Immune-Receptor Clonotypes in Neurologic Disease: Mechanisms, Clinical Relevance, and Emerging Insights

Abstract

The adaptive immune repertoire, characterized by diverse immune-receptor clonotypes including T-cell receptors (TCRs) and B-cell receptors (BCRs), plays a critical role in neurologic diseases through complex mechanisms of immune surveillance, autoimmunity, and neuroinflammation. Recent advances in high-throughput sequencing have enabled precise characterization of clonotype diversity, revealing their diagnostic and therapeutic potential in disorders such as multiple sclerosis, neuromyelitis optica spectrum disorder, autoimmune encephalitis, and paraneoplastic syndromes. This review synthesizes current evidence on immune-receptor clonotypes in neurologic disease, discussing their epidemiology, pathophysiology, clinical implications, diagnostic utility, management strategies, and emerging therapies, while providing guideline-based recommendations for clinicians.

Introduction

Immune-receptor clonotypes are unique antigen-specific rearrangements of TCR and BCR gene segments, reflecting the adaptive immune system’s capacity to recognize a vast array of antigens. In neurologic diseases, aberrant expansion or selection of certain clonotypes may drive pathogenic autoimmunity, contribute to neuroinflammation, or mediate protective responses. Advances in next-generation sequencing (NGS) have revolutionized the mapping of these clonotypes, offering new insights into disease mechanisms and providing novel biomarkers for diagnosis, prognosis, and therapeutic monitoring. As our understanding deepens, integrating clonotype analysis into clinical neurology promises to enhance patient stratification and tailored interventions.

Epidemiology / Disease Burden

Neurologic diseases with immune-mediated pathogenesis, such as multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), autoimmune encephalitis, and paraneoplastic neurological syndromes, represent a significant global health burden. MS alone affects over 2.5 million individuals worldwide, with increasing prevalence in both developed and developing regions. Immune-receptor clonotype dysregulation is implicated in a subset of these disorders, and its detection is becoming more feasible as sequencing technologies advance. Studies indicate that clonotype-driven pathogenesis may underlie both common and rare neurologic autoimmune conditions, highlighting the need for continued epidemiologic surveillance and molecular characterization.

Pathophysiology

The pathophysiology of immune-receptor clonotypes in neurologic disease involves the generation and selection of autoreactive TCR or BCR clonotypes that escape central and peripheral tolerance. These clonotypes can recognize neural self-antigens, leading to T cell or antibody-mediated attack on central or peripheral nervous system tissues. In MS, for example, oligoclonal expansion of specific CD4+ and CD8+ TCR clonotypes has been demonstrated in both peripheral blood and cerebrospinal fluid (CSF), correlating with disease activity. Similarly, NMOSD and autoimmune encephalitis often feature pathogenic BCR clonotypes producing autoantibodies (e.g., anti-AQP4, anti-NMDAR). Mechanisms include molecular mimicry, somatic hypermutation, epitope spreading, and bystander activation. The local CNS milieu, including the blood-brain barrier, further influences clonotype recruitment and persistence, underpinning chronic neuroinflammation.

Risk Factors

Genetic predisposition, such as HLA alleles promoting autoreactive TCR or BCR selection, is a key risk factor for immune clonotype expansion in neurologic disease. Environmental triggers, including infections (e.g., EBV, HSV), vaccinations, and even gut microbiota alterations, can initiate or exacerbate clonotype-mediated autoimmunity via molecular mimicry or by modulating immune checkpoints. Additional risk factors include female sex, family history of autoimmunity, and prior immune checkpoint inhibitor therapy in oncology patients, which can unmask latent autoreactive clonotypes.

Clinical Features

The clinical spectrum of clonotype-driven neurologic diseases is broad, encompassing relapsing-remitting or progressive courses. In MS, patients may present with optic neuritis, transverse myelitis, motor and sensory deficits, and cognitive impairment, often accompanied by oligoclonal bands in CSF. NMOSD typically features severe optic neuritis and longitudinally extensive transverse myelitis, with aquaporin-4 antibody positivity. Autoimmune encephalitis presents with subacute cognitive decline, seizures, psychiatric disturbances, and movement disorders. Paraneoplastic syndromes may manifest as rapidly progressive cerebellar ataxia, limbic encephalitis, or sensorimotor neuropathies. The presence of specific immune-receptor clonotypes can correlate with distinct clinical phenotypes, relapse rates, and prognosis.

Diagnosis

Diagnosis of clonotype-associated neurologic diseases relies on a combination of clinical presentation, MRI, CSF analysis, serology for pathogenic antibodies, and increasingly, NGS-based repertoire profiling. Detection of oligoclonal bands (OCBs) in CSF is a classic surrogate for intrathecal clonotype expansion in MS. High-throughput sequencing of TCR and BCR genes from blood or CSF enables detailed mapping of clonotype diversity and dominance, facilitating diagnosis and monitoring. In autoimmune encephalitis, antibody profiling (e.g., anti-NMDAR, anti-LGI1) in serum or CSF is standard. Paraneoplastic panels are indicated in suspected malignancy-associated disease. Clonotype analysis can also inform disease staging, risk stratification, and response to immunotherapy.

Treatment & Management

Management strategies for immune-receptor clonotype-driven neurologic diseases center on immunomodulation and symptom control. First-line therapies include corticosteroids, plasma exchange, and intravenous immunoglobulin (IVIg) for acute exacerbations. Disease-modifying therapies (DMTs) for MS, such as interferon-beta, glatiramer acetate, monoclonal antibodies (ocrelizumab, alemtuzumab), and sphingosine-1-phosphate receptor modulators, aim to suppress pathogenic clonotype activity. In NMOSD, B-cell depleting agents (rituximab, inebilizumab) and complement inhibitors (eculizumab) are preferred. Autoimmune encephalitis requires prompt immunotherapy (steroids, IVIg, rituximab) and tumor removal if paraneoplastic. Long-term management includes relapse prevention, rehabilitation, and neuropsychological support. Monitoring immune-receptor clonotypes may enable personalized immunotherapy adjustments over time.

Recent Advances / Emerging Therapies

Recent advances have brought NGS-based clonotype sequencing to the forefront of neurologic disease research and clinical application. Ultra-deep sequencing enables identification of disease-specific TCR and BCR signatures, tracking clonal expansions during flares or remission. Adoptive T cell therapy and chimeric antigen receptor (CAR) T cell approaches are under investigation for refractory autoimmunity, aiming to eradicate pathogenic clonotypes or restore tolerance. Targeted B cell therapies, including new monoclonal antibodies and small molecules affecting BCR signaling, show promise for antibody-mediated disorders. Personalized neoantigen vaccines and tolerogenic dendritic cell therapies represent future directions. Integration of clonotype analysis with artificial intelligence may further refine diagnostic and prognostic algorithms.

Guideline Recommendations

Current guidelines from organizations such as the American Academy of Neurology and the European Committee for Treatment and Research in Multiple Sclerosis recommend a multimodal diagnostic approach, including clinical evaluation, MRI, CSF analysis, and antibody profiling. While clonotype sequencing is not yet routine, it is increasingly recognized as a valuable adjunct for atypical or refractory cases, monitoring minimal residual disease, and guiding escalation or de-escalation of immunotherapy. Clinicians are encouraged to participate in registries and biobanking initiatives to advance the integration of immune-receptor clonotype profiling into clinical practice. Ongoing education on sequencing technologies and interpretation is essential as the field evolves.

Conclusion

Immune-receptor clonotypes have emerged as central players in the pathogenesis, diagnosis, and management of neurologic diseases with immune-mediated mechanisms. Advances in high-throughput sequencing offer unprecedented insights into clonotype diversity and dynamics, enabling precision medicine approaches for patient care. Continued research is needed to validate clonotype biomarkers, optimize therapeutic strategies, and translate these discoveries into everyday neurology practice. As the field progresses, integrating clonotype analysis with clinical and radiologic phenotyping holds the potential to transform the management of complex neurologic disorders.