Chronic inflammatory demyelinating polyradiculoneuropathy: from pathology to phenotype

Abstract

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an inflammatory neuropathy, classically characterised by a slowly progressive onset and symmetrical, sensorimotor involvement. However, there are many phenotypic variants, suggesting that CIDP may not be a discrete disease entity but rather a spectrum of related conditions. While the abiding theory of CIDP pathogenesis is that cell-mediated and humoral mechanisms act together in an aberrant immune response to cause damage to peripheral nerves, the relative contributions of T cell and autoantibody responses remain largely undefined. In animal models of spontaneous inflammatory neuropathy, T cell responses to defined myelin antigens are responsible. In other human inflammatory neuropathies, there is evidence of antibody responses to Schwann cell, compact myelin or nodal antigens. In this review, the roles of the cellular and humoral immune systems in the pathogenesis of CIDP will be discussed. In time, it is anticipated that delineation of clinical phenotypes and the underlying disease mechanisms might help guide diagnostic and individualised treatment strategies for CIDP.

Keywords: MYELIN; NEUROIMMUNOLOGY; NEUROPATHY; NEUROPHYSIOLOGY; SCHWANN CELL.

Figure 1

Immunopathogenesis of chronic inflammatory demyelinating polyneuropathy. The putative antigen is presented by antigen presenting cells to autoreactive T cells in the peripheral immune compartment. T cells become activated, undergo clonal expansion, release inflammatory mediators and cross the blood-nerve barrier (BNB). Breakdown of the BNB allows humoral factors such as autoantibodies access to the endoneurium. Further damage may be caused by macrophage-mediated demyelination, complement deposition, deposition of C5b-9/membrane attack complex (MAC), subsequent cell lysis and CD8⁺ direct lysis of cells. Inset: Effects of antibody binding at the node of Ranvier. (A) Binding of an autoantibody to the node of Ranvier could block the function of nodal molecules interfering with saltatory conduction. (B) Binding of an antibody followed by fixation of complement and deposition of the MAC leading to disruption/destruction of the node and surrounding areas.

Figure 2

Semithin sections of biopsies from the (A) sural nerve and (B) brachial plexus in the same patient. Demyelination and small onion bulbs can be seen in the sural nerve biopsy whereas marked hypertrophic changes are also apparent in the plexus. Transmission electron micrographs from sural nerve show onion bulbs as well as (C) macrophage-mediated demyelination (D) and thinly remyelinated axons. Sc, Schwann cell; a, axon; m, macrophage; my, myelin.

Figure 3

Transmission electron micrograph of rat nerve after adoptive transfer experimental autoimmune neuritis showing a lymphocyte leaving a blood vessel and infiltrating the endoneurium.

Figure 4

Indirect immunofluorescence staining of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) sera on transverse nerve sections (A and B) or teased nerve fibres (C and D). Antibodies (green) in the sera of patients with CIDP can be shown binding to the (A) non-compact regions of the Schwann cell, (B) compact myelin (C) nodes of Ranvier, as shown by staining for gliomedin (red) or (D) the paranodes. (E) Serum from a normal blood donor does not bind to teased nerve fibres, node of Ranvier stained for gliomedin (red).

Figure 5

(A) Upper panel—saltatory conduction, with the nerve impulse jumping from a node of Ranvier to the next node along a myelinated axon; Lower panel—demyelination and alteration of nodal function may lead to conduction failure in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) (B) Restoration of conduction may be associated with excitability changes following maintenance intravenous immunoglobulin (IVIg) administration, as demonstrated in threshold electrotonus recordings. There is reduction in hyperpolarising threshold electrotonus from pre IVIg influsion (white) to 1 week post-IVIg infusion (black), which begins to return to pre IVIg values at 2 weeks post-IVIg infusion (grey).