Researchers within the Biomedicine Discovery Institute at Monash University have made a breakthrough in understanding the role played by high-risk immune genes associated with the development of rheumatoid arthritis (RA).
The findings, published in Science Immunology, were the result of a seven-year collaboration led by Monash University, involving Janssen Research and Development, U.S. and the Karolinska Institute, Sweden.
In this study, using mice genetically modified to express the human HLA-DR4 molecule, the team examined, at the molecular and cellular levels, how T cells recognise these HLA-DR4 molecules. The team also showed that highly similar T cell receptors, likely with similar recognition characteristics, are also present in “RA-susceptible” humans expressing these HLA molecules.
“This suggests that there may be an immune signature of RA development, providing a potential avenue for diagnostic development or a window of opportunity for therapeutic development,” says Dr. Hugh Reid, who co-led the study with Professor Jamie Rossjohn and Professor Nicole La Gruta at Monash University.
With the assistance of the Australian Synchrotron, the researchers were able to determine the structure of the molecular complexes that form during the interaction between T cell receptors and altered joint proteins bound to HLA-DR4. Armed with this information, they were able to work out what was important in this deleterious T cell response.
“This research is an excellent example of how collaborative efforts between major academic and industrial partners can lead to breakthroughs in basic science that in turn provide avenues for the development of better therapeutics for common diseases,” says Dr. Reid.
Rheumatoid arthritis is an autoimmune disease affecting about one percent of the world’s population. It is characterised by swollen, painful, stiff joints, and consequently, restricted mobility in sufferers. By working out how T cells recognise altered joint proteins in complex with ‘susceptibility’ HLA molecules, Monash scientists have advanced our understanding of how these HLA molecules may predispose individuals to the development of disease.
The insight provided may greatly assist in achieving the long-term goal of producing personalised medicines and/or preclinical interventions to treat RA.
The HLA-DRB1 gene provides instructions for making a protein that plays a critical role in the immune system. The HLA-DRB1 gene is part of a family of genes called the human leukocyte antigen (HLA) complex. The HLA complex helps the immune system distinguish the body’s own proteins from proteins made by foreign invaders such as viruses and bacteria.
The HLA complex is the human version of the major histocompatibility complex (MHC), a gene family that occurs in many species. The HLA-DRB1 gene belongs to a group of MHC genes called MHC class II. MHC class II genes provide instructions for making proteins that are present on the surface of certain immune system cells.
These proteins attach to protein fragments (peptides) outside the cell. MHC class II proteins display these peptides to the immune system. If the immune system recognizes the peptides as foreign (such as viral or bacterial peptides), it triggers a response to attack the invading viruses or bacteria.
The protein produced from the HLA-DRB1 gene, called the beta chain, attaches (binds) to another protein called the alpha chain, which is produced from the HLA-DRA gene. Together, they form a functional protein complex called the HLA-DR antigen-binding heterodimer. This complex displays foreign peptides to the immune system to trigger the body’s immune response.
Each MHC class II gene has many possible variations, allowing the immune system to react to a wide range of foreign invaders. Researchers have identified hundreds of different versions (alleles) of the HLA-DRB1 gene, each of which is given a particular number (such as HLA-DRB1*04:01).
Other Names for This Gene
- HLA class II histocompatibility antigen, DR-1 beta chain
- human leucocyte antigen DRB1
- lymphocyte antigen DRB1
- major histocompatibility complex, class II, DR beta 1 precursor
- MHC class II antigen
- MHC class II HLA-DR beta 1 chain
- MHC class II HLA-DR-beta cell surface glycoprotein
- MHC class II HLA-DRw10-beta
reference link: https://medlineplus.gov/genetics/gene/hla-drb1/#resources
More information: J.J. Lim el al., “The shared susceptibility epitope of HLA-DR4 binds citrullinated self-antigens and the TCR,” Science Immunology (2021). immunology.sciencemag.org/look … 6/sciimmunol.abe0896