive rheumatoid arthritis (RA). Interestingly, the combined oligoarthritis and RF-negative polyarthritis dataset shares the same association with adult seronegative RA. CONCLUSIONS: The findings suggest the value of using genetic data in helping to classify the categories of this heterogeneous disease. Mapping JIA categories to adult counterparts could enable shared knowledge of disease pathogenesis and aetiology and facilitate transition from paediatric to adult services.

The role of atorvastatin in regulating the immune response leading to vascular damage in a model of Kawasaki disease.

Superantigens have been implicated in a number of diseases including Kawasaki disease (KD), a multi-system vasculitis resulting in coronary artery aneurysms. We have characterized a murine disease model in which coronary arteritis is induced by a novel superantigen found in Lactobacillus casei cell wall extract (LCWE). Using this animal model of KD, we have identified three pathogenic steps leading to coronary artery aneurysm formation. These steps include T cell activation and proliferation, production of the proinflammatory cytokine tumour necrosis factor (TNF)-α and up-regulation of matrix metalloproteinase 9 (MMP-9), an elastolytic protease. In addition to their cholesterol-lowering effects, 3-hydroxy-3-methylglutaryl (HMG) coenzyme A (CoA) reductase inhibitors (statins) have pleotropic immunomodulatory properties. Thus, we examined the effect of atorvastatin in modulating each of these three critical pathogenic processes leading to aneurysm formation in the disease model. Atorvastatin inhibited lymphocyte proliferation in response to superantigen stimulation in a dose-dependent manner. This inhibition was also observed for production of soluble mediators of inflammation including interleukin (IL)-2 and TNF-α. The inhibitory effect on proliferation was rescued completely by mevalonic acid, confirming that the mechanism responsible for this inhibitory activity on immune activation was inhibition of HMG-CoA reductase. Similarly, TNF-α-induced MMP-9 production was reduced in a dose-dependent manner in response to atorvastatin. Inhibition of extracellular-regulated kinase (ERK) phosphorylation appears to be the mechanism responsible for inhibition of MMP-9 production. In conclusion, atorvastatin is able to inhibit critical steps known to be important in the development of coronary aneurysms, suggesting that statins may have therapeutic benefit in patients with KD.

Inhibition of matrix metalloproteinase-9 activity improves coronary outcome in an animal model of Kawasaki disease.

Kawasaki disease (KD) is the leading cause of acquired heart disease of children in North America. It is characterized by a massive immune activation and multi-system vasculitis, which evolves into a site-specific inflammatory response focused at the coronary arteries. Coronary artery (CA) inflammation leads to elastin breakdown, destruction of the vessel wall and aneurysm formation. We have demonstrated recently the pivotal role of tumour necrosis factor (TNF)-alpha-mediated matrix metalloproteinase (MMP)-9 activity in the pathogenesis of elastin breakdown in a murine model of KD, Lactobacillus casei cell wall extract-induced coronary arteritis. Using this model, we evaluated the in vitro effects of doxycycline, an antibiotic with MMP inhibitory function, in modulating key pathogenic stages of disease leading to CA damage. Doxycycline inhibits T cell activation and TNF-alpha production in peripheral immune cells, as assessed by thymidine incorporation and a TNF bioassay respectively. Additionally, doxycycline inhibits directly MMP-9 enzymatic activity derived from TNF-alpha-stimulated vascular smooth muscle cells as assayed by zymography. More importantly, in vivo treatment of Lactobacillus casei cell wall extract (LCWE)-injected mice with doxycycline reduces significantly the incidence of CA elastin breakdown and reduces loss of elastin. Therefore, doxycycline can mitigate TNF-alpha-induced MMP-9-mediated coronary elastin breakdown and improve coronary outcome. Agents with the ability to inhibit both inflammation and the downstream effects of inflammation, such as MMP-9 activity, offer a promising therapeutic strategy for the management of children with KD.

Lessons learned from an animal model of Kawasaki disease.

Kawasaki disease is the most common cause of multisystem vasculitis in childhood. Kawasaki disease has been reported throughout the world and affects children of all ethnicity. Coronary artery damage from Kawasaki disease is the leading cause of acquired heart disease in children in the developed world. Diagnostic tests and prognostic markers are lacking, and questions remain unanswered in our understanding of the etiopathogenesis of the disease, thus limiting our ability to improve therapy and coronary outcome. In this article I will review advances made in an animal model of disease, which has helped advance our understanding of the etiology and pathogenesis of this fascinating clinical syndrome.