A novel AID structure providing new insight into HIGM2

Our immune system is a vital organ that protects us from pathogens, and unlike the heart or lung is a network of ducts and fluids distributed throughout the body. To fight off infection, immunity uses ‘education’ of antibodies for adaptation and memory, providing us with effective, precise, and life long protection. The AID gene is key for shaping those antibodies in our blood, consequently genetic alterations in AID can lead to immune deficiencies. Hyper-IgM (HIGM type I-IV) syndrome encompasses a group of genetic disorders characterised by the excess of basic ‘uneducated’ antibodies. The defect in HIGM patients induces recurrent bacterial and opportunistic infections, with HIGM-II being due to a non-functional AID gene. If detected early, HIGM is manageable with antibody complementation, but HIGM-II patients have a decreased lifespan and enhanced autoimmunity or even lymphoid malignancies. AID induces DNA lesions within the antibody genes altering antibody proteins to bind more effectively, and hence ‘educate’. Classical severe HIGM-II patients have altered AID function, while less severe HIGM-II patients have alterations in genes that act downstream of AID. Yet, a cohort of patients show a severe disease state without apparent changes of the normal AID protein, but as proteins are assembled from building blocks, we anticipate that AID exist in various assembly-forms. With this application, we propose to characterise new forms of AID protein, and anticipate that genetic abnormalities in AID assembly can lead to HIGM-II. Our work will help us understand the physiological and pathological role of AID variants during immunity, and potentially uncover new genetic markers and pharmacological targets for clinical usage in HIGM-II. As gene-therapy is still a distant possibility for these patients, better diagnostics and medical/biological understanding of HIGM are the best possibility for patient care.