Induction of experimental autoimmune neuritis with peripheral myelin protein-22

Abstract

Two myelin proteins, P2 basic protein and P0 glycoprotein, can induce experimental autoimmune neuritis (EAN), a model of human inflammatory neuropathy. We investigated whether peripheral nerve myelin protein-22 (PMP22), the gene for which is duplicated in hereditary motor sensory neuropathy type la, can also induce EAN. PMP22 cDNA produced by the reverse transcriptase-polymerase chain reaction from rat sciatic nerve was expressed in Escherichia coli as a fusion protein with glutathione-S-transferase (GST). Ten Lewis rats were immunized with purified PMP22 fusion protein (50-100 microg) and eight controls with the same amount of GST. Two additional animals were immunized with each of two peptides (250 microg) of the human PMP22 extracellular sequences. Animals were examined daily until 20 days following immunization, when they underwent neurophysiological examination. A serum sample was then taken, prior to perfusion with glutaraldehyde and removal of the sciatic nerves and cauda equina. PMP22-immunized animals developed antibodies to the fusion protein and five out of 10 developed limp tails. No changes were observed in controls immunized with GST or in animals immunized with peptide. The mean compound motor action potentials elicited in the foot muscles by stimulation of the sciatic nerve at the sciatic notch and of the tibial nerve at the ankle were significantly reduced in the PMP22-immunized group (P < 0.05). Spinal roots from the group of animals immunized with PMP22 showed sparse infiltration of mononuclear cells, oedema and demyelination. PMP22 now deserves consideration as an autoantigen in human acute inflammatory demyelinating polyradiculoneuropathy.

Selective Vulnerability of Peripheral Nerves in Avian Riboflavin Deficiency Demyelinating Polyneuropathy

“…Demyelinative changes in both peripheral nerves and spinal nerve roots have also been reported in hypertrophic hereditary motor and sensory neuropathy, 4 protein zero-deficient mice, 9,26 peripheral myelin protein-22 deficient mice, 40 Trembler mice, 2 and Trembler-J mice 13 and in animal models of inflammatory demyelinating neuropathy. 1,14,17,24,38,39 In 2 mice with POEMS, which is a monoclonal plasma cell disorder characterized by polyneuropathy (P), organomegaly (O), endocrinopathy (E), monoclonal gammopathy (M), and skin changes (S), spinal nerve roots and sural nerves showed the same pathologic changes of demyelination, remyelination, and inflammatory cell infiltration, 42,47 and in 3 cases of diabetic neuropathy, there was severe loss of both large and small MF in sural nerves while segmental demyelination and remyelination was the main finding in both dorsal and ventral spinal roots. 32 Distal intramuscular and subcutaneous MF have rarely been examined in demyelinating peripheral neuropathies, although skin biopsy has been used in the diagnosis of disorders involving unmyelinated 21 and myelinated 11,23,25 fiber disorders.…”

Immunological study of hereditary motor and sensory neuropathy type 1a (HMSN1a)

“…[7][8][9][10] We have shown that recombinant, homologous PMP22 induces experimental autoimmune neuritis (EAN) and that these animals develop antibodies against the immunising antigen. 11 We have recently identified anti-PMP22 antibodies in 52% of patients with Guillain-Barré syndrome (GBS) and 35% of those with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). 12 Using a different assay others have detected anti-PMP22 antibodies in 70% of patients with HMSN1a and 60% with HMSN2 as well as in those with other neuropathies.…”

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“…Experimental autoimmune neuritis is an accurate model of the neurophysiological and pathological features of human inflammatory demyelinating polyradiculoneuropathy. It is clearly a primarily T cell mediated disease which can be induced by immunization with P0, P2 and now, PMP22 myelin proteins 26 . Although, each subtype of GBS presumably has a relatively independent immunopathogenesis.…”