Download Tumour necrosis factor alpha is elevated in serum

J Neurol (1996) 243 : 165 170
9 Springer-Verlag 1996
M. Rentzos
C. Nikolaou
A. Rombos
K. Voumvourakis
I. Segditsa
C. Papageorgiou
Received: 19 January 1995
Received in revised form: 2 May 1995
Accepted: 22 May 1995
M. Rentzos ([~) - C. Nikolaou
A. Rombos - K. Voumvourakis
I. Segditsa 9C. Papageorgiou
Department of Neurology,
Athens University Medical School,
74 Vas. Sofias Av, Athens 11528, Greece
Tel 01-7220811 #218
Tumour necrosis factor alpha is elevated
in serum and cerebrospinal fluid
in multiple sclerosis
and inflammatory neuropathies
Abstract Tumour necrosis factor alpha (TNFc~) is a peptide that is derived from T lymphocytes and
macrophages and is used as a marker
of activated cellular immune responses. TNFcz was measured in
paired sera and cerebrospinal fluid
(CSF) from 30 patients with multiple
sclerosis (MS) with worsening disability, 54 patients with other neurological diseases, and 20 normal subjects. A sensitive enzyme-linked i m munosorbent assay was used to determine the TNFc~ levels. We found
significantly elevated serum and CSF
levels in 12 (40%) and 6 (20%) MS
Introduction
The aetiology of multiple sclerosis (MS) has not been
clearly established, although a number of immunological
aberrations, such as the presence of oligoclonal immunoglobulins in cerebrospinal fluid (CSF) [32, 45], the decreased number of T-suppressor lymphocytes in the peripheral blood during acute exacerbations [48], and the
presence of CD4 lymphocytes in MS plaques [58], have
been reported in MS patients. Newly formed plaques in
MS patients have been reported to contain T lymphocytes
and macrophages at their active edges [25]. Activated T
lymphocytes which circulate in sera and CSF accomplish
their cytotoxic activity by producing cytokines [15, 16].
"Cytokine" is a term for a heterogeneous group of polypeptide substances which are involved in immunity, inflammation and tissue damage [6]. Tumour necrosis factor (TNFc0 is a cytokine that has been shown to be capable of selectively damaging oligodendrocytes and myelin
sheaths in vitro [53] as well as being an important media-
patients, respectively, compared with
healthy controls (P < 0.007 and
P < 0.05). Among the 18 patients
with neuropathy, we also found high
serum and CSF TNFt~ values in 3
(17%) and 5 (28%) patients, respectively (P < 0.04 and P < 0.002). Our
study shows that TNFt~ is probably
involved in the pathogenetic mechanisms of MS and other inflammatory
neurological diseases.
Key w o r d s Tumour necrosis factor
alpha. Multiple sclerosis 9
Inflammatory neuropathies
tor in several inflammatory disorders [7, 40, 42, 57]. It has
been reported that in MS patients TNFt~ is produced by
sera and CSF circulating activated macrophages [39]. In
the present study, serum and CSF TNFc~ levels were measured in 30 MS patients, 45 patients with other neurological diseases and in 20 controls in order to examine the
correlation of this cytokine with the immunological disturbances in MS.
Patients and methods
Serum and CSF samples were studied in 95 individuals comprising
the following groups: (1) 30 MS patients (12 men, 18 women,
aged 17-57 years, mean 34); (2) 54 patients with other neurological diseases (20men, 34 women, aged 18-78 years, mean 59): 7 of
these patients had motor neuron disease, 6 were epileptic, 8 had
cerebrovascular disease, 9 had progressive dementia (7 with Alzheimer's disease and 2 with multi-infarct dementia), 6 had Parkinson's disease and 18 had neuropathy [5 with chronic inflammatory
demyelinating polyradiculoneuropathy, 3 with diabetic neuropathy, 1 with post-herpetic cranial neuropathy, 1 with paraneoplastic
neuropathy, 2 with Guillain-Barr6 syndrome (GBS), 2 with cranial
166
mononeuritis of unknown aetiology, 1 with hereditary amyloid
neuropathy and 3 with chronic polyneuropathy of unknown aetiology]; (3) 20 individuals (12 men, 8 women, aged 40-80 years,
mean 55) who were hospitalized for backache and headache and
who had no evidence of organic neurological disease, studied as a
control group.
Of the 30 MS patients, 28 had clinically definite disease according to the criteria of Poser et al. [47]; of these patients 16 had
the relapsing remitting (RR) and 12 the chronic progressive (CP)
type. Two patients had retrobulbar neuritis. The clinical diagnosis
of MS was based on clinical signs supported by objective findings
including the presence of inflammatory lesions as confirmed by
magnetic resonance imaging (MRI), as well as the presence of
oligoclonal bands and increased IgG level in the CSF. The diagnosis of chronic inflammtory demyelinating polyneuropathy (CIDP)
was made according to the criteria of Dyck et al. [8]. This diagnosis was based on the patient's history, clinical findings, nerve conduction studies and CSF examination. None of the MS patients had
taken any corticosteroids or immunosuppressive medication, nor
had plasmapheresis been performed for at least 6 months before
their serum and CSF were sampled. Blood and CSF samples were
taken within 7 days of an acute exacerbation of the disease, were
immediately centrifuged to remove cells and prevent cytokine
leakage from the intercellular compartment, and were stored at
- 7 0 ~ until TNFor measuremtns were made. All CSF samples
were subjected to a cell count by Rosenthal plate. The IgG index
was quantified by nephelometry. The blood-CSF barrier status was
assessed by calculating the CSF/serum albumin ratio 134].
0.3
0.25
0.2
d
0
9 0.15
0 . 1 84
0.05-
1
3
4
5
6
7
8
Fig. 1 Serum tumour necrosis factor alpha (TNFo0 values in all
groups (1 multiple sclerosis, 2 motor neuron disease, 3 epilepsy, 4
cerebrovascular disease, 5 dementia, 6 Parkinson's disease, 7 neuropathy, 8 controls, OD optical density)
0.25-
0.2
TNF assay
Levels of TNFc~ in serum and CSF were measured by a sensitive
sandwich-type enzyme-linked immunosorbent assay (ELISA) with
a purified monoclonal antibody to the human TNFcz and rabbit
polyclonal antihuman TNFo~ antibody (Genzyme). The standard
curve obtained with recombinant TNFo~ ranged fi-om 0 to 1200
pg/ml. Optical densities were determined by means of a microELISA reader (L.P 400, Pasteur diagnostics). The absorbance of
each well was read at 450 nm. CSF and sera were assayed at dilutions of 1:2. The limit of detection was 10 pg/ml.
2
0.15
6
6
0.1-
0.05Statistical analyses
The statistical method applied was the Student's test, since TNFo~
values had normal distribution. P values of < 0.05 were considered
significant.
Results
The levels of TNFc~ in serum and CSF ranged between
0.052-0.283 and 0.044-0.222, respectively, (Figs. 1, 2).
Figures 3 and 4 summarize the mean values of TNF~x in
serum and CSF respectively.
Serum TNFo~ levels
Serum TNFc~ values in MS patients were between 0.068
and 0.258 (mean value 0.16, SD 0.061), in patients with
other neurological diseases 0.052-0.247 (mean value
0.13, SD 0.045), and in the controls 0.052-0.172 (mean
0 -1
Fig.2
2
13
4
5
6
7
8
CSF TNFor wdues in all groups (for detailed, see Fig. 1)
value 0.11, SD 0.038) (Figs. 1, 3). Twelve of the 30 MS
patients (5 with CP and 7 with RR) and 1 with optic neuritis (43%) had serum GNFc~ values higher than the corresponding mean values of the controls +2SD. MS patients
had significantly higher serum T N F ~ levels compared
with the controls (P < 0.007). MS patients with the CP
type of the disease did not have significantly higher serum
T N F ~ levels than those with the RR type (P < 0.8). We
did not find significantly elevated TNFc~ levels in patients
with other neurological diseases compared with controls,
except in neuropathy patients. Of the 18 patients with
neuropathy, 3 (17%) had high serum TNFc~ values compared with the controls (P < 0.043). One had post-herpetic
cranial neuropathy, the second had diabetic neuropathy,
and the third patient had CIDP (Fig. 1).
167
Table 1 CSF IgG index in patients with multiple sclerosis (MS)
0.20.16-
No
1
0.16-
2"
0.14-
3
0.12ei
6
4
5
6
0.1-
7
8
9a
0.080.06-
10
11
12a
13
0.04-
0.020
1
2
3
4
5
6
7
8
Fig.3 Serum TNF~ mean values (for details, see Fig. 1)
14a
15
IgG index
No
IgG index
0.69
0.66
0.76
0.34
0.66
0.67
1.5
0.71
0.57
0.69
0.45
0.84
0.68
0.63
1.92
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
0.6
0.52
0.55
0.46
0.77
0.96
0.46
0.73
1.2
0.45
0.55
0.98
0.41
0.79
0.43
a Patients with high tumour necrosis factor alpha values
0"2I
0.18
as well (Table 1). In all MS patients the number of circulating cells in CSF did not exceed 5/mm 3.
0"16H
0.14j~
0.12-
d
d
Discussion
0.1
0.08
0.06
0.04
0.02
0
1
2
3
4
5
6
7
8
Fig.4 CSF TNFc~ mean values for details, see Fig. 1)
CSF TNFo~ levels
CSF TNF(~ values in MS patients were between 0.044 and
0.219 (mean value 0.118, SD 0.048), in patients with other
neurological diseases 0.049-0.222 (mean value 0.098, S D
0.038) and in the controls 0.044-0.145 (mean value 0.093,
SD 0.031) (Fig. 2, 4). High CSF TNFo~ values were measured in 6 MS patients (20%), 4 with the RR and 2 with
the CP type. CSF TNFo~ values in MS patients were significantly higher than in the controls (P < 0.005). In 10
MS patients, CSF TNFc~ values were higher than the corresponding serum TNFc~ values (Fig 2). Five (28%) of the
patients with neuropathy had higher CSF TNFc~ values
than the controls (P < 0.002). One of these patients had
diabetic neuropathy, 3 had C I D E and 1 had paraneoplastic neuropathy (Fig. 2, 4).
Of 30 MS patients, 18 had an increased CSF IgG index
(higher than 0.65); 4 of these had high CSF TNFc~ values
There is evidence that TNFc~ is involved in the pathogenesis of MS [4]. Robbins et al. [49] reported that activated
astrocytes and microglia cells can produce a substance
analogous to T N F a which has a cytotoxic effect on the
oligodendrocytes in vitro. According to recent studies,
there is evidence that TNFot is present in MS plaques [27,
54] and that it can damage the oligodendrocytes and the
myelin sheath [53].
In the present study, serum T N F a was high in 12 of 30
MS patients. High serum TNFc~ values correspond to the
blood circulating activated lymphocytes and macrophages
which are present at the sites of MS lesions. Serum TNFc~
values were high in both CP and RR course MS patients,
and this can be explained by an equivalent lymphocyte activation in both types of the disease. It is not clear what
exactly is the role of TNFc~ in MS pathogenetic mechanisms and when in MS evolution the activation of T cells
and TNF(x production happens. Increased production of
TNFc~ may precede clinical relapse in the RR form of MS
and may thus trigger off exacerbations [3]. B and T cell
mitogen-stimulated whole blood cells in patients with
MS, obtained 2 weeks before to 4 weeks after clinical exacerbation, secrete 5-100 ng/ml TNFc~ when cells from
patients with MS in remission and normal control subjects
produce only 1-3 ng/ml TNFo~ [3]. The early (that is, before the clinical exacerbation) T N F ~ production and its
gradual reduction after the relapse may be the cause of
low serum and CSF T N F a values in many studies of patients with MS [13].
168
High CSF T N F a values were found in 6 MS patients in
whom a very small number of CSF circulating cells was
measured. It is possible that intrathecal concentrations of
TNFc~ are more important than the systemic levels during
MS activity, indicating that TNFc~ can also be derived from
the central nervous system. Astrocytes can become activated by viruses or endotoxins and produce TNFc~ [33, 49].
High serum and CSF T N F a values were found in 1 and
3 patients with CIDR respectively. CIDP is an immunemediated polyneuropathy in which both humoral and cellular immune responses are implicated [17, 18, 29, 31].
Interactions between the various compartments of the immune system are regulated by cytokines [1, 41]. Their role
in the pathogenesis of immune-mediated polyneuropathies
has not been completely explored to date. In two published reports, high serum interleukin 2 (IL2) and serum
and CSF IL6 values were found in patients with GBS and
CIDP [2, 19, 22, 36]. The worsening of experimental allergic neuritis (EAN) upon interferon g a m m a (IFN- 7)
administration also underscores the pathogenic role that
T-cell cytokines may play in inflammatory disorders of
the peripheral nervous system [20]. Recently, abnormally
high TNFc~ levels have been reported in the serum and
CSF of patients with GBS [11, 56, 59]. In our study the
number of cases is very small but the high CSF TNFc~
values in most of the CIDP patients examined may support
the notion that there is T lymphocyte and macrophage activation in CIDR
TNFc~ was localized by immunostaining of teased
nerve fibres of rats with EAN induced either by active immunization with myelin [60] or by adoptive transfer of P2
autoreactive T cells [50]. In that condition nerve roots are
infiltrated by T cells and macrophages. T N F ~ is synthesized and released mainly by activated inacrophages [51.
T ceils and macrophages in EAN are believed to cause
segmental demyelination by mechanisms that are still
only partially understood and they have recently been
shown to express INF-y in nerve roots prior to demyelination [24, 52]. INF-7 is a potent stimulus for production of
TNFc~ [43]. Thus, IFN-y may be the stimulus that attracts
activated TNFo~ positive macrophages. TNFo~ produced
by these macrophages may cause damage to the myelin
sheats, probably mediating toxic oxygen radical production which has also been shown to play an important pathogenic role in EAN [23, 24]. TNFc~ intraneural injections
into peripheral nerves of C3H/HeJ mice cause axonal
damage [51]. TNfot is also produced by IL2 activated
macrophages in vitro and in vivo [10, 30].
TNFo~ may be secondarily released by INF-y or IL2
and may contribute to GBS pathogenesis [20-22, 56].
Monitoring and follow-up of patients with the syndrome
may prove that clinical improvement is associated with a
decrease in TNFc~ levels. This will provide evidence that
high TNFcz levels play an important role in peripheral demyelination in GBS and are not an incidental immunological abnormality [56], TNFcz overproduction is not the
unique immune-mediated interaction in that syndrome.
Both cellular and humoral immune mechanisms and complement cascade activation may result in the inflammatory demyelinating process [28]. In a study referred to
above [56] serum T N F ~ of CIDP patients could not be detected and this may indicate either a difference in severity
or sampling time in relation to disease onset, or a different
pathogenetic mechanism [9]. The high serum TNFc~ value
in 1 patient with post-herpetic neuropathy may be a further demonstration of the inflammatory process in this
disease. TNFc~ produces haemorrhagic necrosis of tumours in vivo, and cytostatic or cytotoxic effects on transformed cells in vitro [37, 44]. It is also increased in the
CSF of patients with central nervous systems neoplasia,
such as metastatic melanoma [61]. The high CSF T N F ~
value in a patient with paraneoplasmatic neuropathy may
reflect the immune activation against tumour cells. The
high serum and CSF TNFff values in a patient with diabetic neuropathy are probably the result of a coincident
infection.
No correlation between TNFc~ levels and IgG index
was found in our MS patients. The intrathecal synthesis of
TNFc~ is probably not continuous during the myelin damage, and it might participate in lesion development by
promoting demyelination, enhancing local immune responses [35].
There is conflicting evidence regarding the serum and
CSF T N F ~ levels of MS patients [13, 14, 26, 35, 46, 55,
59, 61]. This can be explained by the different sensitivities of the methods applied [38], or by the variation in
time of sampling after an acute exacerbation of the RR
type, or in CSF and serum storage conditions, because
TNF c~ has a limited half-life [12, 13]. The increased CSF
TNFo~ levels could also precede the MS exacerbation and
trigger off the demyelination process [3, 35].
The significance of TNFot detection in MS patients is
not yet completely understood. TNFc~ may be produced in
the central nervous system during an acute MS exacerbation in the RR or an increase on the Kurtzke Expanded
Disability Scale for the CP form of the disease, but it can
also be present in a number of other inflammatory conditions characterized by a demyelinating process, such as in
chronic inflammatory polyneuropathy or GBS. However,
further studies will hopefully clarify the possible relationship between TNFct accumulations and the clinical course
of MS as well as the possible role of TNFo~ in the pathogenesis of this disease.
169
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