Articles

The pathogenesis of CIDP

Rationale for treatment with immunomodulatory agents
Klaus V. Toyka, MD; and Ralf Gold, MD

Article abstractCurrent knowledge about the pathogenic mechanisms involved in chronic inflammatory demyelinating
polyradiculoneuropathy (CIDP) supports an autoimmune etiology. Some of the cell and humorally mediated immune
responses that contribute to the development of CIDP resemble those implicated in multiple sclerosis (MS). The effector
role of circulating antibodies has recently been revisited. In addition, similar to the situation in MS, histopathologic
studies support the heterogeneity of disease mechanisms in CIDP, with variants showing axon damage. In addition to
intravenous immunoglobulin (IVIg), prednisone, and plasma exchange, immunomodulatory drugs also were used to treat
CIDP, although no definitive trial data are available. One class of immunomodulators, interferon beta formulations, has
proven efficacy in the treatment of MS, and because of clinical similarities between the two diseases it is attractive to
investigate whether some agents that are effective in the treatment of MS would also be effective in CIDP. Preliminary
studies have evaluated the effects of interferon beta formulations in the treatment of CIDP, one of which has shown
promising results and warrants further investigation.
NEUROLOGY 2003;60(Suppl 3):S2S7

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an acquired demyelinating disease of

the peripheral nervous system (PNS), characterized by
relapsing or progressive proximal and distal muscle
weakness with possible sensory loss.1-5 Key identifying
electrophysiologic features of CIDP include nerve conduction block and slowed conduction velocities suggestive of demyelination.
The exact mechanisms that underlie the pathogenesis of CIDP remain unclear.6 However, based on
the observations that a significant proportion of patients with CIDP are responsive to immunotherapy7
and that an inflammatory response is observed at
sites of active disease,8 it is generally accepted that
CIDP is an autoimmune disorder with myelin the
likely target for the immune response. The pathogenic mechanisms that appear to precede the development of CIDP broadly resemble those implicated
in MS. In fact, CIDP is considered the peripheral
counterpart of MS because of similarities between
the two diseases in the relapsing or progressive disease course, the presence of focal demyelination and
concomitant axon damage, and the immunemediated pathophysiology. Because of similarities in
the presumed underlying pathogenic mechanisms in
CIDP and MS, it is possible that some agents that
are effective in the long-term management of MS
may also be effective for treatment of CIDP, also a

chronic disease requiring treatment appropriate for

long-term use.
Interferon beta (IFN) has proven efficacy in the
treatment of MS,9-15 and most preliminary studies of
one IFN formulation in patients with CIDP have
shown promising results (Vallat et al., in this
supplement).16-19 This article reviews what is known
about the cellular and humoral immune responses
involved in the pathogenesis of CIDP. Similarities in
the putative pathophysiological process involved in
CIDP and MS, as well as the mechanisms of action of
IFN in MS, are discussed.
Pathogenesis of CIDP. The presence of onion
bulb formations, perivascular inflammatory infiltrates, and predominant demyelination are hallmarks of CIDP pathology,2,20-22 although they may
not always be found on limited biopsies. The onion
bulb formation is a manifestation of excessive proliferation of Schwann cell processes and is often produced by segmental repetitive demyelination and
remyelination.1,23 As the disease progresses, secondary axon degeneration becomes more established,
but it also may occur early in the disease course.24
The precise mechanisms that lead to demyelination
of peripheral nerves in CIDP are not known but are
believed to be mediated by both cellular and humoral
immune factors. The putative mechanisms that lead

From the Department of Neurology, Clinical Research Unit for Multiple Sclerosis and Neuroimmunology, Julius-Maximilians University, Wurzburg,
Germany.
Publication of this supplement was supported by an unrestricted educational grant from Biogen, Inc.
Address correspondence and reprint requests to Dr. Klaus V. Toyka, Department of Neurology, Julius-Maximilians University, Josef-Schneider-Strasse 11,
D-97080 Wurzburg, Germany; e-mail: kv.toyka@mail.uni-wuerzburg.de
S2

Copyright 2003 by AAN Enterprises, Inc.

to demyelination of axons in the CNS, as observed in

MS, are similar.
How local factors in the target tissue modulate
recovery from an immune attack is not clear. For the
PNS, as yet unknown genetic susceptibility factors
may modulate the inflammatory process itself and
the response of axons and myelinating Schwann cells
to the inflammatory assault. As an example, axon
degeneration occurring in autoimmune neuropathies
clearly affects prognosis.24 Parallel expression of neurotrophic factors and their receptors in CIDP may
reflect such survival mechanisms in the PNS.25
Cellular immune factors. Inflammatory infiltrates on nerve biopsy, consisting primarily of macrophages and T cells,8 suggest that a T-cell-mediated
delayed hypersensitivity reaction directed toward
myelin antigens is a probable cause of inflammatory
tissue damage in CIDP. Inflammatory immune reactions are coordinated by a number of soluble chemical mediators and selective adhesion molecules,
including the following: direct differentiation and migration of T cells; translocation of T cells across the
vascular endothelium; stimulation of protease release; and recruitment of macrophages and additional T cells to sites of inflammation.26 In both CIDP
and MS, dysregulation of these chemical mediators
(i.e., cytokines, chemokines, and adhesion molecules)
is postulated to play a role in the breakdown of the
bloodnerve and blood brain barriers, respectively.
Furthermore, dysregulation of chemical mediators
may be responsible for aberrant trafficking of T cells
into the PNS/CNS and perpetuation of inflammatory
responses that lead to demyelination. In both the
PNS and CNS, inflammatory T cells are eliminated
by apoptosis, either during the natural disease
course or after treatment with glucocorticosteroids.27
Experimental autoimmune neuritis (EAN). An
acute or relapsing experimental autoimmune inflammatory disorder that resembles features of the human inflammatory neuropathies can be induced by
active immunization with PNS proteins and glycolipids in rats and mice. A different approach is the
adoptive transfer EAN induced by injection of
primed autoreactive T cells to naive recipients. In
acute and chronic inflammatory (demyelinating)
neuropathies, many of the putative immune mechanisms have been modeled and need to be tested in
the human disorders.28
With regard to the immunopathogenesis of
immune-mediated neuropathies, EAN also may be
generated by non-neural antigens (e.g., ovalbumin).
If ovalbumin is injected into the peripheral nerves of
rats, the subsequent adoptive transfer of ovalbuminspecific primed CD4 T cells induces EAN.29,30 If this
is translated to human inflammatory neuropathies,
it can be speculated that any infectious agent that
primes T cells may be recognized by a T-cellmediated immune reaction once it is expressed or
presented in the PNS. Subsequently, inflammatory
tissue damage may induce a secondary immune response to neural antigens, thereby circumventing

the need for a primary autoimmune attack. Indeed,

in patients with CIDP, a preceding infectious disease
has been described, in one large study in as high as
70% of patients.31
Cytokine production. Th1 cells produce interleukin-2 (IL-2), tumor necrosis factor (TNF), and interferon (IFN)-, thereby activating macrophages
and inducing delayed-type hypersensitivity responses. Type 2 Th cells (Th2) produce interleukin
(IL)-4, IL-5, and IL-10, which suppress cell-mediated
immunity.32,33
Elevated serum levels of IL-2, soluble IL-2 receptors, and mutant CD8 T-cell clones also have been
observed in patients with CIDP, suggesting a chronic
systemic activation of T cells in CIDP.34,35 Furthermore, defective suppressor T-cell activity due to
CD8 T-cell dysfunction has been observed in both
CIDP and MS patients.36,37 TNF- may also be involved in the pathogenesis of demyelination and the
breakdown of the bloodnerve barrier in patients
with CIDP. TNF- has been shown to have toxic
effects on myelin, Schwann cells,38 and endothelial
cells.21,39-41 Misawa et al.42 measured serum concentrations of TNF- in 20 patients with CIDP and compared TNF- levels with clinical symptoms and
electrophysiologic abnormalities. Results showed increased serum levels of TNF- in five patients (25%),
which were associated with subacute progression, severe neurologic disabilities, and symmetric weakness
of proximal and distal muscles. All five patients had
symmetric, predominantly motor polyneuropathy involving proximal and distal muscles. In this subgroup of patients, TNF- levels increased during the
active phase of the disease. In addition, patients
with elevated TNF- levels showed abnormal electrophysiologic features consistent with nerve demyelination compared with patients with undetectable
levels of TNF-. High levels of TNF- were correlated with longer distal latencies and slower nerve
conduction velocities in median, ulnar, and tibial
studies.42 However, another study showed no increase in levels of TNF- in patients with CIDP.43
Co-stimulatory pathways. T-cell activation and
induction require two signals from antigen presenting cells (APCs) (e.g., macrophages). The first signal
is binding of the T-cell receptor to its antigen-major
histocompatibility complex (MHC) ligand, and the
second is simultaneous delivery of a co-stimulatory
signal to the APC.44,45 The most potent of the known
co-stimulatory signals is generated by the family of
B7 proteins, which involves at least two molecules,
B7-1 (CD80) and B7-2 (CD86) and their counterreceptors, CD28 and CTLA-4, on T cells.45 There is
evidence of dysfunction in this family of costimulatory signals in both MS and CIDP.
In MS, for example, one study has shown that the
B7/CD28 pathway is involved in the development of
an animal model of MS, experimental autoimmune
encephalomyelitis (EAE). In this study, antibodies to
B7-1 (CD80) prevented induction of EAE in mice and
induced a shift in the cytokine profile to Th2,
April 2003

NEUROLOGY 60(Suppl 3)

S3

whereas antibodies to B7-2 (CD86) increased disease

severity.45 Furthermore, another study has shown
significantly higher levels of several co-stimulatory
molecules in MS patients compared with healthy controls and patients with other neurologic diseases.46
In patients with CIDP, Kiefer et al.47 showed upregulation of B7-1 expression on macrophages in the
endoneurial region of peripheral nerves. The involvement of B7-mediated T-cell co-stimulation is further
underscored by findings in a B7-2-deficient nonobese
diabetes (NOD) mouse strain. In these mice, although the block in the B7-2 pathway prevented diabetes, there was spontaneous development of
autoimmune peripheral neuropathy.48 Murata and
Dalakas49 reported an upregulation of B7-1 molecules on myelinating Schwann cells in CIDP patients. Furthermore, on endoneurial T cells that
were close to the B7-1-positive Schwann cells, there
was an upregulation of the counter-receptors to B7-1,
CTLA-4, and CD28. It has been demonstrated that
treatment with anti-CD28 MAb JJ316 markedly
ameliorates the disease course of EAN (Schmidt et
al., submitted), further underlining the crucial influence of co-stimulatory molecules in the autoimmune
response. It has recently been described that a specific epitope on the CD28 molecule, also recognized
by MAb JJ316, directly evoked protective immunity
by regulatory T cells.50
A role for Schwann cells in CIDP pathogenesis
was also suggested by the finding that the adhesion
molecule CD58 is expressed on Schwann cells in five
of seven CIDP patients but not in controls.51 CD58
has been shown to interact with CD2 on T cells and
natural killer (NK) cells, and increased expression of
this adhesion molecule correlates with increased production of IFN-, IL-2, and TNF-.52,53 In addition,
Schwann cells are armed with the death molecule
CD95 and its ligand,54 which may act as a defense
mechanism or a susceptibility factor.
Another line of investigation that adds to the evidence of cell-mediated immune responses in CIDP is
the increased expression of the nuclear transcription
factor NF-B.55 This family of transcription factors is
implicated in the induction of a variety of genes that
lead to the production of important immune mediators,
including adhesion molecules, proinflammatory cytokines, and reactive oxygen intermediates. The increase
in NF-B reported by Andorfer et al.55 was localized
to macrophages in the epi- and endoneurial regions
of inflamed peripheral nerves in CIDP patients.
Humoral immune factors. Antibody binding to
major glycolipid or myelin protein antigens has been
shown in both CIDP and MS. Antibodies may bind to
macrophages via their Fc portion, activating phagocytosis and release of inflammatory mediators toward the myelin sheath. An alternative mechanism
is through neuromuscular blocking antibodies. An
early study of the functional activity of serum IgG
antibodies demonstrated a slowing of nerve conduction in marmoset monkeys after passive transfer of
purified IgG from CIDP patients.56,57 Recently, IgG
S4

NEUROLOGY 60(Suppl 3)

April 2003

antibodies that are capable of blocking neuromuscular transmission were identified in CIDP patient serum (Buchwald, Ahangari, and Toyka, unpublished
observations). This neuromuscular blockade by IgG
antibodies also has been observed in Guillain-Barre
syndrome (GBS).58 The autoantigens recognized by
these sera have not yet been identified, but gangliosides or myelin proteins such as P0 are candidates. In
MS, the myelin proteins myelin basic protein (MBP),
proteolipid protein (PLP), and myelin oligodendrocyte
glycoprotein (MOG) are putative autoantigens.59-63
Human peripheral nerve myelin contains acidic
glycosphingolipids such as sulfated glucuronyl paragloboside (SGPG) and sulfated glucuronyl lactosaminyl paragloboside (SGLPG).64,65 One study found
elevated IgM anti-SGPG antibody titers in six of
nine patients (67%) with CIDP.66 In earlier studies,
antibodies to a variety of glycolipid antigens were
described, including LM1, GM1, and GD1a.67 Unexpectedly, antibodies to galactocerebrosides were not
commonly found, although this antigen is highly neuritogenic in rabbits and, on immunization, induces a
CIDP-like animal model.68,69 Moreover, the HNK-1 carbohydrate epitope, which is common to some glycolipids and other cell adhesion molecules, is a candidate
antigen in chronic inflammatory neuropathies.65
EAN, a usually acute animal model of human inflammatory neuropathy, can be induced by immunization of an animal with myelin proteins such as P2
basic protein, P0 glycoprotein, and peripheral myelin
protein 22 (PMP22).70-73 Gabriel et al.74 investigated
whether PMP22 might be important in inducing human inflammatory neuropathy. The sera of patients
with GBS, CIDP, other neuropathies (ONP), and
normal controls were evaluated for IgM and IgG antibodies against PMP22. Antibodies were detected in
52% of patients with GBS, 35% with CIDP, and 3%
with ONP; no antibodies were detected in normal
controls.74 In addition, Koehler et al.75 demonstrated
elevated T-cell-independent IgM production against
PMP22 in actively induced EAN. Furthermore, Ritz
et al.76 reported PMP22 antibodies in three of six
(50%) CIDP patients. In contrast, Kwa et al.77 reported the absence of these antibodies in sera from
24 patients with CIDP. The discrepancy among the
results of these studies may be due to differences in
the PMP22 antigen used to test the sera.77 When
linear peptide epitopes of PMP22 and purified
PMP22 protein from overexpression in Escherichia
coli were used, a higher percentage of patient sera
showed reactivity. However, when PMP22 protein
was expressed in mammalian cells under native conditions, the sera failed to show any reactivity.77
In any chronic autoimmune inflammatory condition, several antigens may be involved via epitope
spreading,78 making it difficult to identify the culprit
antigen in an individual patient. Moreover, antibodies display a variety of affinities and avidities, and
some may activate the complement cascade whereas
others may not.79 Therefore, it is not easy to define
the pathogenic role of individual binding specifici-

ties. Given the heterogeneity of CIDP, it is likely

that different antibodies are critically involved in the
pathogenesis of this disease.
Recent evidence demonstrates that antibodies
against myelin protein zero (P0), a major structural
protein of myelin, might play a role in CIDP.80 There
is indirect evidence that P0 may have immunologic
relevance. In an experimental study of heterozygous
P0 knockout mice, an animal model of Charcot-MarieTooth disease, Schmid et al.81 showed that (a) myelin
degeneration and impairment in nerve conduction
were attenuated when the immune system was impaired, and (b) T cells isolated from these mutant mice
demonstrated enhanced reactivity to myelin proteins
such as P0 and P2. P0, an adhesive cell-surface molecule of the Ig superfamily and the most abundant protein of myelin on the peripheral nerves, has multiple
functions in the development and maintenance of myelin.82 An increase in macrophages with a subsequent
increase in T cells was observed within the nerves of
heterozygous P0 knockout mice.81 It was hypothesized
that a reduction in P0 could result in an instability in
myelin, which then could lead to an attraction of macrophages and a macrophage-mediated attraction of T
lymphocytes. Activation of autoimmune T cells by
antigen-presenting macrophages could lead to cellular
and humoral immune reactions, which ultimately
could result in demyelination.81
Yan et al.80 studied the sera of 21 CIDP patients
for antimyelin activity using immunofluorescence
and for binding to myelin proteins using Western
blot analysis. Results showed that the sera of six
patients (29%) contained anti-P0 IgG antibodies, and
four of these caused conduction block and demyelination when injected intraneurally into experimental
animals. These results suggest that P0 is an autoantigen in some patients with CIDP.80 However, in another study, serum antibodies to P0 were found in
only one of 24 (4%) CIDP patients.77
More work is needed to ultimately define the precise nature of circulating antibodies and their pathogenic role in CIDP.
Is there a role for therapeutic IFN in CIDP?
IFN has proven efficacy in the treatment of MS.9-15
The immunomodulatory properties of IFN1a that
are believed to mediate its beneficial effects in MS
suggest that it also may be effective in the treatment
of patients with CIDP (table). IFN has been shown
to inhibit T-cell proliferation.83,84 IFN also downregulates IFN--induced MHC class II molecule production, inhibits production of proinflammatory Th1
cytokines (IL-2, TNF-, IFN-), upregulates antiinflammatory Th2 cytokines (IL-4, IL-10), and enhances suppressor cell activity.37,69,84-90 The correlation
between increased CSF IL-10 levels and a favorable
clinical response among patients with MS suggests
that the induction of IL-10 may be a key underlying
mechanism for the immunoregulatory properties of
IFN1a.87 In addition, IFN selectively inhibits
mRNA expression of two chemokines involved in the

Table Immunoregulatory properties of IFN

In vitro decrease in T-cell proliferation83,84
Increase in anti-inflammatory Th2 cytokines (IL-4, IL-10)85-88
Decrease in proinflammatory Th1 cytokines (IL-2, TNF,
IFN-)83,84,88
Augmentation of suppressor T-cell function37,89
Downregulation of MHC class II marker expression90
Downregulation of chemokines (RANTES, MIP-1) and their
receptor (CCR5)91
IL interleukin; TNF tumor necrosis factor; MHC major
histocompatibility complex; RANTES regulated upon activation, normal T cell expressed and secreted; MIP-1 macrophage inflammatory protein; IFN interferon.

trafficking of Th1 proinflammatory cells [regulated

upon activation, normal T cell expressed and secreted (RANTES) and macrophage inflammatory
protein (MIP-1)] and their receptor CCR5. IFN1a
appears to regulate the production of RANTES and
MIP-1 and the surface expression of the receptor
CCR5, the latter of which significantly affects the
migratory properties of peripheral T cells toward
RANTES and MIP-1.91 Migration of proinflammatory T cells toward chemokines is closely associated
with recruitment of inflammatory cells at the affected
site. An inhibitory effect of IFN on metalloproteinases
has been described, which may be particularly relevant in MS and possibly in CIDP. No apoptosis was
induced by IFN, as described by Schmidt et al.92
Recently, a prospective, open-label clinical trial
examined the safety, tolerability, and efficacy of
once-weekly IFN1a (intramuscularly injected
Avonex) in a cohort of 20 patients with CIDP (Vallat et al., this supplement). The trial showed a treatment effect despite the fact that patients were not
ideal candidates for treatment because they had not
responded to previous IVIg (treatment-resistant
patients). The trial included six relapsing and 14
progressive cases, with variable duration and intensity of pretreatment, particularly related to glucocorticosteroids and other immunosuppressive drugs.
The trial design does not allow firm conclusions regarding efficacy. However, it was primarily a safety
and tolerability study and was not powered to evaluate treatment efficacy. A small, double-blind, crossover phase II clinical pilot trial on the therapeutic
role of subcutaneously injected IFN1a (Rebif) three
times weekly included 10 treatment-resistant
CIDP patients receiving IFN1a for 12 weeks and
then placebo. This study showed no treatment effect.93 However, its trial design was criticized for its
low power and short duration. Differences in dose,
frequency, or formulation may also have contributed
to the disparate results seen. To draw firm conclusions on the efficacy of IFN in CIDP, a large, randomized double-blind trial is necessary.
Conclusions. There are similarities in the cellular
and humoral immune responses involved in the
April 2003

NEUROLOGY 60(Suppl 3)

S5

pathophysiology of MS and CIDP. In general, research into the immunologic mechanisms underlying
lesion formation in MS and inflammatory neuropathies suggests that the disease processes are
autoimmune-mediated, with activated CD4 T cells
crossreacting with myelin and PNS antigens. Cytokines and chemokines released during activation attract these T cells along with monocytes and
macrophages, facilitate inflammatory cell infiltration
to the PNS, and precipitate the release of proinflammatory enzymes. In turn, these enzymes break down
the blood brain/bloodnerve barrier, allowing free
entry of antimyelin antibodies and complement. By
destroying myelin and axons, additional autoreactivities may be generated via epitope spreading. It is
likely that the magnitude of the immunoinflammatory insult, including all of the components discussed, is quite different in the various subtypes of
CIDP and is probably most pronounced in acute relapses. All types of treatments aimed at interfering
with these immunologic processes are of interest.
The therapeutic benefits and mechanisms of action of some IFN in MS suggest that it might also
be effective for the treatment of CIDP. Both MS and
CIDP are chronic diseases requiring long-term therapy. The results of the recent prospective, multicenter, open-label phase II trial (Vallat et al., this
supplement) that examined the safety, tolerability,
and efficacy of intramuscular IFN1a (Avonex) in
CIDP, together with several anecdotal reports, suggest that intramuscular IFN1a may be effective in
some patients with CIDP or multifocal motor
neuropathy.16-19 To draw firm conclusions, a large,
multicenter double-blind trial with a well-defined patient cohort is now warranted.
Acknowledgments

10.
11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.
22.

23.

24.

25.

26.

The work cited in this review that was carried out in the authors
laboratories was funded by Deutsche Forschungsgemeinschaft
(German Research Association), Hertie Foundation, Bundesministerium fu r Bildung, Wissenschaft und Forschung (German Federal Ministry for Education, Science and Research), and by the
State of Bavaria. We thank our colleagues who participated in
carrying out this research work.

27.

28.

29.

References
1. Barohn RJ, Saperstein DS. Guillain-Barre syndrome and chronic inflammatory demyelinating polyneuropathy. Semin Neurol 1998;18:49-61.
2. Barohn RJ, Kissel JT, Warmolts JR, Mendell JR. Chronic inflammatory
demyelinating polyradiculoneuropathy: clinical characteristics, course, and
recommendations for diagnostic criteria. Arch Neurol 1989;46:878-884.
3. Cornblath DR, Feasby TE, Hahn AF, et al. Ad Hoc Subcommittee of the
American Academy of Neurology AIDS Task Force. Research criteria
for diagnosis of chronic inflammatory demyelinating polyneuropathy
(CIDP). Neurology 1991;41:617-618.
4. Ensrud ER, Krivickas LS. Acquired inflammatory demyelinating neuropathies. Phys Med Rehab Clin North Am 2001;12:321-334.
5. Mendell JR. Chronic inflammatory demyelinating polyneuropathy.
Annu Rev Med 1993;44:211-219.
6. Sabatelli M, Madia F, Mignogna T, Lippi G, Quaranta L, Tonali P. Pure
motor chronic inflammatory demyelinating polyneuropathy. J Neurol
2001;248:772-777.
7. Hughes R. Chronic inflammatory demyelinating polyradiculoneuropathy. Pract Neurol 2002;2:198-207.
8. Schmidt B, Toyka KV, Kiefer R, et al. Inflammatory infiltrates in sural
nerve biopsies in Guillian-Barre syndrome and chronic inflammatory
demyelinating polyneuropathy. Muscle Nerve 1996;19:474-487.
9. The IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a
S6

NEUROLOGY 60(Suppl 3)

April 2003

30.

31.
32.

33.
34.

35.

36.

37.

multicenter, randomized, double-blind, placebo-controlled trial. Neurology 1993;43:655-661.

Fischer JS, Priore RL, Jacobs LD, et al. Neuropsychological effects of interferon -1a in relapsing multiple sclerosis. Ann Neurol 2000;48:885-892.
Jacobs LD, Cookfair DL, Rudick RA, et al., for the Multiple Sclerosis
Collaborative Research Group (MSCRG). Intramuscular interferon
beta-1a for disease progression in relapsing multiple sclerosis. Ann
Neurol 1996;39:285-294.
The PRISMS (Prevention of Relapses and Disability by Interferon -1a
Subcutaneously in Multiple Sclerosis) Study Group. Randomised
double-blind placebo-controlled study of interferon -1a in relapsing/
remitting multiple sclerosis. Lancet 1998;352:1498-1504.
Rudick RA, Fisher E, Lee J-C, Simon J, Jacobs L, and the Multiple
Sclerosis Collaborative Research Group. Use of the brain parenchymal
fraction to measure whole brain atrophy in relapsing-remitting MS.
Neurology 1999;53:1698-1704.
Simon JH, Jacobs LD, Campion M, et al. Magnetic resonance studies of
intramuscular interferon -1a for relapsing multiple sclerosis. Ann
Neurol 1998;43:79-87.
Simon JH, Lull J, Jacobs LD, et al. A longitudinal study of T1 hypointense lesions in relapsing MS. MSCRG trial of interferon -1a. Neurology 2000;55:185-192.
Chaudhary PP, Thompson N, Hughes RAC. Improvement following
interferon beta in chronic inflammatory demyelinating polyneuropathy.
J Neurol 1995;242:252-253.
Kuntzer T, Radziwill AJ, Lettry-Trouillat R, et al. Interferon-1a in
chronic inflammatory demyelinating polyneuropathy. Neurology 1999;
53:1364-1365.
Martina ISJ, van Doorn PA, Schmitz PIM, Meulstee J, van der Meche FGA.
Chronic motor neuropathies: response to interferon-1a after failure of conventional therapies. J Neurol Neurosurg Psychiatry 1999;66:197-201.
Van den Berg-Vos RM, Van den Berg LH, Franssen H, Van Doorn PA,
Merkies ISJ, Wokke JHJ. Treatment of multifocal motor neuropathy
with interferon-1A. Neurology 2000;54:1518-1521.
Krendel DA, Parks HP, Anthony DC, St. Clair MB, Graham DG. Sural
nerve biopsy in chronic inflammatory demyelinating polyradiculoneuropathy. Muscle Nerve 1989;12:257-264.
Uncini A, Di Muzio A, Di Guglielmo G, et al. Effect of rhTNF- injection
into rat sciatic nerve. J Neuroimmunol 1999;95:88-94.
Vital C, Vital A, Lagueny A, et al. Chronic inflammatory demyelinating
polyneuropathy: immunopathological and ultrastructural study of peripheral nerve biopsy in 42 cases. Ultrastruct Pathol 2000;24:363-369.
Bosboom WMJ, van den Berg LH, Franssen H, et al. Diagnostic value of
sural nerve demyelination in chronic inflammatory demyelinating polyneuropathy. Brain 2001;124:2427-2438.
Dalakas MC. Advances in chronic inflammatory demyelinating polyneuropathy: disease variants and inflammatory response mediators and
modifiers. Curr Opin Neurol 1999;12:403-409.
Yamamoto M, Ito Y, Mitsuma N, Li M, Hattori N, Sobue G. Parallel
expression of neurotrophic factors and their receptors in chronic inflammatory demyelinating polyneuropathy. Muscle Nerve 2002;25:601-604.
Gold R, Dalakas M, Toyka KV. Immunotherapy in autoimmune neuromuscular disorders. Lancet Neurol 2003;2:22-32.
Gold R, Hartung HP, Lassmann H. T-cell apoptosis in autoimmune
diseases: termination of inflammation in the nervous system and other
sites with specialized immune-defense mechanisms. Trends Neurosci
1997;20:399-404.
Ma urer M, Toyka KV, Gold R. Immune mechanisms in acquired demyelinating neuropathies: lessons from animal models. Neuromuscul Disord 2002;12:405-414.
Harvey GK, Gold R, Hartung HP, Toyka KV. Nonneural-specific T
lymphocytes can orchestrate inflammatory peripheral neuropathy.
Brain 1995;118:1263-1272.
Pollard JD, Westland KW, Harvey GK, et al. Activated T cells of nonneural specificity open the blood-nerve barrier to circulating antibody.
Ann Neurol 1995;37:467-475.
McCombe PA, Pollard JD, McLeod JG. Chronic inflammatory demyelinating polyradiculoneuropathy. Brain 1987;110:1617-1630.
Mosmann TR, Coffman RL. Th1 and Th2 cells: different patterns of
lymphokine secretion lead to different functional properties. Annu Rev
Immunol 1989;7:145-173.
Seder RA, Paul WE. Acquisition of lymphokine-producing phenotype by
CD4 T cells. Annu Rev Immunol 1994;12:635-673.
Hartung HP, Reiners K, Schmidt B, et al. Serum interleukin-2 concentrations in Guillain-Barre syndrome and chronic idiopathic demyelinating polyradiculoneuropathy: comparison with other neurological
diseases of presumed immunopathogenesis. Ann Neurol 1991;30:48-53.
Van den Berg LH, Mollee I, Wokke JH, Logtenberg T. Increased frequencies of HPRT mutant T lymphocytes in patients with GuillainBarre syndrome and chronic inflammatory demyelinating polyneuropathy:
further evidence for a role of T cells in the etiopathogenesis of peripheral
demyelinating diseases. J Neuroimmunol 1995;58:37-42.
Antel J, Bania M, Noronha A, Neely S. Defective suppressor cell function mediated by T8 cell lines from patients with progressive multiple
sclerosis. J Immunol 1986;137:3436-3439.
De Luca G, Lugaresi A, Iarlori C, Marzoli F, Uncini A, Gambi D.

38.

39.
40.
41.

42.
43.
44.
45.
46.
47.
48.
49.
50.
51.

52.
53.
54.
55.
56.
57.
58.
59.
60.
61.

62.
63.
64.
65.

Interferon beta normalizes suppressor cell function in dysimmune neuropathies. J Neuroimmunol 1998;82:1-4.
Weishaupt A, Bruck W, Hartung T, Toyka KV, Gold R. Schwann cell
apoptosis in experimental autoimmune neuritis of the Lewis rat and
the functional role of tumor necrosis factor-alpha. Neurosci Lett 2001;
306:77-80.
Selmaj KW, Raine CS. Tumor necrosis factor mediates myelin and
oligodendrocyte damage in vitro. Ann Neurol 1988;23:339-346.
Redford EJ, Hall SM, Smith KJ. Vascular changes and demyelination
induced by the intraneural injection of tumor necrosis factor. Brain
1995;118:869-878.
Hall SM, Redford EJ, Smith KJ. Tumor necrosis factor- has few morphological effects within the dorsal columns of the spinal cord, in contrast to its effects in the peripheral nervous system. J Neuroimmunol
2000;106:130-136.
Misawa S, Kuwabara S, Mori M, Kawaguchi N, Yoshiyama Y, Hattori
T. Serum levels of tumor necrosis factor-alpha in chronic inflammatory
demyelinating polyneuropathy. Neurology 2001;56:666-669.
Melendez-Vasquez C, Redford J, Choudhary PP, et al. Immunological
investigation of chronic inflammatory demyelinating polyradiculoneuropathy. J Neuroimmunol 1997;73:124-134.
Chambers CA, Allison JP. Costimulatory regulation of T cell function.
Curr Opin Cell Biol 1999;11:203-210.
Kuchroo VK, Das MP, Brown JA, et al. B7-1 and B7-2 costimulatory
molecules activate differentially the Th1/Th2 developmental pathways:
application to autoimmune disease therapy. Cell 1995;80:707-718.
zenci V, Mustafa M, Link H. EleTeleshova N, Bao W, Kivisakk P, O
vated CD40 ligand expressing blood T-cells are reversed by interferon-
treatment. Scand J Immunol 2000;51:312-320.
Kiefer R, Dangond F, Mueller M, Toyka KV, Hartung H. Enhanced B7
costimulatory molecule expression in inflammatory human sural nerve
biopsies. J Neurol Neurosurg Psychiatry 2000;69:362-368.
Salomon B, Rhee L, Bour-Jordan H, et al. Development of spontaneous
autoimmune peripheral polyneuropathy in B7-2-deficient NOD mice. J
Exp Med 2001;194:677-684.
Murata K, Dalakas M. Expression of the co-stimulatory molecule BB-1,
the ligands CTLA-4 and CD28 and their mRNAs in chronic inflammatory demyelinating polyneuropathy. Brain 2000;123:1660-1666.
Lu hder F, Huang Y, Dennehy KM, et al. Topological requirements and
signaling properties of T-cell activating anti-CD28 antibody superagonists. J Exp Med, in press.
Van Rhijn I, Van den Berg LH, Bosboom WMJ, Otten HG, Logtenberg
T. Expression of accessory molecules for T-cell activation in peripheral
nerve of patients with CIDP and vasculitic neuropathy. Brain 2000;123:
2020-2029.
Gollob JA, Li J, Kawasaki H, et al. Molecular interaction between CD58
and CD2 counter-receptors mediates the ability of monocytes to augment T cell activation by IL-12. J Immunol 1996;157:1886-1893.
Le Guiner S, Le Drean E, Labarriere N, et al. LFA-3 costimulates
cytokine secretion by cytotoxic T lymphocytes by providing a TCRindependent activation signal. Eur J Immunol 1998;28:1322-1331.
Wohlleben G, Ibrahim SM, Schmidt J, Toyka KV, Hartung HP, Gold R.
Regulation of Fas and FasL expression on rat Schwann cells. Glia
2000;30:373-381.
Andorfer B, Kieseier BC, Mathey E, et al. Expression and distribution
of transcription factor NF-B and inhibitor IB in the inflamed peripheral nervous system. J Neuroimmunol 2001;116:226-232.
Heininger K, Liebert UG, Toyka KV, et al. Chronic inflammatory polyneuropathy: reduction of nerve conduction velocities in monkeys by systemic
passive transfer of immunoglobulin G. J Neurol Sci 1984;66:1-14.
Toyka KV, Heininger K. Humoral factors in peripheral nerve disease.
Muscle Nerve 1987;10:222-232.
Buchwald B, Toyka KV, Zielasek J, et al. Neuromuscular blockade by
IgG antibodies from patients with Guillain-Barre syndrome: a macropatch-clamp study. Ann Neurol 1998;121:1257-1266.
Allegretta M, Nicklas JA, Sriram S, Albertini RJ. T cells responsive to
myelin basic protein in patients with multiple sclerosis. Science 1990;
247:718-721.
Chou YK, Bourdette DN, Offner H, et al. Frequency of T cells specific for
myelin basic protein and myelin proteolipid protein in blood and cerebrospinal fluid in multiple sclerosis. J Neuroimmunol 1992;38:105-113.
Zhang J, Markovic-Plese S, Lact B, Raus J, Weiner HL, Hafler DA.
Increased frequency of interleukin-2-responsive T cells specific for myelin basic protein and proteolipid protein in peripheral blood and cerebrospinal fluid of patients with multiple sclerosis. J Exp Med 1994;179:
973-984.
Bernard CC, Johns TG, Slavin A, et al. Myelin oligodendrocyte glycoprotein: a novel candidate autoantigen in multiple sclerosis. J Mol Med
1997;75:77-88.
Schmidt S. Candidate autoantigens in multiple sclerosis. Mult Scler
1999;5:147-160.
Quarles RH. Glycoproteins of myelin sheaths. J Mol Neurosci 1997;8:1-12.
Willison HJ, Yuki N. Peripheral neuropathies and anti-glycolipid antibodies. Brain 2002;125:2591-2625.

66. Yuki N, Tagawa Y, Handa S. Autoantibodies to peripheral nerve glycosphingolipids SPG, SLPG, and SGPG in Guillain-Barre syndrome and
chronic inflammatory demyelinating polyneuropathy. J Neuroimmunol
1996;70:1-6.
67. Fredman P, Vedeler CA, Nyland H, Aarli JA, Svennerholm L. Antibodies in sera from patients with inflammatory demyelinating polyradiculoneuropathy react with ganglioside LM1 and sulphatide of peripheral
nerve myelin. J Neurol 1991;238:75-79.
68. Stoll G, Schwendemann G, Heininger K, et al. Relation of clinical,
serological, morphological, and electrophysiological findings in
galactocerebroside-induced experimental allergic neuritis. J Neurol
Neurosurg Psychiatry 1986;49:258-264.
69. Toyka KV, Hartung H-P. Chronic inflammatory polyneuritis and related neuropathies. Curr Opin Neurol 1996;9:240-250.
70. Gabriel CM, Hughes RA, Moore SE, Smith KJ, Walsh FS. Induction of
experimental autoimmune neuritis with peripheral myelin protein-22.
Brain 1998;121:1895-1902.
71. Hahn AF, Feasby TE, Wilkie L, Lovgren D. P2-peptide induced experimental allergic neuritis: a model to study axonal degeneration. Acta
Neuropathol (Berl) 1991;82:60-65.
72. Milner P, Lovelidge CA, Taylor WA, Hughes RA. P0 myelin protein
produces experimental allergic neuritis in Lewis rats. J Neurol Sci
1987;79:275-285.
73. Rostami A, Gregorian SK. Peptide 53-78 of myelin P2 protein is a T cell
epitope for the induction of experimental allergic neuritis. Cell Immunol 1991;132:433-441.
74. Gabriel CM, Gregson NA, Hughes RA. Anti-PMP22 antibodies in patients
with inflammatory neuropathy. J Neuroimmunol 2000;104:139-146.
75. Koehler NKU, Martin R, Wietholter H. The antibody repertoire in experimental allergic neuritis: evidence for PMP22 as a novel neuritogen.
J Neuroimmunol 1996;71:179-189.
76. Ritz M, Lechner-Scott J, Scott RJ, et al. Characterisation of autoantibodies to peripheral myelin protein 22 in patients with hereditary and
acquired neuropathies. J Neuroimmunol 2000;104:155-163.
77. Kwa MSG, van Schaik IN, Brand A, Baas F, Vermeulen M. Investigation of serum response to PMP22, connexin 32 and P0 in inflammatory
neuropathies. J Neuroimmunol 2001;116:220-225.
78. Lehmann PV, Forsthuber T, Miller A, Sercarz EE. Spreading of T-cell
autoimmunity to cryptic determinants of an autoantigen. Nature 1992;
358:155-157.
79. Janeway CA, Travers P, Walport M, Shlomchik MJ. Immunobiology
the immune system in health and disease. New York: Churchill Livingstone, 2001.
80. Yan WX, Archelos JJ, Hartung H, Pollard JD. P0 protein is a target
antigen in chronic inflammatory demyelinating polyneuropathy. Ann
Neurol 2001;50:286-292.
81. Schmid CD, Stienekemeier M, Oehen S, et al. Immune deficiency in
mouse models for inherited peripheral neuropathies leads to improved
myelin maintenance. J Neurosci 2000;20:729-735.
82. Martini R, Schachner M. Molecular bases of myelin formation as revealed by investigations on mice deficient in glial cell surface molecules.
Glia 1997;19:298-310.
83. Noronha A, Toscas A, Jensen MA. Interferon decreases T cell activation and interferon production in multiple sclerosis. J Neuroimmunol
1993;46:145-154.
84. Rep MHG, Hintzen RQ, Polman CH, van Lier RAW. Recombinant
interferon- blocks proliferation but enhances interleukin-10 secretion
by activated human T-cells. J Neuroimmunol 1996;67:111-118.
85. Kozovska ME, Hong J, Zang YCQ, et al. Interferon beta induces
T-helper 2 immune deviation in MS. Neurology 1999;53:1692-1697.
86. Rudick RA, Ransohoff RM, Peppler R, VanderBrug Medendorp S, Lehmann P, Alam J. Interferon beta induces interleukin-10 expression:
relevance to multiple sclerosis. Ann Neurol 1996;40:618-627.
87. Rudick RA, Ransohoff RM, Lee J-C, et al. In vivo effects of interferon
beta-1a on immunosuppressive cytokines in multiple sclerosis. Neurology 1998;50:1294-1300.
88. Zang YCQ, Yang D, Hong J, Tejada-Simon MV, Rivera VM, Zhang JZ.
Immunoregulation and blocking antibodies induced by interferon beta
treatment in MS. Neurology 2000;55:397-404.
89. Noronha A, Toscas A, Jensen MA. Interferon beta augments suppressor
cell function in multiple sclerosis. Ann Neurol 1990;27:207-210.
90. Panitch HS, Folus JS, Johnson KP. Beta interferon prevents HLA class
II antigen induction by gamma interferon in MS. Neurology 1989;
39(suppl 1):171. Abstract.
91. Zang YCQ, Halder JB, Samanta AK, Hong J, Rivera VM, Zhang JZ.
Regulation of chemokine receptor CCR5 and production of RANTES
and MIP-1 by interferon-. J Neuroimmunol 2001;112:174-180.
92. Schmidt J, Sturzebecher S, Toyka KV, Gold R. Interferon-beta treatment
of experimental autoimmune encephalomyelitis leads to rapid nonapoptotic termination of T cell infiltration. J Neurosci Res 2001;65:59-67.
93. Hadden RDM, Sharrack B, Bensa S, Soudain SE, Hughes RAC. Randomized trial of interferon -1a in chronic inflammatory demyelinating
polyradiculoneuropathy. Neurology 1999;53:57-61.

April 2003

NEUROLOGY 60(Suppl 3)

S7