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HLA-DR4: The human antigen with subtypes that are strongly linked to type 1 diabetes

Researchers have identified three amino acid residues that are responsible for the variable association of HLA-DR4 subtypes with type 1 diabetes.

The human leukocyte antigen (HLA) system is a gene complex in humans that encodes cell-surface proteins responsible for the regulation of the immune system. HLA-DR is a class of cell-surface receptors encoded for by the HLA system. HLA-DR molecules are upregulated in response to infection. HLA-DR4 is an HLA-DR serotype. In other words, HLA-DR4 cells are variations of HLA-DR immune cells.

Mutations in HLA genes have been associated with autoimmune diseases, such as type 1 diabetes (T1D). It has been estimated that 15 out of 100,000 people suffer from T1D around the world – this figure is rising. Historically, it has been recognised that HLA-DR4 subtypes may be associated with risk, neutrality or protection of T1D. However, the pathobiological mechanisms that underly the relationship between HLA-DR4 subtypes and T1D remains largely unknown, until now.

Association of HLA-DR4 subtypes with type 1 diabetes

Recently, a study used a novel approach to investigate the contribution of HLA-DR4 in the pathogenesis of T1D. The scientists conducted two main studies, one of which was a case-control analysis of over 950 T1D patients in Sweden. The second study used The Environmental Determinants of Diabetes in the Young (TEDDY) to examine more than 7,850 children with T1D.

The key findings were as follows:

  • Three amino acid residues called β71, β74, and β86, in a common antigen of HLA-DR4 (HLA-DRB1), were responsible for the variable associations of HLA-DR4 subtypes with T1D.
  • β71, β74 and β86 formed seven motifs, four of which were associated with increased T1D risk. A motif is a short recurring pattern of DNA that indicate sequence-specific binding sites for proteins.
  • Residues β71, β74, and β86 in HLA-DRB1 were responsible for excessive associations with seroconversion. This is the development of specific antibodies in the blood serum due to infection.

Hierarchically organised DRB1 alleles by similarities of protein sequences observed in the case-control study. Alleles are deemed neutral alleles (coloured in black font), if their corresponding p-values are greater than 0.05. Image credit: L. Zhao et al, 2021

Overall, the results showed that HLA-DR4 subtypes had a distinct structural motif, defined by β71, β74, and β86 amino acid residues. Investigations showed that the combination of the residues were determinants for T1D susceptibility, neutrality or resistance. It was also found that a single change to the residues could alter the association from ‘risk’ to ‘protection’. Singularly, residue β74 presented the strongest correlation with risk of and resistance to T1D.

Future investigations into HLA-DR4 subtypes

The fact that a single change in β71, β74 or β86 can alter the residue association with T1D is hugely exciting. Although additional experimental investigation is needed to explore the details of these substitutions, the implications for possible therapeutic treatments are beneficial.

The researchers speculated that environmental factors could play a role in the association between the residues and risk of T1D. Further detailed structural studies for specific peptides is now required to answer this query, specifically pre-T1D.

Image credit: The Evolution and Biology of Sex, Sehoya Cotner and Deena Wassenberg

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