Immunoglobulins and Complement in Neural Repair and Activity: A More Complex Story Emerges

Adham Keshavarzi^*
*Correspondence: Adham Keshavarzi, Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan, Email:

Introduction

The Central Nervous System (CNS) has traditionally been viewed as an immune-privileged site, largely shielded from the systemic immune system by the Blood-Brain Barrier (BBB). For decades, immune molecules such as immunoglobulins (antibodies) and components of the complement system were believed to play minimal roles in the healthy brain, with their presence primarily associated with pathological conditions such as neuroinflammation or neurodegenerative disease. However, emerging research over the last two decades has dramatically challenged this paradigm, revealing that these immune mediators are not just accidental bystanders in the CNS but active participants in neural development, synaptic remodeling, and repair following injury. The growing body of evidence suggests that immunoglobulins and complement proteins have highly context-dependent functions at times neuroprotective and regenerative, and at other times potentially neurotoxic. This nuanced understanding underscores the importance of re-evaluating the roles of these molecules in neural physiology and pathology. In this review, we explore the evolving and multifaceted functions of immunoglobulins and complement proteins in modulating neuronal activity, synaptic plasticity, and tissue repair, highlighting recent discoveries that have reshaped our view of neuroimmunology [1].

Description

In healthy neural tissue, a surprising array of immune molecules has been detected, prompting questions about their functions beyond host defense. Immunoglobulins, particularly IgG, have been observed in the CNS under non-pathological conditions, either derived from peripheral sources that cross a compromised BBB or produced locally by B cells that reside within the meningeal or perivascular spaces. These antibodies can bind to neuronal surface proteins and modulate synaptic transmission, neuronal excitability, and plasticity. Some studies suggest that autoantibodies once thought solely pathological may serve regulatory or signaling roles under tightly controlled conditions. For instance, naturally occurring IgMs have been implicated in the clearance of apoptotic cells and debris, a function that may help maintain homeostasis in the CNS microenvironment. Complement proteins, long known for their role in innate immunity and pathogen elimination, have similarly been found to participate in neuronal development and repair. During early brain development, components such as C1q and C3 are involved in synaptic pruning a process crucial for shaping efficient and functional neural circuits [2].

Microglia, the resident immune cells of the brain, express complement receptors and use complement tagging to identify and eliminate excess or underused synapses. While this process is essential during development, dysregulation of complement activity later in life has been associated with pathological synapse loss in conditions like Alzheimerâ??s disease, schizophrenia, and lupus-related neuropsychiatric syndromes. After neuronal injury, such as stroke, trauma, or demyelinating diseases like multiple sclerosis, both immunoglobulins and complement become significantly involved. B cells infiltrate damaged CNS regions, producing antibodies that may bind myelin or axonal antigens. Depending on the context, these antibodies can either exacerbate injury through mechanisms such as Antibody-Dependent Cellular Cytotoxicity (ADCC) or opsonization, or they may aid in recovery by neutralizing toxic proteins, promoting remyelination, or modulating inflammatory cascades. Complement proteins also play a dual role: on the one hand, they can exacerbate inflammation and cell death via the Membrane Attack Complex (MAC); on the other hand, they contribute to clearance of cellular debris and recruitment of reparative immune cells, facilitating tissue remodelling [3].

A key emerging theme is the concept of immune modulation rather than simple immune activation. Both the immunoglobulin and complement systems exhibit plasticity and adaptability, responding to cues from the neural environment. Local signals such as cytokines, neurotransmitters, and Damage-Associated Molecular Patterns (DAMPs) influence how these molecules behave either tipping the balance toward neuro inflammation and degeneration or toward protection and repair. Furthermore, neuronal and glial cells themselves can produce or respond to these immune mediators, suggesting a deeply integrated neuro immune network that challenges the traditional compartmentalization of brain and immune system functions. New technologies, such as single-cell RNA sequencing, advanced imaging techniques, and in vivo biosensors, have accelerated our understanding of this complex interplay. These tools have revealed that immune functions in the brain are not monolithic but highly specialized depending on cell type, brain region, and disease context. For example, specific subsets of microglia express complement-related genes during neural repair, while astrocytes can modulate the deposition of immunoglobulins in demyelinated lesions. Such findings open new therapeutic avenues such as targeting complement signalling pathways to limit synapse loss, or engineering monoclonal antibodies that can promote neuronal regeneration without provoking inflammation [4].

To effectively train a machine learning model, meaningful features must be extracted from the pre-processed EEG data. These features may include time-domain statistics (mean, variance), frequency-domain characteristics (power spectral density, dominant frequency), and nonlinear measures (entropy, fractal dimension, wavelet coefficients). These features help differentiate seizure activity from normal brain states. Support Vector Machines are supervised learning algorithms well-suited for binary classification problems like seizure vs. non-seizure detection. SVM works by finding an optimal hyper plane that separates the feature space into distinct classes. With the use of kernel functions (e.g., radial basis function or polynomial kernels), SVMs can handle non-linear data distributions effectively, making them highly suitable for EEG signal analysis [5].

Conclusion

The traditional dichotomy of the immune system as either beneficial or detrimental in the CNS is rapidly giving way to a more nuanced and dynamic model. Immunoglobulins and complement proteins, once considered purely pathological intruders in the brain, are now recognized as active participants in maintaining neuronal health, shaping synaptic architecture, and responding to injury. Their roles are context-dependent and finely regulated, with the potential for both harm and healing. This complexity presents challenges for developing therapeutic strategies blanket immunosuppression may blunt regenerative processes, while unchecked immune activation can lead to neuro degeneration. Understanding the precise conditions under which immunoglobulins and complement proteins switch roles will be key to harnessing their full potential in neuro regenerative medicine. As research continues to uncover the diverse and unexpected functions of these molecules, it becomes increasingly clear that the relationship between the nervous and immune systems is far more intricate than previously imagined. We stand at the threshold of a new era in neuroimmunology one where immunological tools may become essential components of neural repair strategies and treatments for a wide range of CNS disorders.

Acknowledgement

None.

Conflict of Interest

None.

References

1. Jolles, S., W. A. C. Sewell and S. A. Misbah. "Clinical uses of intravenous immunoglobulin." Clin Exp Immunol 142 (2005): 1-11.

Google Scholar Cross Ref Indexed at

2. Thom, Vivien, Thiruma V. Arumugam, Tim Magnus and Mathias Gelderblom. "Therapeutic potential of intravenous immunoglobulin in acute brain injury." Front Immunol 8 (2017): 875.

Google Scholar Cross Ref Indexed at

3. Soelberg Sorensen, Per. "Intravenous polyclonal human immunoglobulins in multiple sclerosis." Neurodegener Dis 5 (2007): 8-15.

Google Scholar Cross Ref Indexed at

4. Halperin, Saar T., Bert A. t Hart, Antonio Luchicchi and Geert J. Schenk. "The forgotten brother: The innate-like b1 Cell in multiple sclerosis." Biomedicines 10 (2022): 606.

 Google Scholar Cross Ref Indexed at

5. Prieto, J. M. B. and M. J. B. Felippe. "Development, phenotype and function of non-conventional B cells." Comp Immunol Microbiol Infect Dis 54 (2017): 38-44.

Google Scholar Cross Ref Indexed at