Stage-dependent immunity orchestrates AQP4 antibody-guided NMOSD pathology: A role for netting neutrophils with resident memory T cells in situ

Neurology Medical Laboratory Science Medicine Basic Medical Sciences Cell Biology Life Sciences Immunology
neuromyelitis optica spectrum disorder multiple sclerosis neutrophil extracellular DNA traps melanoma cell adhesion molecule-positive helper T cells forkhead box P3-positive regulatory T cells tissue-resident memory T cells

Stage-Dependent Immune Responses Mediated by AQP4 Antibodies in NMOSD Pathology in the Central Nervous System

Academic Background

Neuromyelitis optica spectrum disorders (NMOSD) are autoimmune diseases of the central nervous system (CNS), characterized by the production of specific antibodies against the water channel protein Aquaporin-4 (AQP4). Although animal model studies suggest that anti-AQP4 antibodies primarily lead to the loss of AQP4-expressing astrocytes through complement-dependent cytotoxicity, many disease mechanisms remain unknown. For instance, it is unclear how anti-AQP4 antibodies cross the blood-brain barrier (BBB) into the CNS, how NMOSD extends into extensive transverse myelitis or optic neuritis, how it occurs in a multiphasic process, and how attacks can be prevented without depleting circulating anti-AQP4 antibodies.

Research Source

This study, authored by Akihiro Nakajima and colleagues, includes researchers from Niigata University School of Medicine and several other academic institutions in Japan. The academic paper was published on March 25, 2024, in the journal Acta Neuropathologica.

Research Process

To bridge existing knowledge gaps, the research team conducted a comprehensive investigation of the “stage-dependent” cellular immune components in human NMOSD lesions using pathological techniques. The study involved 25 Japanese patients with NMOSD, multiple sclerosis (MS), and other diseases. The researchers performed immunohistochemistry and in situ hybridization analyses on brain and spinal cord samples from these patients to study the characteristics of immune cells at various stages.

Results

The study found three main results:

  1. In the early or active stages of NMOSD, there is a significant increase in neutrophils and MCAM+ Th17/Tc17 cells in the reticular imaging, proportional to the area of NMOSD lesions.
  2. Foxp3+ regulatory T cells are rapidly recruited to NMOSD lesion areas during the early and active stages, indicating a quick suppression of multifocal inflammatory autoimmune events.
  3. Long-term inflammation-potential resident memory immune cells, including CD103+ tissue-resident memory T cells (TRM), remain in a “standby” state at all stages. TRM cells show high levels of Granzyme B/Perforin-1 during early or active stages.

Research Methods

The study used formalin-fixed, paraffin-embedded sections for data analysis, combining techniques such as H&E staining, Kluver-Barrera staining, and immunostaining using various polyclonal or monoclonal primary and secondary antibodies. To obtain accurate quantitative data on immune cells, the researchers used ImageJ software for manual counting and performed statistical analysis using cluster analysis and heatmap generation tools (ClustVis).

Conclusion

The primary conclusion of this study is that the pathology of NMOSD depends on unique immune cell characteristics at each stage. These immune features regulate the multistep pathological mechanism mediated by AQP4 antibodies in NMOSD, including complement and cytotoxic T cell activation in lesion areas, the occurrence and resolution of inflammation, the long-term standby state of resident memory T cells, and the role of Foxp3+ regulatory T cells in regulating over-inflammatory responses.

Research Highlights

  1. Discovery of the Role of Reticular Imaging Neutrophils: The study provides the first direct link between the number of reticular imaging neutrophils in the CNS and the area of NMOSD lesions.
  2. Significance of MCAM+ Th17/Tc17 Cells: The study reveals the importance of MCAM+ Th17/Tc17 cells in the early stages of lesions, with a significant correlation between their number and lesion expansion.
  3. Characteristics of Long-Acting Inflammatory TRM Cells: The study finds that TRM cells remain in a “standby” state at all stages and exhibit high levels of cytotoxic proteins such as Granzyme B and Perforin-1 during early active stages.

Application Value

This study provides potential therapeutic strategies, including targeting reticular imaging neutrophils (e.g., inhibiting cytoplasmic protein arginine deiminase 4), MCAM+ Th17/Tc17 cells (e.g., neutralizing IL-17 or IL-6 receptor antibodies), and increasing the number of Foxp3+ regulatory T cells to effectively treat and prevent NMOSD relapses.

Other Important Information

The study suggests that future research should involve multi-racial large sample cohorts for single-cell level and spatial resolution multi-omics analysis to further clarify the role of immune cell characteristics at various stages in NMOSD lesions.

Conclusion

This study reveals the complexity and multistage characteristics of NMOSD pathology, proposing new treatment and prevention strategies, and providing valuable insights for future NMOSD research and clinical treatment.