Low Levels of Specific Immune Cell Linked to Ankylosing Spondylitis Manifestations, Mouse Study Suggests
Malfunction of the ankylosing spondylitis-associated gene, ERAP1, is connected to the loss of a certain type of immune cell, which seems to contribute to the inflammation process associated with the disease, according to a mouse study.
Researchers now want to move to human trials in the coming years to validate these findings.
The study, “ERAP1 deficient mice have reduced Type 1 regulatory T cells and develop skeletal and intestinal features of Ankylosing Spondylitis,” was published in Scientific Reports.
The ERAP1 gene directs the production of a protein called endoplasmic reticulum aminopeptidase 1 (ERAP1), which, according to molecular studies, has two known functions:
- It cuts several proteins found on the cell surface known as cytokine receptors. By doing so, ERAP1 diminishes these receptors’ ability to transmit chemical signals into the cell, directly affecting the body’s inflammatory response.
- It cleaves many types of proteins into smaller pieces called peptides so that they can be recognized — as good (healthy) or bad (diseased) — by the immune system. The immune system then “decides” whether to destroy the cells where these peptides are located, depending on whether they are good or bad.
Ankylosing spondylitis (AS), a common inflammatory arthritis of the spine that can affect people as young as 17 years old, is associated with genetic variations in the human leukocyte antigen (HLA) gene, specifically with the HLA-B*27 gene mutation.
However, the exact mechanism underlying inflammation and spinal fusions in AS is still not understood.
“For example, while over 90% of AS patients have an HLA-B*27 variant, only 1–5% of individuals carrying HLA-B*27 develop AS, suggesting that additional risk factors must be present,” the researchers explained.
While HLA-B*27 is thought to contribute to 23% of the genetic risk for AS, there are strong genetic interactions between the presence of specific ERAP1 gene variants and HLA-B*27.
Genome-wide association studies have shown that the alteration of just one of ERAP1’s gene building blocks, called a nucleotide, somehow compromises ERAP1’s function. Nonetheless, it remains unclear how this gene contributes to the disease mechanisms underlying AS.
Using mice without a functional ERAP1 gene, researchers investigated the potential role of ERAP1 in AS-related immune, intestinal, and muscular changes.
Examination of the bone morphology of ERAP1-deficient mice revealed hallmark skeletal features of AS, including fusion of the bones that make up the spine, deterioration of bone tissue (osteoporosis), and inflammation of the spine.
Intestinal disturbances, which have been previously linked to AS, were also present in these animals. These included dysbiosis — imbalance of the gut bacteria, where the “bad” kind of microorganisms dominate — and increased susceptibility to dextran sodium sulfate (DSS)-induced colitis (i.e. inflammation of the colon). The DSS-induced colitis model is widely used because of the many similarities with human ulcerative colitis.
To find out if they could eliminate intestinal dysbiosis, researchers separated newborn mouse pups without a functional ERAP1 gene to a new cage to be raised by a healthy surrogate rather than their biological mother.
This led to significant changes in gut bacteria. However, despite the observed changes in intestinal microbiota, these did not impact AS-related skeletal and muscular features.
Importantly, immunological analysis revealed that ERAP1-deficient mice had lower levels of type 1 regulatory T-cells (Tr1) and tolerogenic dendritic cells than control animals. Both cell types are involved in the production of immune tolerance.
“We’ve demonstrated in mice that loss of proper ERAP1 activity correlates with loss of certain immune cells called Tr1s, which we know are directly responsible for controlling excessive immune responses that can attack healthy tissue and cells,” Andrea Amalfitano, PhD, an Osteopathic Heritage Foundation endowed professor of pediatrics, microbiology and molecular genetics professor at Michigan State University, said in a press release. “Our finding allows us to zero in on the role the gene and Tr1 cells have in AS.”
Amalfitano led the study with Yuliya Pepelyayeva, a doctoral student in Michigan’s microbiology and molecular genetics program.
“We know that Tr1 cells are implicated in digestive issues such as inflammatory bowel disease, and it’s possible that the reduction of these cells is responsible for the increased inflammatory responses we saw in mice and is associated with ankylosing spondylitis as well,” Pepelyayeva said.
These results suggest that mice without ERAP1 are an important and useful new animal model for studying the disease mechanisms of the most important skeletal and intestinal manifestations found in AS patients.
This model could also be used for testing therapeutic agents targeting skeletal, immune, and intestinal manifestations of AS.
“There’s more work to be done, but a new immunotherapy treatment where more Tr1 cells are infused back into the patient, ultimately correcting the deficiency, could be a possibility,” Pepelyayeva said.
This new immunotherapy could help regulate the immune response and thus correct the disease-associated spine inflammation and spinal fusions, she said.