乌鸦传媒

Indolent systemic mastocytosis (ISM) is a type of mastocytosis in which fewer clonal mast cells accumulate, thereby slowing the disease course and offering a better prognosis than other, more aggressive forms of the disease.

But first, some background. The mast cells in mastocytosis accumulate in tissues that generally release more mediators (histamine, cytokines, and proteases). The number of basophils, which can react like mast cells, is usually normal in patients with mastocytosis. However, they can be activated and release more mediators, thereby contributing to allergic reactions. According to a new study, basophils are activated 鈥渁fter engagement of Fc蔚RI and other receptors, such as the formyl peptide receptors . . . which are G protein-coupled receptors that bind a chemotactic factor derived from bacteria, namely, N-formylmethionyl-leucyl-phenylalanine (fMLP).鈥�¹ However, it鈥檚 not clear whether the responses of basophils are increased in patients with ISM, secondary to a rise in inflammatory mediators.¹

To learn more about this topic, a study was designed and conducted by biologist Yuzhi Yin, MD, PhD, and his colleagues at the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), and published online in The Journal of Allergy and Clinical Immunology.¹

Key findings in ISM basophil reactivity

While examining basophil responsiveness in patients with ISM to Fc蔚RI cross-linking, using the flow cytometry-based basophil activation test (BAT), Dr. Yin and his fellow researchers discovered that basophils were abnormally responsive to fMLP.¹ The investigators then compared the basophil reactivity to fMLP in patients with ISM (n=15) with that of reactivity in healthy controls (n=14). They also looked at fMLP receptor (FPR) expression. Could altered basophil responsiveness, they wondered, be contributing to symptoms in these patients?

For the BAT, the investigators used cell surface CD63 expression as the activation marker. Study participants with ISM were 32 to 76 years of age and had the KIT D816V mutation, as measured either in bone marrow or blood. Their serum tryptase levels were between 14 and 225 ng/mL.

The CD63 expression levels and the percentage of cells expressing CD63 at baseline were similar in the ISM patients and the controls. There was also no difference in this expression in response to anti-immunoglobulin E (anti-IgE). However, when the basophils were stimulated with fMLP, the percentage and expression levels were significantly increased in the patients with ISM (P < .01 and P < .001, respectively), a finding that the authors did not expect.

The experts dive deeper into the data

To explain the 鈥渨hy鈥� behind this difference in responses to fMLP, the NIH investigators looked at the expression of FPRs on basophils from patients with ISM versus healthy controls. The team found that the expression of FPR1 was higher on the basophil surfaces and that there was a higher percentage of FPR1-positive cells in the patients with ISM. However, there was no expression of FPR2 or FPR3 on basophils in either cohort.

To see whether signals in the patients鈥� serum could induce upregulation, the investigators incubated basophils from the serum of 3 healthy controls with plasma from patients with ISM; the expression level of FPR1 was not affected.

When the investigators used fMLP treatment for 30 minutes, they found a significant decrease in FPR1 expression levels on the cell surfaces of basophils in both patients with ISM and in healthy controls (P < .05). Conversely, activation of the basophils with anti-IgE did not decrease this expression; it actually enhanced it. This, the authors said, indicated specificity to the fMLP-FPR1 interaction. Based on these findings, they concluded that 鈥�. . . fMLP engages FPR1 and induces FPR1 internalization, a process thought to represent a negative feedback mechanism to prevent excessive activation of immune cells and maintain immune homeostasis.鈥�¹

Limitations and conclusions

The authors mentioned several limitations to their 鈥減reliminary鈥� study, including its cross-sectional design and small sample size. Additionally, they measured CD63 expression only, not other markers of activation of basophils. They also couldn鈥檛 exclude the possibility that fMLP binding with FPR1 blocked antibody binding to the receptor. There was also no examination of the relationship between basophil activation and clinical symptoms.

Finally, because the authors weren鈥檛 able to incubate the basophils for a longer time, they couldn鈥檛 exclude the possibility of there being long-term effects of patient sera on mRNA synthesis, mRNA, or protein stability, calling into question the accuracy of the testing to see whether signals in the patients鈥� serum could cause upregulation.

Despite these various shortcomings, this study identified evidence of abnormal basophil activation with increased responsiveness of basophils to fMLP in patients with ISM. These findings may lead to continued investigation of the underlying mechanisms for mediator release and the functional responses of basophils (in addition to mast cells). The authors stated that it鈥檚 possible that the increased gut permeability that occurs in patients with mastocytosis increases fMLP and other factors that contribute to the activation of basophils with the release of vasoactive and proinflammatory mediators. Further study, they concluded, might be able to identify novel therapeutic targets.

Published: October 24, 2024