Researchers have revealed important features of the biological processes underpinning autoimmune anterior uveitis, ankylosing spondylitis, and potentially many other autoimmune diseases. The study, published in Nature, investigated T cell specificity, and showed that T cells that react to microbes may also react to normal human proteins.
Autoimmune diseases arise when T cells ‘accidently’ recognise and target normal healthy human proteins. Sometimes the proteins that are identified are very similar to proteins on microbes. This means that microbial infection can trigger some autoimmune diseases. However, the implicated protein fragment is often unknown.
T cells are only one aspect of autoimmune destruction. The human leukocyte antigen (HLA) family of proteins are like ’hands’ that present peptides to T cells. The shape formed by the HLA molecules with the presented protein is recognised by the T cell receptor, which leads to activation of the T cell. HLA molecules present all types of peptides, which also include microbial peptides. A microbial peptide that looks similar to a human peptide could activate T cells that then go on to destroy healthy tissues.
The HLA genes have the greatest level of genetic variation in the human population. Specific variants of HLA genes are associated with a wide range of autoimmune diseases for unknown reasons. HLA-B*27 is a HLA variant that is strongly associated with two autoimmune diseases: ankylosing spondylitis, which involves joint inflammation in the spine and pelvis, and acute anterior uveitis, which involves inflammation in the eye. Scientists have postulated that HLA-B*27 molecules present a healthy protein fragment that T cells mistakenly identify as dangerous. This triggers autoimmune attacks and inflammation in the spine and eyes.
The human protein implicated in the misidentification theory has not been identified. Researchers at the University of Oxford, Washington University School of Medicine and Stanford University School of Medicine, developed a method to identify the protein fragments and also the T cells that recognise them.
Wayne Yokoyama, co-senior author and Professor of Arthritis Research at Washington University said, “This paper outlines a strategy for figuring out why certain HLA variants are linked to certain diseases. It also provides strong evidence that cross-reactivity between human and microbial proteins drives autoimmunity in at least two diseases and probably many others. Now that we understand the underlying drivers, we can start focusing on the approaches that are most likely to yield benefits for patients.”
Investigating the misidentification hypothesis
The researchers used single cell sequencing to analyse the abundance of certain T cells in the blood and joints of people with ankylosing spondylitis and in the eyes of people with acute anterior uveitis.
The researchers identified protein fragments that triggered a T cell response when presented on HLA-B*27 molecules. The fragments were then cross referenced and mapped against the human genome and five bacterial genomes. This allowed them to determine where the particular protein fragment originated from. A small number of human and microbial proteins were whittled down from millions.
The researchers also used biophysical and structural analysis to characterise the T cell receptors on T cells that were isolated from ankylosing spondylitis patients and uveitis patients. They found that the structures of the receptors were very similar, which provides strong evidence for the misidentification hypothesis. The findings suggest that T cells at the sites of inflammation recognise HLA-B*27 molecules that present both self and microbial antigens.
Geraldine Gillespie, Associate Professor at the University of Oxford said, “By combining recently developed technologies, we have revisited an old hypothesis that asks if the traditional antigen-presenting function of HLA-B*27 contributes to disease initiation or pathogenesis in the autoimmune conditions ankylosing spondylitis and uveitis.”
The findings highlight the potential use of targeted therapeutic approaches to treat both the diseases investigated in this study and other autoimmune diseases.
Michael Paley, co-first author and Assistant Professor at Washington University said, “For ankylosing spondylitis, the average time between initial symptoms and actual diagnosis is seven to eight years. Shortening that time with improved diagnostics could make a dramatic impact on patients’ lives, because treatment could be initiated earlier. As for therapeutics, if we could target these disease-causing T cells for elimination, we could potentially cure a patient or maybe even prevent the disease in people with the high-risk genetic variant. There’s a lot of potential for clinical benefit here.”