C5 inhibitors tied to partial immune recovery in PNH, study finds
T-cell subsets improved, but other immune cells did not recover
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Treatment with C5 inhibitors, a class of approved medications for paroxysmal nocturnal hemoglobinuria (PNH) that block activation of the complement cascade — a part of the immune system that is overactive in the disease — was associated with partial recovery of certain immune cell populations, a study in China suggests.
Researchers found that treatment was associated with changes in several immune cell populations, particularly T-cell subsets, whose levels moved closer to those of healthy individuals over time. The findings suggest that overactivation of the complement system in PNH may be involved not only in red blood cell destruction but also in broader immune changes, including immune escape mechanisms thought to contribute to disease development.
“This is the first study to systematically analyze immune status alterations following C5 complement inhibitor treatment in PNH patients, suggesting that the complement system may be involved in the development of immune escape mechanisms in PNH,” researchers wrote.
The study, “Analysis of the Recovery of Immune Status in the Patients With Paroxysmal Nocturnal Hemoglobinuria After Treatment With C5 Complement Inhibitor,” was published in the Journal of Clinical Laboratory Analysis.
C5 inhibitors are used to treat PNH
PNH occurs when acquired mutations in blood-forming stem cells lead to blood cells that lack certain surface proteins, including proteins that help protect them from complement-mediated destruction. The expansion of these abnormal cell populations, or clones, is thought to be driven in part by immune evasion, meaning these cells can evade recognition and elimination by the immune system.
These abnormal cell populations can gain a survival advantage and expand over time. As a result, blood cells — particularly red blood cells — are destroyed too early by an overactive complement system, a cascade of proteins involved in the immune response. This leads to symptoms such as blood in the urine, blood clots, and fatigue due to anemia or low red blood cell levels.
C5 inhibitors, such as Soliris (eculizumab) or PiaSky (crovalimab), block complement activation by inhibiting the complement protein C5. By doing so, they reduce complement-mediated red blood cell destruction, reduce the need for blood transfusions, and lower the risk of blood-clot-related complications.
“However, the effect of complement C5 inhibitors on the immune function of PNH patients has not been reported,” the researchers wrote.
To address this, researchers retrospectively analyzed data from 27 people with PNH treated with C5 inhibitors at a single hospital in China from January 2021 to December 2023, along with 30 age- and sex-matched healthy controls. They tracked changes in several types of immune cells over time to better understand how treatment may affect immune function.
The group included 15 men and 12 women, with a median age of 35. A total of 22 participants received PiaSky, while five received Soliris. After treatment, 70.3% no longer needed blood transfusions.
T-cell subsets moved closer to normal
Before treatment, participants with PNH had significantly higher levels of T-cells — a type of immune cell that helps coordinate the body’s defenses — compared with healthy individuals (78.5% vs. 67.3%). After starting treatment, T-cell levels initially dropped during the first six months, then showed a slight increase at one and two years, but remained lower than before treatment.
Looking more closely at T-cell subtypes, CD4+ T-cells — often called “helper” cells because they help coordinate immune responses — were lower than those of healthy individuals before treatment (38.9% vs. 48.5%). Their levels gradually increased after treatment and returned to near-normal levels within one to two years.
In contrast, CD8+ T-cells — which destroy abnormal or infected cells — were higher than in healthy individuals at the study’s start (49.3% vs. 41.7%) and declined over time with treatment.
As a result, the CD4/CD8 ratio — a key measure of immune balance — was significantly reduced before treatment but improved steadily over time, moving closer to levels seen in healthy individuals after two years.
B cells, which are responsible for producing antibodies, were also significantly lower than normal before treatment (6.5% vs. 12.7%). Their levels increased soon after treatment, but reached a plateau between six months and two years and remained below those of healthy individuals.
Some immune cells did not recover
Other immune cells showed little or no recovery. Regulatory T cells (Tregs), which normally act as “brakes” on the immune system, and natural killer (NK) cells — which help detect and destroy abnormal cells — were both significantly reduced compared with healthy controls and did not show meaningful improvement during treatment. Dendritic cells, another type of immune cell, also showed no significant change after treatment. These findings suggest some immune cells may be regulated through other pathways, the researchers noted.
Because certain immune cell abnormalities improved after complement inhibition, the findings suggest the complement system may contribute to immune dysfunction in PNH. Previous research indicates that T-cells in PNH may help drive immune responses that preferentially target normal blood-forming cells, while abnormal cells can evade this attack and gain a survival advantage.
“These results suggest that the complement system plays an important role in the immune escape mechanisms of PNH,” the researchers wrote. Further studies, they added, are needed “to confirm the stability of T and B cell recovery over time” and “to clarify how complement inhibition affects T and B cell function in PNH.”
