To find the cause of rheumatoid arthritis using humanized mouse models with the major polymorphic genes; HLA-DR and NCF1

Purpose and objective: Investigate the cause of rheumatoid arthritis (RA) using unique mouse strains expressing the major disease-associated human alleles (DRB1 and NCF1) to develop novel diagnostic and preventive treatments.Project plan: It has been difficult to identify and thereby analyze the specific alleles that cause RA and other autoimmune diseases.

We have confirmed the importance of the major alleles in the major histocompatibility complex type II region, the DRB1*04:01 and DRB1*04:05, and the gene controlling oxidative regulation, the NCF1 gene.

By establishing mouse strains physiologically expressing their human counterparts, we have made them susceptible to RA.We will use these strains to investigate the priming and onset of arthritis controlled by human genes. It will be done by challenging the mice with environmental stimuli, triggering arthritis.

The antibody and T-cell responses will undergo the same tests that we have previously validated in human disease.

We will try to find out which environmental factors and gene combinations trigger autoimmunity and which leads to the onset of arthritis.

With this knowledge, we will try to improve the diagnostics of RA and develop new preventive and curative treatments based on novel immune tolerizing vaccines.Importance: This project aims to identify the causative mechanisms leading to RA and also to develop and validate preventive treatments that can be more safely translated to humans.