www.elsevier.com/locate/jneuroim

Journal of Neuroimmunolog

Alterations in cell-mediated immune response in subacute

sclerosing panencephalitis

Sibel P. Yentur a, Candan Gurses b, Veysi Demirbilek c, Gulden YNlmaz d,

Ayse Emel Onal e, Zuhal YapNcN f, Cengiz YalcNnkaya c, Ozlem Cokar g,

Aysen Gokyigit b, Guher Saruhan-Direskeneli a,*

a Department of Physiology, Istanbul Medical Faculty, Istanbul University, Turkeyb Department of Neurology, Istanbul Medical Faculty, Istanbul University, Turkey

c Department of Neurology, Cerrahpasa Medical Faculty, Istanbul University, Turkeyd Department of Microbiology, Cerrahpasa Medical Faculty, Istanbul University, Turkeye Department of Public Health, Istanbul Medical Faculty, Istanbul University, Turkey

f Division of Child Neurology, Department of Neurology, Istanbul Medical Faculty, Istanbul University, Turkeyg Neurology, Haseki Hospital, Istanbul, Turkey

Received 15 April 2005; accepted 9 September 2005

Abstract

To investigate T cell responses in subacute sclerosing panencephalitis (SSPE), we analyzed proliferation and cytokine secretion of cells

from 35 patients and 42 healthy controls (HC) in response to central nervous system (CNS) antigens. The proliferation in response to myelin

basic protein (MBP), myelin oligodendrocyte-glycoprotein (MOG) and aB-crystallin did not differ between groups. There was a trend

towards a decrease in IL-12 production in response to MBP and in vitro IL-12 secretion of SSPE patients to measles virus vaccine (MVV)

was lower than controls. Proliferation, as well as IFN-g, IL-12 and IL-10 production in response to purified protein derivate (PPD) was

impaired in SSPE patients.

The results did not demonstrate any by-stander cellular response against myelin antigens, implicating that CNS is not a predominant target

of an autoimmune response in SSPE. The recall responses were lower in SSPE as reported in measles before.

D 2005 Elsevier B.V. All rights reserved.

Keywords: Subacute sclerosing panencephalitis (SSPE); MBP; MOG; aB-crystallin; IL-121

1. Introduction

Subacute sclerosing panencephalitis (SSPE) is an invar-

iably fatal progressive disease of the central nervous system

(CNS). It is caused by a persistent measles virus (MV). The

virus harbors in the body for years and attacks neurons, glia,

myelin sheaths, and supporting elements causing an inflam-

matory demyelination. The cause of persistence or the late

reactivation of MV and the pathogenesis of SSPE is still

0165-5728/$ - see front matter D 2005 Elsevier B.V. All rights reserved.

doi:10.1016/j.jneuroim.2005.09.002

* Corresponding author. I.U.Istanbul TNp Fakultesi, Fizyoloji AD, 34093

Capa, Istanbul, Turkey. Tel./fax: +90 212 6352631.

E-mail address: gsaruhan@istanbul.edu.tr (G. Saruhan-Direskeneli).

unresolved, however both viral and host factors seem to be

involved (Dyken, 2001; Graves, 1984).

Immune reactions towards MVare unique, as the infection

induces both antiviral effector mechanisms as well as

significant immunosuppression (Schneider-Schaulies et al.,

2001; van Els and Nanan, 2002). The abnormalities include

suppression of delayed type hypersensitivity (DTH) skin test

responses (Tamashiro et al., 1987), depression of in vitro

lymphoproliferative responses to phytohemagglutinin

(PHA), PPD and MV antigens (Hirsch et al., 1981, 1984;

Karp, 1999). In vitro MV infection has also been shown to

block proliferation of MBP- and PPD-specific T cells in

response to antigens (Bell et al., 1997). The suppression of

DTH responses with predominant humoral immune response

y 170 (2005) 179 – 185

S.P. Yentur et al. / Journal of Neuroimmunology 170 (2005) 179–185180

is attributed to the generalized dominance of type 2 pattern of

cytokines (Karp, 1999).

Measles infection affects monocytes/macrophages and

dendritic cells (DCs), which are the principal IL-12

producing cells in vivo and are also prime targets of MV

in natural infection. The interaction of MV with antigen

presenting cells (APCs) leads to profound inhibition of IL-

12 production (Esolen et al., 1993, Fugier-Vivier et al.,

1997; Grosjean et al., 1997), which may contribute to the

suppression of cell-mediated immunity (CMI) following

measles infection.

In SSPE, although no universal abnormality has been

identified in the immune system, impairment of MV-specific

CMI has been observed. SSPE patients produced comparable

lymphoproliferative responses with healthy controls (HC) to

matrix, fusion, hemagglutinin and nucleocapsid proteins of

MV (Dhib-Jalbut et al., 1988). Anti-MV antibodies are

present in serum and cerebrospinal fluid (CSF). Thus, it is

likely that Th1 is generally down-regulated and Th2 function

is well preserved. MV-specific Th1/Th2 imbalance sug-

gested in SSPE patients may reflect a persistence of a relative

dominance of Th2 response at the initial measles infection

(Hara et al., 2000).

Considering tissue damage, specific immunity against

CNS components could participate in the disease patho-

genesis of SSPE. An increased cellular immunity to MBP

was reported in addition to MV in SSPE patients compared

with HC (Sheremata et al., 1978). Similarly, proliferative

responses to MBP from measles patients with encephalo-

myelitis were significantly more frequent than from patients

with measles but without encephalomyelitis (Johnson et al.,

1984). A by-stander T cell response in SSPE could well

have a role in the progression of the brain damage and

cytokines related to the immune regulation may take part in

this process. Thus, we examined the peripheral blood

mononuclear cells (PBMC) of SSPE patients in vitro for

CNS specific as well as recall antigen and measles virus

vaccine (MVV) specific proliferation. As the type of

immune response elicited is dependent on the predominant

cytokine, secretion pattern of IL-10, IL-12 and IFN-g has

also been evaluated to provide insight into the mechanism of

the immunoregulation.

2. Materials and methods

2.1. Patients and controls

Thirty-five SSPE patients and 42 HC were included in

the study. The ages of SSPE patients ranged between 1 and

30 years with a mean of 7.5 (T5.6) and 24 (68.6%) were

boys. All of the patients with SSPE fulfilled the diagnostic

criteria as clinical features, anti-MV antibodies in CSF and

typical electroencephalography showing slow-wave com-

plexes early in the disease. Totally 26 of 35 patients had

natural measles occurring between the ages of 3 months and

4 years (mean: 16 months) and the measles history was

unknown in the other 9 patients. Measles vaccination has

been applied to 20 patients and 7 patients’ parents could not

give information about the vaccination status. All of the

patients had antibodies against MV in the CSF and sera and

oligoclonal IgG bands were present in the CSF of all

patients. None of the patients received immunomodulatory

treatment at the time of blood drawing. The HC were

randomly selected from individuals between ages of 22 and

44 (mean: 36.3T5.4 years) and 15 (35.7%) were men. The

control group could not be matched for age, measles

infection or vaccination and 12 (28.6%) of HC had anti-

MV antibodies in their sera. Because of limitations in the

number of PBMC recovered, not all assays were performed

in all subjects. All parents and adult participants had given

their informed consent to donate blood for the study.

2.2. Antigens

Human native MBP prepared from human brain and

recombinant human extracellular immunoglobulin domain

of myelin oligodendrocyte glycoprotein (MOG) (provided

by R. Hohlfeld, Martinsried, Germany) were used as CNS-

specific auto-antigen candidates. Human recombinant aB-

crystallin (aBC) (provided by J. van Noort, Amsterdam,

The Netherlands) as well as MVV (Pasteur Merieux

Connaught), PPD (Tuberculin purified protein derivate from

human strains of Mycobacterium tuberculosis, Evans

Medical, London, UK) and PHA (Biological Industries,

Israel) were applied for in vitro stimulations.

2.3. Proliferation assays and supernatant collection

PBMC were freshly isolated from EDTA venous blood

of SSPE patients and HC with Ficoll-Histopaque density

gradient centrifugation (Sigma, St. Louis, MO, USA) and

seeded at 2�105 viable cells/well as quadruplicate in 96-

well round-bottom plates (Nunc, Denmark) at 37 -C in

humidified air with 5% CO2. Cells were incubated with

MBP (10 Ag/ml), MOG (15 Ag/ml), aBC (10 Ag/ml),

MVV (1/200), PPD (3 Ag/ml), PHA (5 Ag/ml) or without

antigen in culture medium, containing RPMI-1640, 10%

human AB serum, 100 IU/100 Ag/ml penicillin/streptomy-

cin (Sigma, St.Louis, USA) and 2 mM l-glutamine (Gibco,

Berlin, Germany). After 72 h, culture supernatants were

harvested and fresh medium was added. At day 5, cultures

were pulsed with 0.5 ACi/well [3H]thymidine (20 Ci/mmol,

American Radiolabeled Chemicals, St. Louis, USA) and

the cells were harvested at day 6. The incorporated

thymidine was measured by h-scintillation counter (Pack-

ard, Canberra, Australia) and presented as counts per

minute (cpm). Stimulation indices (SI) were calculated as

mean proliferative response in the presence of antigen,

divided by the mean proliferative response without antigen

of quadruplicate cultures. A SI >2 was taken as a positive

response.

Table 1

Proliferative responses (cpm) and median (minimum–maximum) cytokine

levels of unstimulated PBMC of SSPE patients and healthy controls (HC)

SSPE HC p

cpm 628.3 (145–5446) 1414.2 (168–9847) p <0.001

n 35 42

IFN-g 2.1 (0–65) 2.1 (0–62)

n 30 34

IL-10 6.2 (0–96) 0.0 (0–30) p =0.06

n 19 18

IL-12 31.8 (0–1551) 26.0 (0–242)

n 30 35

S.P. Yentur et al. / Journal of Neuroimmunology 170 (2005) 179–185 181

2.4. Measurement of cytokines

Collected culture supernatants were kept frozen at �80

-C until quantitative cytokine determinations. IL-12 (p40

and p70), IFN-g and IL-10 were measured by ELISA

according to the manufacturer’s instructions (Biosource,

Belgium) with detection limits of 4.5, 5.7 and 4.6 pg/ml,

respectively. Cytokine values below the limit of detection

were extrapolated between 0 and the lower limit of

detection for the purposes of statistical analysis (Moss et

al., 2002).

2.5. Anti-measles antibody assay

Sera and CSF samples from SSPE patients and sera from

HC were tested for anti-MV IgG with ELISA (Trinity

Biotech, Jamestown, NY, USA). Sensitivity of the test was

99.3% and specificity was 91.0%.

2.6. Statistical analysis

As none of the data showed the characteristics of

normal distribution, results are presented as median

values. Nonparametric analysis was applied using the

Mann–Whitney U test for comparison of unpaired data

between groups. Ratios of individuals with a positive

response to antigens were compared by using the v2 test

with Fisher’s modifications. A p value<0.05 was regarded

as significant.

Table 2

Proliferative responses (SI) and median (minimum–maximum) cytokine levels (pg

patients and HC

MBP MOG

SSPE HC SSPE

SI 1.0 (0.2–4.6) 0.9 (0.1–4) 1.2 (0.3–3.7)

n 35 42 33

IFN-g 0.0 (0–25) 0.0 (0–937) 0.0 (0–293)

n 30 33 30

IL-10 5.6 (0–147) 0.6 (0–34) 40.2 (0–165)

n 19 19 19

IL-12 0.0 (0–502) 4.6 (0–141) 25.3 (0–782)

n 31 34 31

3. Results

3.1. Proliferative responses of PBMC from SSPE patients

and HC

Firstly we analyzed the spontaneous proliferative res-

ponses of cells. Proliferation of PBMC in culture was

significantly lower in SSPE patients than HC (628 vs. 1414

cpm, p <0.001) (Table 1).

When proliferation of PBMC towards CNS proteins was

analyzed, 5 out of 35 (14.3%) SSPE patients and 2 out of 42

(4.8%) HC have mounted proliferative responses (SI>2) to

MBP with no difference between groups (median SI: 1.0 vs.

0.9). Similarly, there was no significant difference in the

proliferation of MOG or aBC stimulated cells between

SSPE patients and HC (1.2 vs. 0.9 and 1.1 vs. 0.8,

respectively) (Table 2). However, although statistically not

significant, 9 out of 34 (26.5%) SSPE patients and 6 out of

40 (15.0%) HC had SI>2 for aBC.

In this study we used live attenuated MVV as disease

specific antigen for in vitro stimulations. Proliferative

responses towards MVV were positive in 7 out of 32

(21.9%) SSPE patients and 6 out of 42 (14.3%) HC. No

significant difference was observed when these responses

against MVV were compared between groups either (SI: 1.2

vs. 1.1) (Table 3).

However, the proliferation against the recall antigen,

PPD was significantly lower in SSPE patients than in HC

(1.8 vs. 26.2, p <0.001). Only 15 of 35 (42.9%) SSPE

patients responded to PPD in vitro with SI values greater

than 2 compared to 38 of 41 (92.7%) HC. The distribution

of anti-PPD responses in both groups is shown in Fig. 1a.

3.2. Cytokine production PBMC from SSPE patients and

HC

Analysis of the spontaneous cytokine secretions of

PBMC at the 72 h of culture revealed that IL-10 levels

were higher in SSPE patients than HC with a trend towards

a significant difference (6.2 vs. 0.0 pg/ml, p =0.06) (Table

1). Among the patients 10 out of 19 and from the controls

only 2 out of 18 had detectable levels of IL-10.

/ml) of PBMC stimulated with MBP, MOG or aB-crystallin (aBC) in SSPE

aBC

HC SSPE HC

0.9 (0.2–3.2) 1.1 (0.1–5.1) 0.8 (0.1–4.3)

39 34 40

0.6 (0–39) 0.0 (0–2270) 0.4 (0–39)

34 30 33

16.8 (0–96) 0.0 (0–200) 0.0 (0–17)

19 19 19

38.5 (0–444) 0.1 (0–769) 8.9 (0–472)

35 31 34

Table 3

Proliferative responses (SI) and median (minimum–maximum) cytokine

secretion levels (pg/ml) against MVV in SSPE patients and HC

SSPE HC p

SI 1.2 (0.2–6.0) 1.1 (0.3–5.4)

n 32 42

IFN-g 0.0 (0–99) 0.0 (0–44)

n 30 34

IL-10 0.0 (0–15) 0.0 (0–6)

n 19 19

IL-12 0.0 (0–406) 4.7 (0–72) p <0.001

n 31 35

S.P. Yentur et al. / Journal of Neuroimmunology 170 (2005) 179–185182

When in vitro induced cytokine productions were

analyzed, IL-12 secretion was less frequently detected in

the supernatants of MBP stimulated cells from patients

(29%) than HC (50%) with a trend towards significant

difference ( p=0.06). MBP induced IL-10 secretion by

PBMC from 52.6% of SSPE patients and 20% of HC,

whereas IFN-g was only detectable in 13.3% and 18.2% of

cultures from respective groups. However, IL-12, IFN-g and

IL-10 production levels of MBP and MOG stimulated cells

were not different between groups (Table 2).

Fig. 1. Responses to PPD: (a) The distribution of PPD-induced proliferations of P

stimulated with PPD secreted significantly lower IL-12 (b), IFN-g (c) and IL-10

respectively.) Median levels (bold horizontal lines) and inter-quartile ranges are s

With aBC stimulation, induction of IL-12, IFN-g and IL-

10 production was not different in SSPE patients and HC,

although the levels of cytokines varied considerably (Table

2). Interestingly however, only 7 out of 31 SSPE patients

(22.6%), but 18 out of 34 (52.9%) HC have secreted

detectable IL-12 from aBC stimulated PBMC ( p =0.02).

When MVV induced cytokines were evaluated, IL-12

production of PBMC was significantly lower in SSPE

patients than in HC (Table 3). Four out of 31 SSPE patients

(12.9%) and 19 out of 35 (54.3%) HC had secretion levels

above the detection limit for IL-12 with median levels of 0.0

vs. 4.7 pg/ml of IL-12 in SSPE patients and HC ( p =0.001).

IFN-g and IL-10 levels of MVV stimulated cells were not

different between groups (Table 3).

PPD-induced IL-12 levels were significantly decreased

in SSPE patients than in HC (0.0 vs. 14.8 pg/ml, p <0.001,

Fig. 1b). IL-12 levels were measurable only in 19.4% of

SSPE patients and in 65.7% of HC ( p <0.001). In parallel to

IL-12, the level of IFN-g secretion was significantly lower

in SSPE patients than in HC (0.0 vs. 680.2 pg/ml, p <0.001,

Fig. 1c) and IFN-g production to PPD was measurable only

in 7 out of 30 (23.3%) SSPE patients and in 28 out of 34

BMC (as stimulation indices) in SSPE patients and HC ( p <0.001). PBMC

(d) levels in SSPE patients than HC ( p <0.001, p <0.001 and p <0.045,

hown in boxes.

S.P. Yentur et al. / Journal of Neuroimmunology 170 (2005) 179–185 183

(82.4%) HC ( p <0.0001). Secreted IL-10 levels against

PPD were also significantly lower in SSPE patients than in

HC (0.0 vs. 2.4 pg/ml, p =0.045, Fig. 1d). When stimulated

with PPD, PBMC of only one out of 19 (5.3%) SSPE

patients and 8 out of 19 (42.1%) HC produced measurable

IL-10 in vitro ( p =0.02).

4. Discussion

Alterations in immune response have been demonstrated

in measles infection and in SSPE. Antigen-specific cell

proliferation and cytokine secretions are evaluated in a high

number of SSPE patients in this study.

Spontaneous proliferation of PBMC from SSPE patients

was lower compared to healthy adult controls, which

emphasize the difference of SSPE from natural measles

infection where the proliferation was reported as increased

during the infection period (Griffin et al., 1989; Ward et al.,

1990). Lower spontaneous proliferation in patients may be

related to higher levels of IL-10 suggesting a cytokine

related suppression of PBMC activity in this disease state.

As reported in measles encephalitis (Johnson et al.,

1984), virus-induced autoimmune reactivity could also be

contributing to SSPE. SSPE patients had markedly elevated

levels of antibodies to MBP in their CSF specimens

(Ruutiainen et al., 1981). The reaction with MBP was

shown consistently more pronounced in SSPE than in

multiple sclerosis (MS) and antibodies to measles and to

MBP could have been directed against similar antigenic

determinants (Panitch et al., 1980). However, specific

immunity against CNS components in the disease patho-

genesis of SSPE has been not supported by this study.

Increased cellular response to MBP and MOG was not

detected in all SSPE patients, making a by-stander T cell

response against self-antigens of CNS in SSPE not

probable.

aB-crystallin is a small heat-shock protein with restricted

expression including oligodendrocytes and astrocytes in MS

lesions and identified as a dominant human T cell antigen in

myelin derived from MS patients (Bajramovic et al., 1997).

To see whether demyelination of SSPE may be caused by

similar mechanisms to MS, aBC has been used for in vitro

stimulations. Although higher number of patients responded

to this antigen in vitro, the difference with the HC was not

significant. Interestingly though, IL-12 production was less

frequently detected in SSPE patients than HC both with

MBP and aBC, that may indicate an ineffective inflamma-

tory/Th1 response to the antigens.

A previous finding in SSPE indicated increased cellular

immunity to measles in SSPE patients as compared with

healthy persons (Sheremata et al., 1978). However, at least

some patients have an apparent defect in their cellular

immune response to MV (Dhib-Jalbut et al., 1989). As

reflected by increased antibody production, T helper cells

should be generated during measles infection and persist or

regenerated in SSPE development for effective immunity.

We have used live attenuated virus vaccine as exogenous

antigen and could not detect any effective response of cells

in SSPE. When PBMC of 4 SSPE patients were stimulated

with whole MV or proteins separately before, the response

did not reveal any significant difference between patients

and controls either (Dhib-Jalbut et al., 1988). CD4 T cell-

dependent immunity was also often not demonstrable or

only minimal in measles (Greenstein and McFarland, 1983).

Although MV-specific MHC class II-restricted cytolytic

CD4 cell responses have been reported during measles (van

Binnendijk et al., 1990, Howe et al., 2005), we did not find

any evidence for Th0, Th1 or Th2 related cytokines (IFN-g

or IL-4 (data not shown), IL-10) in SSPE in vitro either.

Whether the persistence of MV is enhanced by the

inefficiency of CMI or changes in virus strain account for

this phenomenon, has to be evaluated with respect to virus

genotypes in SSPE, which is underway.

There is both in vivo and in vitro evidence of a type 2

polarization in cytokine response during and after measles

(Griffin and Ward, 1993). Infection of monocytes with MV

down-regulated the stimulated production of IL-12 by

measles binding to CD46 (Karp et al., 1996). IL-12

production (p40 and p70) by peripheral blood monocytes

from patients with measles is markedly suppressed and this

suppression is also demonstrable after recovery from acute

infection (Atabani et al., 2001). Infection of DC in vitro with

MV has induced markedly enhanced IL-12 synthesis in an

other study, however mature DC gave a negative signal to

inhibit lymphocyte proliferation (Schnorr et al., 1997). In

SSPE, no significant difference was observed in IFN-g and

IL-10 production of PBMC stimulated with live MVV in

vitro between controls and patients and minimal IL-12 and

IL-4 production to MV was observed in both groups (Hara

et al., 2000). Our experiments with MVV did also not

induce different levels of IFN-g or IL-10 in SSPE and HC

groups, however significantly decreased level of IL-12 in

SSPE patients and the lower frequencies of IL-12 secretion

in response to MVV, aBC and MBP stimulated cultures

coincide well with the reported depression of IL12

production in response to antigen specific stimulation of

cells. Based on the Th1/Th2 model of CD4+ T cells

responses, decreased IL-12 release would be expected to

favor predominance of a Th2-like response and immuno-

suppression in measles (Gans et al., 1999). As IL-12 is

crucial for the induction of IFN-g, a major Th1 cell

cytokine, which is not evident in our findings, this data

may still implicate an ineffective Th1 response without any

Th2 dominance though in SSPE (Gans et al., 1999).

Moreover, the observed reduction of IL-12 production in

response to different stimuli supports a non-specific

immunosuppression mechanism probably acting on APCs

like monocytes or DC, which are infected by measles virus

(Esolen et al., 1993).

Although SSPE patients did respond to MVV compara-

ble to healthy controls, the response to PPD was consid-

S.P. Yentur et al. / Journal of Neuroimmunology 170 (2005) 179–185184

erably lower and less frequent. CMI to PPD skin test was

reported as defective in SSPE patients (Aysun et al., 1984)

and in the first weeks of measles infection (Tamashiro et al.,

1987). In early measles infection specific responses to PPD

and to rubella and mumps virus antigens were suppressed,

whereas mitogen stimulation tests were normal, which

recovered after infection (Ilonen et al., 1980; Hirsch et al.,

1984) suggesting that MV infections alter immune regu-

lation rather than causing global immunosuppression.

As a conclusion, proliferative responses to CNS auto-

antigens as MBP and MOG are not changed in SSPE,

whereas IL-12 secretion is decreased against PPD and

MVV. These results point to a defective Th1 response in

SSPE.

Acknowledgements

The authors thank Drs. M. Barlas, M. Eraksoy, S. Ayta,

M. Guler (Istanbul Medical Faculty), A. Yuksel (Cerrahpasa

Medical Faculty), F. Erdogan (Kayseri GN Medical Faculty)

N. Pazarci (Sisli Etfal Hospital), E. Tufan (Kocaeli Medical

Faculty) for referring the patients.

The study is supported by grants from the Istanbul

University Research Fund (#1530 and #192).

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