Mutant Blood Cells Relatively Common in AAV Patients and Carry Risks and Benefits, Study Suggests

Mutant Blood Cells Relatively Common in AAV Patients and Carry Risks and Benefits, Study Suggests

The development of a population of mutated blood cells — a phenomenon called clonal hematopoiesis of indeterminate potential — is more frequent in ANCA-associated vasculitis (AAV) patients than in healthy people, and may modify the clinical outcomes of the disease, a study reports.

Some patients with such blood cell populations have fewer disease complications, but because the mutated cells keep growing in more than one-quarter of these patients, researchers advise closer monitoring of CHIP-positive patients. They are at risk of progression to a blood cancer.

The study, “Clonal Hematopoiesis In Patients With ANCA-Associated Vasculitis,” was published in the journal Haematologica.

Clonal hematopoiesis of indeterminate potential, or CHIP, happens when blood stem cells — or other types of progenitor blood cells — give rise to a genetically distinct population of blood cells that shares the same unique mutation. They are considered genetic clones of each other.

CHIP is commonly associated with aging, and is known to increase the risk of blood cancer or cardiovascular disease, but it may also occur in people who are completely healthy.

At the molecular level, CHIP can arise when a progenitor blood cell acquires one or more mutations that make it grow faster than other cells, like mutations in cancer-related genes. Alternatively, it may arise by chance.

CHIP seems to be involved in chronic inflammation and some autoimmune diseases. Some data suggest that mutations common in people with CHIP may contribute to the development of the harmful, self-attacking ANCA antibodies in people with ANCA-associated vasculitis (AAV).

AAV is a group of autoimmune disorders that cause small blood vessels to inflame and swell. It is caused by autoantibodies called ANCAs, or anti-neutrophilic cytoplasmic autoantibodies, that attack the inside of neutrophils, a type of white blood cells. This provokes the uncontrolled activation of neutrophils, which makes them attack a person’s own blood vessels.

Interested in better understanding the possible role of CHIP in the disease, researchers characterized the prevalence of CHIP and how it related with clinical profiles in a group of 112 AAV patients, referred to nephrology departments and wards in Berlin.

An age- and gender-matched group of 112 healthy controls was included for comparison. Mean age of all participants was about 65.

To identify people with CHIP, blood DNA samples were screened by next-generation sequencing to pinpoint the presence of mutated blood cells.

CHIP was detected in 34 AAV patients (30.4%), who carried a total of 46 mutations in their blood cells. This was a significantly greater prevalence compared to both healthy people reported in prior studies (13.5%), and the healthy control group included in this study (17.9%).

This prevalence was as high as that reported in people with cancer, aplastic anemia (when the body stops producing red blood cells), and cardiovascular disease.

While 25 patients had a single mutation, eight had two, and one person had five. The most frequently mutated genes were DNMT3A (39.1%), TET2 (15.2%), and ASXL1 (8.7%), which are commonly mutated in other cases of CHIP as well.

During a follow-up monitoring of 19 patients with CHIP (median duration of 2.3 years, range 0.3–10.9 years), five (26.3%) showed a relevant growth in the mutated population of blood cells, or clones. Two patients had slightly decreasing clones and 12 others showed no change in clone size over time.

Patients with CHIP were significantly older than those without CHIP (median 70.5 vs. 63.0 years), but CHIP prevalence was not higher in patients previously treated with immunosuppressive or cell toxic agents, including steroids, cyclophosphamide, rituximab, azathioprine, or methotrexate.

Additionally, the development of cancer, disease activity, and AAV relapse risk did not seem to differ in respect to CHIP.

However, patients with granulomatosis with polyangiitis (GPA) who were positive for CHIP had fewer kidney (68.2% vs. 88.5%) and nervous system complications (0% vs. 19.2%), compared to those who did not have CHIP.

Lab assays that mimicked the activation of neutrophils by ANCAs showed that neutrophils from CHIP-positive patients were less activated that those from CHIP-negative ones.

Backing these observations, neutrophils from CHIP-negative patients produced more MPO and PR3 – the proteins to which ANCA antibodies bind to inside neutrophils — compared to healthy controls.

This suggests that a greater amount of ANCA-stimulating molecules (antigens) are produced in patients who do not have CHIP, as a result of uncontrolled inflammation. Conversely, CHIP-positive patients are less prone to inflammation and boosting of ANCAs.

These findings reveal “a new association of AAV with CHIP with potentially disease-modifying effects as shown for neutrophil activation, autoantigen transcription regulation [expression] and organ manifestation,” the researchers wrote.

However, the expansion of the mutated cell population in many of the patients with CHIP warrants “closer monitoring of affected AAV patients because of the known risk of progression to MDS [myelodysplastic syndromes] or AML [acute myeloid leukemia],” two types of blood cancer, the team emphasized.

Ana is a molecular biologist enthusiastic about innovation and communication. In her role as a science writer she wishes to bring the advances in medical science and technology closer to the public, particularly to those most in need of them. Ana holds a PhD in Biomedical Sciences from the University of Lisbon, Portugal, where she focused her research on molecular biology, epigenetics and infectious diseases.
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Inês holds a PhD in Biomedical Sciences from the University of Lisbon, Portugal, where she specialized in blood vessel biology, blood stem cells, and cancer. Before that, she studied Cell and Molecular Biology at Universidade Nova de Lisboa and worked as a research fellow at Faculdade de Ciências e Tecnologias and Instituto Gulbenkian de Ciência. Inês currently works as a Managing Science Editor, striving to deliver the latest scientific advances to patient communities in a clear and accurate manner.
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Ana is a molecular biologist enthusiastic about innovation and communication. In her role as a science writer she wishes to bring the advances in medical science and technology closer to the public, particularly to those most in need of them. Ana holds a PhD in Biomedical Sciences from the University of Lisbon, Portugal, where she focused her research on molecular biology, epigenetics and infectious diseases.
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