Astrocytic Stress Response Induced by Exposure to Astrocyte-Binding Antibodies in Pediatric Acute Transverse Myelitis Cases
B-cell Response in Pediatric Acute Transverse Myelitis
Acute transverse myelitis (ATM) is an autoimmune-mediated inflammatory disease of the spinal cord with an incidence of 1.7-2 cases per million children per year. ATM typically presents with limb weakness, sensory loss, and bladder/bowel dysfunction, with symptoms rapidly developing over hours to days. Magnetic resonance imaging (MRI) is the primary diagnostic tool for ATM, although 20-50% of cases display normal cerebrospinal fluid (CSF) proteins and cell counts. ATM accounts for 20-30% of cases of first-acquired demyelinating syndromes (ADS) in children and can present as the initial symptom of Multiple Sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), or myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD).
Research Background and Purpose
Compared to adults, the incidence of Multiple Sclerosis in pediatric ATM patients is lower. Epidemiological studies show that about one-third of adult ATM patients are eventually diagnosed with MS, while only 22% of pediatric ATM patients develop MS. Moreover, compared to adults, children usually show improvement within two weeks after acute immunotherapy (such as corticosteroids, IVIG, plasma exchange), and about half of them completely recover within two years.
The role of B-cells, particularly in Multiple Sclerosis, is particularly important in the pathogenesis of central nervous system (CNS) autoimmune diseases. However, our current understanding of B-cells in pediatric ATM is limited. The authors’ previous research has shown that plasmablasts (PBs), as the earliest antibody-producing B-cell subtype, are expanded in adult ATM patients and produce self-reactive antibodies against neurons. This study aims to explore the frequency, phenotype, immunoglobulin selection, and B-cell receptor reactivity of PBs in pediatric ATM patients to better understand the role of B-cells in the disease.
Source of Research
The team of authors includes Chad Smith, Kiel M. Telesford, Sara G. M. Piccirillo, and others. Their affiliated institutions include UT Southwestern Medical Center, J. Craig Venter Institute, University of New Mexico Health Sciences Center, and others. The paper was published in the “Journal of Neuroinflammation” in 2024.
Research Methods
The research team compared the frequency and phenotype of PBs in 5 pediatric ATM patients and 10 healthy controls (HCs), and contrasted this with previously reported flow cytometric data of adult ATM patients. The researchers purified total IgG from plasma samples and cloned 20 types of recombinant human antibodies (rhAbs) from individual PBs. The self-reactivity of these antibodies in mouse brain or spinal cord and primary human astrocytes was measured by mean fluorescence intensity (MFI). The potential impact of these antibodies on the health of astrocytes was studied by measuring stress and apoptotic responses in astrocytes.
Main Results
PB Frequency and Phenotype
The study found that the frequency of peripheral blood PBs was reduced in pediatric ATM patients. The self-reactivity of serum IgG against neurons in the EAE spinal cord was similar in pediatric ATM patients and HCs. However, in the EAE spinal cord, the self-reactivity of IgG against astrocytes was reduced in pediatric ATM patients, and the affinity of individual PB clones for astrocytes depended on the accumulation of somatic hypermutations.
Antibody Self-Reactivity
IgG purified from the patient serum showed high binding strength to neurons and astrocytes in the mouse spinal cord, particularly to astrocytes in the EAE spinal cord. This suggests that antibodies in pediatric ATM patients may have higher self-reactivity, which could lead to specific types of neuroinflammation.
Astrocyte Stress
Primary human astrocytes exposed to these antibodies exhibited increased stress responses but did not undergo apoptosis. This indicates that while these antibodies can induce stress responses, they are not lethal. Further research is needed to determine whether these antibodies cause chronic damage to cells over time.
Research Conclusions and Significance
This study reveals differences in PB frequency, IgG self-reactivity, and immunogenetic characteristics between pediatric ATM patients and healthy controls. These findings help to understand the pathological mechanisms of pediatric ATM and may provide new directions for future treatment strategies.
Scientific Value
The study reveals for the first time the humoral immune response characteristics that distinguish pediatric ATM patients from healthy controls, which is vital for understanding the role of the immune system in CNS diseases in children.
Application Prospect
The study suggests that therapy targeting PB expansion may help inhibit further nerve damage induced by these antibodies. This could aid in the development of more precise treatment methods in the clinical setting to reduce long-term disease risk in pediatric ATM patients.
Research Highlights
- Discovery of the Uniqueness of Antibody Binding to Astrocytes: The study found that the strength of antibody binding to astrocytes depends on the accumulation of somatic hypermutations, providing new direction for future research.
- Cell Stress Response Mechanism: Revealing that astrocytes produce stress responses without undergoing apoptosis after exposure to specific antibodies offers a new perspective on understanding the specific mechanisms of cell stress responses.
Other Valuable Information
The authors discuss that further in-depth research should be carried out on these findings, especially whether long-term exposure can cause chronic damage to cells and the long-term effects of specific antibody-binding patterns on the health of the central nervous system. Long-term observation and subsequent studies of pediatric ATM patients will contribute to a better understanding of the potential mechanisms behind these findings.
Through this research, scientists have gained new insights into the humoral immune response in pediatric ATM, which not only helps to understand its pathological mechanisms but also provides new possible avenues for clinical treatment.