Immune-Mediated Peripheral Neuropathies

Immune‐mediated peripheral neuropathies encompass a spectrum of disorders in which the body’s own immune system targets the peripheral nervous system, leading to sensory disturbances, motor weakness and autonomic dysfunction. Key entities include Guillain–Barré syndrome, a typically acute monophasic illness often preceded by infection; chronic inflammatory demyelinating polyradiculoneuropathy, a more protracted demyelinating disorder; multifocal motor neuropathy, characterised by asymmetric motor involvement; and paraproteinaemic neuropathies such as IgM anti‐MAG neuropathy. Pathogenesis involves both cellular and humoral mechanisms: autoreactive T cells infiltrate peripheral nerves, autoantibodies bind to nodal and paranodal proteins or glycolipids on Schwann cells and axons, and activation of complement amplifies nerve injury. Clinical presentation varies from rapid ascending paralysis to slowly progressive sensorimotor loss. Diagnosis relies on clinical examination, electrophysiology, cerebrospinal fluid analysis and detection of disease‐specific autoantibodies. Standard treatments include intravenous or subcutaneous immunoglobulins, plasma exchange and corticosteroids, while emerging strategies aim to target B‐cell subsets, specific cytokine signalling pathways and pathogenic autoantibodies for more personalised therapy.

Research from Nature Portfolio

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Research from all publishers

Recent work has defined a clonally expanded lineage of CD4+ T cells that produce interleukin-21 and drive inflammatory neuropathy in experimental models. Single‐cell transcriptomics coupled with T-cell receptor sequencing revealed two IL-21‐expressing subsets resembling follicular and peripheral helper phenotypes, sharing clonotypes and upregulating CXCR6 to home into peripheral nerves. Mice lacking the IL-21 receptor showed marked protection against neuropathic changes, implicating IL-21–CXCR6 signalling as a potential therapeutic target.

In parallel, studies of multifocal motor neuropathy have identified a subgroup of patients harbouring IgM antibodies against ganglioside GM2 that bind selectively to Schwann cells. These antibodies fix complement, leading to deposition of C3 on Schwann cell membranes and generation of C5a, and correlate with an earlier age of onset. Functional assays confirmed that anti-GM2 binding and complement activation compromise Schwann cell integrity, underscoring the role of anti-glycolipid immunity in motor‐predominant neuropathies and suggesting complement inhibitors as a rational treatment approach.

Immune-Mediated Peripheral Neuropathies publication trend

The graph below shows the total number of articles in immune-mediated peripheral neuropathies across all publications each year (not limited to Nature Index journals).

Technical terms

Autoantibody: An antibody produced by the immune system that recognises and binds to the body’s own proteins or lipids, contributing to tissue damage.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP): A long‐standing immune‐mediated disease characterised by progressive demyelination of peripheral nerves and nerve roots.

Complement activation: A cascade of plasma proteins that amplifies immune responses, leading to opsonisation, inflammation and cell lysis.

Interleukin-21 (IL-21): A cytokine produced by T cells that modulates B-cell differentiation, T-cell expansion and can drive autoimmune inflammation.

Single‐cell RNA sequencing (scRNA-Seq): A technique that profiles gene expression in individual cells, allowing identification of rare pathogenic cell subsets within complex tissues.

References

1. A pathologically expanded, clonal lineage of IL-21–producing CD4+ T cells drives inflammatory neuropathy. Journal of Clinical Investigation (2024).
2. IgM anti-GM2 antibodies in patients with multifocal motor neuropathy target Schwann cells and are associated with early onset. Journal of Neuroinflammation (2024).