Patients show distinct immune cell profile, might help to diagnose aHUS
Activity of select genes also may mark disease states, aiding management
People with atypical hemolytic uremic syndrome (aHUS) have an immune cell profile distinct from that of healthy people and unaffected family members, a recent study reported.
Its scientists identified a range of immune cell types, genes, and signaling pathways that could ultimately serve as disease biomarkers — with the ability to differentiate between stable and unstable disease. But further investigation is required.
“This … study is the first to confirm immune cell dysregulation in aHUS pathogenesis [disease mechanisms], offering valuable insights into molecular mechanisms and potential new diagnostic and disease activity markers,” the researchers wrote.
The study, “Dysregulation of Immune Cell Subpopulations in Atypical Hemolytic Uremic Syndrome,” was published in the International Journal of Molecular Sciences.
Lack of disease-specific markers hinders aHUS diagnosis, management
A type of thrombotic microangiopathy, aHUS is marked by the formation of blood clots in small blood vessels. Three cardinal symptoms of the disease are hemolytic anemia, which happens when red blood cells are destroyed faster than they’re made, thrombocytopenia, or low platelet counts, and acute kidney injury.
In most cases, aHUS arises due to genetic mutations that cause an abnormal activation of the body’s immune complement cascade in response to certain triggers, such as infection, pregnancy, or some medications.
Symptom severity and treatment response vary significantly among patients, making it a difficult disease to manage.
“The challenges in diagnosing and managing aHUS largely stem from the absence of specific diagnostic markers and the disease’s rapid progression,” the researchers, all in Taiwan, wrote. “The identification of a molecular marker for disease activity is of utmost importance.”
Because the complement system is involved in coordinating immune responses, the scientists sought to investigate whether certain populations of immune cells might be dysregulated in aHUS and could serve as disease biomarkers.
Using a technology called single-cell sequencing to look at gene activity — also called gene expression — in individual cells, they explored the immune profile of 13 aHUS patients (ages 30 to 81), three family members without a disease diagnosis, and four unrelated healthy adults as a control group.
Among the patients, nine had stable disease and four were determined to have unstable disease. Five patients were being treated with plasma exchange therapy alone, and eight were receiving it alongside complement inhibitor therapies.
Analysis found a number of immune cell populations were altered in aHUS patients, several of which were in higher abundance relative to healthy people. For some cell types, patients’ unaffected family members had immune cell numbers that were in an intermediate range between aHUS and healthy samples.
Immune cells called intermediate monocytes seen as potential markers of activity
Differences also were observed in patients depending on their disease course and treatment status.
For example, people with unstable disease had higher numbers of intermediate monocytes — a class of immune cells that serve as a major source of pro-inflammatory molecules called cytokines during an immune response — than did those with stable disease.
Therefore, “we suggest intermediate monocytes as potential aHUS disease activity markers,” the researchers wrote.
In contrast, immune cells called plasmacytoid dendritic cells — a type of immune cell involved in antiviral immunity — showed an opposite pattern, being most abundant in healthy people, followed by family members without aHUS.
For some immune cell clusters, certain genes had altered activity in aHUS patients relative to controls, whereas other genes differed between patients with stable or unstable disease.
Specifically, unstable disease patients had higher activity in the genes NEAT1, MT-ATP6, MT-CYB, VIM, ACTG1, RPL13, and KLRB1 in some immune cells relative to stable patients, who had elevated activity levels in RPS27, RPS4X, RPL23, and GZMH.
“These genes may serve as potential clinical markers for aHUS disease activity,” the researchers wrote.
An observed increase in the activity of genes involved in the function of mitochondria, organelles that serve as energy production centers for cells, also “suggested a potential influence of cell metabolism on the clinical progression of the disease,” according to the scientists, who noted this finding warrants further study.
Additional analyses revealed a distinct pattern of immune cell differentiation — the process of certain immune cell types transitioning into others — in aHUS, as well as immune cell-complement interactions and immune signaling profiles that were unique to aHUS relative to healthy people and family members.
Notably, the immune profile observed in these aHUS patients did not overlap with previous studies of other autoimmune conditions, “highlighting the unique immune cell profile in aHUS,” the team wrote.
Researchers noted that, as with all rare diseases, their study was limited by the small number of aHUS patients available for analysis.
“Going forward, we aim to undertake more exhaustive and far-reaching studies to mitigate this issue and enhance the robustness of our findings,” they wrote.