Elsevier

Autoimmunity Reviews

Volume 11, Issue 3, January 2012, Pages 191-195
Autoimmunity Reviews

Review
Autoimmune diseases of the peripheral nervous system

https://doi.org/10.1016/j.autrev.2011.05.011Get rights and content

Abstract

Autoimmune-mediated diseases targeting the peripheral nerve represent a group of disorders often associated with high clinical disability. At present, therapeutic options are limited. The application of innovative and cutting-edge technologies to the study of immune-mediated disorders of the peripheral nervous system (PNS) have generated a better understanding of underlying principles of the organization of the immune network present in the peripheral nerve and its dialogue with the systemic immune system. These insights may foster the development of specific and highly effective therapies for autoimmune diseases of the peripheral nerve. Of great interest in this context is the application of monoclonal antibodies, such as rituximab or alemtuzumab, which in small observational studies provided promising clinical results. But also other immunomodulatory or immunosuppressive drugs used in other indications currently find their way to PNS autoimmunity. Clearly, prospective controlled clinical trials are warranted before making firm conclusions on the feasibility of these innovative therapeutic approaches for treating immune-mediated disease of the peripheral nerve.

Introduction

The peripheral nervous system (PNS) is separated from the systemic immune compartment by the blood-nerve barrier (BNB), which does restrict access of immune cells and soluble mediators. This restriction, however, is not complete. Anatomically the BNB is practically absent at the most proximal and distal parts of peripheral nerve, i.e. nerve roots, dorsal root ganglia, and nerve terminals. Traditionally the PNS has been considered an ’immunologically privileged’ site, yet not as strictly as the central nervous system (CNS). However, this view has undergone revision in recent years [1]. Immune surveillance is operative in the PNS, executed by patrolling activated T and B lymphocytes that cross the BNB irrespective of their antigenic specificity. Moreover, antigen-presenting cells, such as macrophages, are abundant in peripheral nerve tissue. Schwann cells (SC) also can function as antigen presenting cells (APCs) and contribute to the local immune network [2].

During recent years understanding of the molecular and cellular mechanisms resulting in inflammatory damage of the PNS has advanced considerably, based on observations in affected patients, studies in experimental animal models, and in vitro experiments [3]. The prototypic immune-mediated peripheral neuropathy is the Guillain-Barré syndrome (GBS), which is now recognized as a group of heterogeneous conditions with diverse pathology and pathogenesis that share a similar clinical phenotype. It appears that chronic inflammatory demyelinating polyneuropathy (CIDP) is similarly heterogeneous. Other dysimmune neuropathies can also be recognized, e.g. multifocal motor neuropathy (MMN) and non-systemic vasculitic neuropathies. Peripheral nerves are also target for immune attacks in the context of a multitude of systemic disorders.

Immune-mediated inflammatory disorders of the PNS are characterized by cellular infiltration, demyelination and to a varying degree axonal loss in the affected part of the nerve. Most of these changes can be reproduced in the model disorder experimental autoimmune neuritis (EAN), an animal model of the human Guillain-Barré syndrome (GBS) [4], [5]. EAN can be elicited in susceptible animals by active immunization with whole peripheral nerve homogenate, myelin, myelin proteins P0 and P2 or peptides thereof, and galactocerebroside. It can also be produced by adoptive transfer of autoreactive, P2, P2 peptide-specific, P0, and P0 peptide-specific T cell lines [6].

The pathological hallmark of EAN is the infiltration of the PNS by lymphocytes and macrophages, which results in multifocal demyelination of axons predominantly around venules. From studies in patient nerve biopsies and animal models, it is known that activated T-lymphocytes invade the peripheral nerve. Apparently, the T-cell populations are heterogeneous and belong to both the CD4 and CD8 subgroups and carry the αβ or the γδ T cell receptor [7], [8], [9], [10], [11]. In a study of patients with GBS or Miller-Fisher syndrome frequent oligoclonal expansion of T cells bearing particular type T-cell receptor Vβ and Vδ genes was noted, suggesting that T cells are critically involved in the development of these neuropathies [12].

In order to generate inflammatory lesions in the peripheral nerve, activated T cells need to cross the BNB. This complex process of homing, adhesion, and transmigration has been studied in EAN in great detail [13]. In patients with inflammatory neuropathies, increased serum or cerebrospinal fluid (CSF) levels, or both of soluble adhesion molecules [14], [15], chemokines [16], [17], and matrix metalloproteinases [18], [19] can be detected, indicative of active T cell migration across the BNB.

Macrophages actively strip off myelin lamellae from axons, induce vesicular disruption of the myelin sheath, and phagocytose both intact and damaged myelin, as shown by electron microscopy [20], [21]. Macrophages, numerous as resident cells in the endoneurium, represent the predominant cell population in the inflamed PNS, and they are located in spinal roots as well as in more distal segments of the affected nerves [22] (Fig. 1).

It remains presently elusive how the cascade of autoimmune responses targeting PNS structures is ignited. One pathogenic mechanism of special relevance to autoimmune neuropathies is molecular mimicry. In a proportion of patients with GBS epitopes shared between the enteropathogen Campylobacter jejuni, cytomegalovirus (CMV) or Haemophilus influenzae and nerve fibers have been identified as targets for aberrant cross-reactive B cell responses [23], [24], [25]. The concept of an aberrant B cell response, primarily mounted against glycolipids and related conjugates, is commonly accepted as a key mechanism in the pathogenesis of immune-mediated demyelination of the peripheral nerve occurring in the context of GBS variants. A role for such antibodies has clearly been documented in rabbit EAN induced by immunization with GM1 gangliosides [26]. Antibodies can conceivably induce myelin damage by three mechanisms: (1) upon binding to the Fc receptor of macrophages they can direct these to the putative (auto-) antigenic structures and induce so-called antibody-dependent cellular cytotoxicity; (2) by opsonizing target structures, they can promote their internalization by macrophages; and (3) upon binding to the antigenic epitopes, they can activate the classic complement pathway with subsequent assembly of the terminal complement complex (C5b-9) [27]. This results in pore formation allowing calcium influx, which triggers myelin-integral proteases that degrade the myelin sheath. Current knowledge suggests that complement may be important in recruiting macrophages into the endoneurium, in also opsonizing myelin for phagocytosis, in amplifying ongoing inflammatory reactions, in disintegrating the myelin sheath (see above) and disrupting the neuromuscular junction [28]. Besides mediating structural damage, antibodies may impair nerve impulse propagation and neuromuscular transmission when binding at or close to the node of Ranvier or the motor terminals (reviewed in [13]) (Fig. 1).

Despite significant advances in understanding pathology and pathogenesis the cause and the heterogeneity of acute and chronic immune neuropathies still remain largely unresolved.

Section snippets

The clinical spectrum of autoimmune diseases of the peripheral nerve

The clinical picture of autoimmune mediated polyneuropathies (PNP) ranges from the acute inflammatory demyelinating polyneuropathy (AIDP), the so called Guillain-Barré syndrome, to chronic forms, the chronic inflammatory demyelinating polyneuropathy (CIDP), with all its subforms and clinical distinct clinical presentations, such as the multifocal motor neuropathy (MMN) or the Lewis-Sumner syndrome (LSS) (reviewed in [29]). In immune-mediated neuropathies steroids, plasma exchange (PE),

Classical immunomodulatory agents

The mainstay in the immunomodulatory therapy of GBS are currently PE as well as IVIG, both of which proven to exhibit clinical efficacy in various double-blinded, placebo-controlled clinical trials (reviewed in [2]). No difference in efficacy between IVIG and PE could be demonstrated, a conclusion that has been reemphasized in the recently updated systemic Cochrane review that summarized a series of clinical studies. The optimal dose of IVIG, however, still remains to be determined.

Conclusion

Our present knowledge of the principles that govern immune responses in the peripheral nerve is still limited. Given the large heterogeneity of the various acute and chronic immune-mediated disorders of the peripheral nerve as well as the inflammatory involvement in hereditary neuropathies it becomes more important to understand the deleterious but also potentially beneficial effects of the individual cellular and humoral immune component involved during inflammation in the PNS. It is hoped

Disclosure statement

The authors disclose any actual or potential conflict of interest including financial, personal or other relationships with other people or organizations within the last 3 years that could inappropriately influence their work.

Take-home messages

  • New insights into the elements involved in the pathogenesis of immune-mediated disorders of the peripheral nervous system (PNS) provide a better understanding of the complex interplay of these cellular and molecular components in the immunology of the PNS.

  • Immune-mediated polyneuropathies present as a heterogeneous group of disorders.

  • Immunoglobulins, corticosteroids, and plasma exchange represent the main therapeutic strategies for most chronic forms of immune neuropathies.

  • A greater

Acknowledgements

The authors wish to thank Sabine Püngel for her editorial assistance.

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