Minor protein changes can dramatically impact the immune system

Even minor changes in genetic sequences in human leukocyte antigen (HLA) molecules can impact dramatically on immune function, according to a study from an international team of researchers.

HLA molecules are a group of proteins that help the immune system identify foreign invaders, such as viruses and bacteria, and impact a wide variety of clinical outcomes, including infection and cancer. The genes that encode HLA molecules are extremely diverse, with different HLA variants displaying different peptide antigens at the cell surface. This genetic variation influences outcomes as wide-ranging as adverse drug reactions and whether a patient will react negatively to a donor transplant.

The new study, led by the Monash Biomedicine Discovery Institute’s (BDI) Professor Anthony Purcell, demonstrated that even very minor changes in genetic sequences in HLA molecules can impact dramatically on immune function.

Published in Nature Communications, the study explored the impact of micropolymorphism on three closely related HLA molecules associated in different ways with drug hypersensitivity and HIV ‘elite control’ — where an individual’s immune system seems to help keep HIV infection at bay.

“The only difference between these HLA molecules is a few amino acids strategically placed in the clefts of these molecules where peptide antigens sit,” Prof Purcell said.

“We knew there might be subtle differences in the sort of peptides bound to these molecules, but what we wanted to do in a systematic way was to understand what the differences are and what sort of functional impact the differences might have,” he said.

“It’s quite easy now to map polymorphism, and map changes in amino acid sequences; the difficulty is really translating that to say what that might mean, to be able to predict to some extent how different alleles will select different peptide antigens and how this impacts on immunity.”

“It’s striking the way that with such minor differences in the HLA you are getting both differences in the peptide interaction with the HLA molecule and also in the shape of the peptides, which makes it a drastically different target for the immune system,” said Dr Patricia Illing, joint first author.

Prof Purcell said the study, part of research spanning 25 years, provided fundamental insights that may help explain such processes as elite control in HIV or why individuals who have closely related HLA molecules can have problematic or ‘taboo’ mismatches in transplantation.

The knowledge gained may also help in the development of personalised vaccines.

“In my view, understanding how polymorphism impacts on antigen presentation or peptide presentation will actually aid the predictive tools that will be used to formulate vaccines, for example in cancer or infectious disease,” Prof Purcell said.

It also has broader implications. “The study helps us to understand how the immune system is evolving to try different ways of presenting peptides, and how the genetic diversity of the human population has been shaped by pathogens,” Prof Purcell said.

This is the second study published recently in which Prof Purcell and other researchers have made insights into peptides; another paper. published in Science Immunology on ‘trans-spliced peptides’, highlighted the unanticipated diversity of the immuno-peptidome.

The research was supported by the National Health and Medical Research Council.