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Screening and diagnosis of autoimmune diseases focusing on Sjogren’s syndrome and Lupus

Garvan Institute of Medical Research

  • Early-Mid Career Fellowship
Date Funded:
  • 1 February, 2017
Chief Investigator/s:
  • Dr. Joanne Reed

Antibodies are the effector molecules of the immune system and are responsible for neutralising pathogens with remarkable specificity and memory. However, 5 per cent of Australians suffer from autoimmune diseases, such that their antibodies recognise their own cells, tissues and organs (autoantibodies). Autoantibody-mediated disorders account for a large burden of chronic disease and can be difficult to diagnose and treat due to heterogeneous symptoms ranging from arthritis, dry eyes/mouth to kidney failure and giving birth to a child with cardiac abnormalities. The unpredictability of disease outcomes reduces patient quality-of-life, while posing significant costs to healthcare systems for ongoing monitoring and treating symptoms as they occur. Treatment options are limited to non-specific steroids and expensive biologics that are only effective in a subset of patients.

The objective of this research is to use cutting-edge genomic technology to characterise human autoantibodies to improve diagnosis and monitoring of disease. This approach traces the cellular source of autoantibodies revealing novel and specific therapeutic targets.

There are two ways to characterise an antibody: i) antigen specificity – what the antibody interacts with; ii) the genes that form the antigen binding site on the antibody (variable (V), diversity (D) and joining (J) genes). For the last 40 years, the former method has been employed by clinical diagnostics to detect autoantibodies but has limited value for predicting disease outcome. For example, maternal autoantibodies binding the Ro self-antigens are associated with foetal cardiac abnormalities such that weekly echocardiograms from 12-22 weeks gestation are recommended for all Ro autoantibody-positive pregnancies. However only 2 per cent of these pregnancies result in this disease. A more specific biomarker would identify patients at highest risk, allowing for early intervention and improved disease management.

Advances in genomic technologies for sequencing antibody genes now make it possible to evaluate VDJ-genes for diagnostic purposes. Specific VDJ-genes have become useful diagnostic and prognostic indicators of lymphoma. Extending this approach to autoimmunity creates the exciting possibility of stratifying autoantibodies according to VDJ-gene usage and clinical symptoms. Previous research by others and myself has revealed distinct subsets of Ro autoantibodies that cause disease pathology. These “pathogenic” Ro autoantibodies cannot be distinguished from “quiescent” Ro autoantibodies by routine diagnostic assays. Genetic analysis of Ro autoantibodies is limited but has revealed biases in VDJ-gene usage across multiple patients. This research will extend these promising preliminary studies to evaluate the diagnostic utility of sequencing VDJ-genes and reveal where autoantibodies come from.