Journal of Clinical & Experimental Neuroimmunology
Open Access

Autoimmune encephalitis; Neuroinflammation; Autoantibodies; NMDA receptor; LGI1; CASPR2; T cells; B cells; Blood-brain barrier

Introduction

Autoimmune encephalitis (AE) encompasses a spectrum of conditions where the immune system mistakenly targets neuronal antigens, leading to inflammation and dysfunction within the central nervous system (CNS) [1,2]. Unlike infectious encephalitis, AE is driven by autoimmune mechanisms, often involving autoantibodies against neuronal surface or synaptic proteins. The clinical manifestations of AE are highly variable, ranging from subtle cognitive changes and psychiatric symptoms to seizures, movement disorders, and coma. The discovery of specific autoantibodies targeting neuronal antigens, such as the N-methyl-D-aspartate receptor (NMDAR), leucine-rich glioma-inactivated 1 (LGI1), and contactin-associated protein-like 2 (CASPR2), has significantly advanced our understanding of AE pathogenesis. This review provides a comprehensive overview of the neuroimmunological mechanisms involved in AE, exploring the roles of various immune components and their clinical implications.  

Results

The pathogenesis of AE involves a complex interplay of innate and adaptive immune responses. A key feature of AE is the presence of autoantibodies targeting neuronal surface or synaptic proteins. In NMDAR encephalitis, autoantibodies against the GluN1 subunit of the NMDAR lead to receptor internalization and reduced synaptic transmission. Similarly, in LGI1 and CASPR2 encephalitis, autoantibodies target these proteins located at the juxtaparanodes of myelinated nerve fibers, disrupting neuronal excitability and synaptic function. These autoantibodies can directly impair neuronal function through various mechanisms, including receptor modulation, cross-linking, and complement activation [3]. While autoantibodies play a central role, T cells also contribute to the inflammatory process in AE. Studies have shown the presence of CD4+ and CD8+ T cells in the cerebrospinal fluid (CSF) and brain tissue of patients with AE . These T cells can recognize neuronal antigens presented by antigen-presenting cells (APCs) within the CNS and contribute to neuroinflammation through the release of pro-inflammatory cytokines such as IFN-γ and TNF-α [4]. B cells, the producers of autoantibodies, also play a critical role in AE pathogenesis. B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL), which promote B cell survival and differentiation, have been found to be elevated in the CSF of AE patients . The blood-brain barrier (BBB), a highly selective barrier that regulates the passage of molecules and cells between the bloodstream and the brain, is often disrupted in AE. This disruption allows for the infiltration of peripheral immune cells, including autoantibody-producing B cells and pro-inflammatory T cells, into the CNS, further exacerbating neuroinflammation . Genetic factors can also influence susceptibility to AE. Certain HLA (human leukocyte antigen) alleles, which are involved in antigen presentation, have been associated with an increased risk of developing specific subtypes of AE. The role of innate immunity, including microglia and astrocytes, in AE is also being increasingly recognized. Activated microglia can release pro-inflammatory cytokines and contribute to neuronal damage, while astrocytes can become reactive and contribute to the formation of glial scars . Furthermore, studies have shown that in some forms of AE, such as those associated with tumors (paraneoplastic syndromes), the immune response is initially directed against tumor antigens, but cross-reactivity with neuronal antigens can trigger the development of AE.  

Discussion

The findings summarized in this review highlight the complex neuroimmunological mechanisms underlying AE. Autoantibodies targeting neuronal surface or synaptic proteins play a crucial role in disease pathogenesis, directly impairing neuronal function. T cells and B cells contribute to neuroinflammation through the release of cytokines and autoantibody production, respectively. Disruption of the BBB facilitates the entry of peripheral immune cells into the CNS, further exacerbating the inflammatory process [5-7]. Genetic and innate immune factors also contribute to disease susceptibility and progression. Understanding these complex mechanisms is crucial for the development of targeted therapeutic strategies. Current treatments for AE often involve immunosuppression with corticosteroids, intravenous immunoglobulin (IVIG), or plasma exchange. In cases refractory to these treatments, B cell depletion therapy with rituximab or other immunomodulatory agents may be considered. Early diagnosis and prompt initiation of immunotherapy are critical for achieving optimal patient outcomes and minimizing long-term neurological sequelae [8]. Further research is needed to fully elucidate the specific triggers and pathways involved in AE pathogenesis and to develop more targeted and effective therapies.  

Conclusion

Autoimmune encephalitis is a complex group of disorders characterized by autoantibody-mediated neuronal dysfunction and neuroinflammation. The interplay of autoantibodies, T cells, B cells, the BBB, and genetic factors contributes to disease pathogenesis. Early diagnosis and prompt initiation of immunotherapy are essential for improved patient outcomes. Ongoing research continues to unravel the intricate neuroimmunological mechanisms involved in AE, paving the way for the development of novel diagnostic and therapeutic strategies.

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