Long-standing Link Between AS and HLA-B27 Explained
Results could explain how immune system mistakenly targets health tissue
Some immune T-cells that react to microbial proteins also target normal human proteins in people who carry HLA-B27 variants, the strongest genetic risk factor contributing to ankylosing spondylitis (AS), a study revealed.
The shape of the protein fragments targeted by the immune T-cells, whether human or bacterial, was almost identical.
These results may explain how the immune system mistakenly targets healthy tissue in people with HLA variants and cause autoimmune diseases like AS, as well as the inflammatory eye condition acute anterior uveitis (AAU).
“This paper … provides strong evidence that cross-reactivity between human and microbial proteins drives autoimmunity in at least two diseases and probably many others,” Wayne Yokoyama, MD, study co-lead and professor at Washington University School of Medicine in St. Louis, said in a university press release. “Now that we understand the underlying drivers, we can start focusing on the approaches that are most likely to yield benefits for patients.”
The study, “Autoimmunity-associated T cell receptors recognize HLA-B*27-bound peptides,” was published in the journal Nature.
Human leukocyte antigen B27 (HLA-B27) is a well-established risk factor for AS, a type of arthritis mainly affecting the sacroiliac joints, where the base of the spine meets the pelvis. However, the disease-causing HLA-B27 mechanisms linked to AS and AAU are not fully understood.
“Of all genes, the HLA genes have the greatest amount of variation across the human population,” said Yokoyama. “There are many, many autoimmune diseases that are associated with specific variants of the HLA genes, and in most cases we don’t know why.”
Peptide antigens
HLA genes carry instructions for a family of proteins found on the surface of immune cells that regulate immune responses. These proteins hold and present small fragments of protein, called peptide antigens, derived from microbes or the human host (self-peptides) to immune cells.
In this way, the immune system can distinguish between microbial and human proteins, thus activating immune responses against microbes while suppressing responses against the body’s own tissues. In autoimmune diseases like AS, this process is faulty, triggering the immune system to mistakenly attack healthy tissue.
The arthritogenic peptide hypothesis is a long-standing idea whereby, in autoimmune diseases like AS and AAU, immune T-cells that recognize microbial peptides presented by HLA-B27 also interact with HLA-B27 bound to self-peptides. As a result, T-cells are activated against human tissue.
Until now, however, methods to identify candidate peptides have been limited.
Researchers at Washington University, along with colleagues at Stanford University School of Medicine and Oxford University, devised a new method to identify such candidates.
First, the team isolated T-cells from patients with AS and AAU that carried disease-associated T-cell receptors (TCR) — the protein on the surface of T-cells that directly interacts with HLA-bound peptides. Then, these AS- and AAU-derived TCR proteins were used to screen an extensive library of peptide molecules to find shared microbial peptides and self-peptides that activated these TCRs.
“This study reveals the power of studying T cell specificity and activity from the ground up; that is, identifying the T cells that are most active in a given response, followed by identifying what they respond to,” said study co-lead K. Christopher Garcia, PhD, at the Stanford University School of Medicine, in California.
Two HLA-B27 subtypes tested
To investigate further, the team tested the peptide/T-cell activation with two HLA-B27 subtypes: HLA-B27:05, a variant strongly linked to AS, and HLA-B27:09, which appears to be protective for AS. These two HLA subtype proteins differ by a single amino acid, a protein building block.
Cells with these two HLA subtypes were mixed individually with five peptides (four self, one bacterial) and T-cells with AS- and AAU-derived TCRs. The results showed that three of the self-peptides activated cells with HLA-B27:05 but not HLA-B27:09. In contrast, similar T-cell activation was observed for the other two peptides, when presented by either HLA-B27:05 or HLA-B27:09.
“Our data suggest that features of peptide binding and presentation exhibited by disease-associated versus non-disease-associated HLA-B*27 subtypes could contribute to the [development of AS],” the researchers wrote.
To visualize this process, the team analyzed the individual atomic three-dimensional structures of seven TCR proteins bound to HLA-B27:05 with three peptides (two self, one bacterial). Structural analysis revealed a shared binding motif across all structures, meaning the shape of peptides, either self or bacterial, and the TCRs that interact with them when bound to HLA, were almost identical, thus explaining the TCR cross-reactivity, the team noted.
“These findings support the hypothesis that microbial antigens and self-antigens could play a pathogenic role in HLA-B*27-associated disease,” they wrote.
“Clearly these patient-derived TCRs are seeing a spectrum of common antigens, and that may be driving the autoimmunity,” said Garcia. “Proving this in humans is very difficult, but that is our future direction and could lead to therapeutics.”
“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,” said Geraldine M. Gillespie, PhD, study co-lead, at the University of Oxford in the U.K.
“Our findings that T cells at the sites of pathology recognize HLA-B*27 bound to both self and microbial antigens adds a very important layer of understanding to these complex conditions that also feature strong inflammatory signatures,” Gillespie said. “Our hope is that this work will one day pave the way for more targeted therapies, not only for these conditions but ultimately, for other autoimmune diseases.”
Co-first author Michael Paley, MD, PhD, of Washington University, added, “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.”
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