relationship between herpesvirus 6 and 7 infections and ... · hhv-6 and hhv-7 • roseolovirus...
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Frequency of HHV-6 and HHV-7 Infection Markers in Rheumatoid Arthritis and
Osteoarthritis Patients and Changes in Cytokine Expression Levels
Anda Kadisa, Zaiga Nora-Krukle, Svetlana Kozireva,
Peteris Studers, Aivars Lejnieks, Modra Murovska
“Promotion of International Cooperation
Activities of Riga Stradiņš University in Science and Technologies”, agreement
No. 2010/0200/2DP/2.1.1.2.0/10/APIA/VIAA/006
HHV-6 and HHV-7
• Roseolovirus genus in Betaherpesvirinae subfamily
• Up to 90% of adults being seropositive
• Primary infection commonly occurs in early childhood
↓
latency
↓
reactivation under conditions of stress and immunocompromised state
↓
contribution of further immunosupression
Caselli E, Di Luca D. Molecular biology and clinical associations of Roseoloviruses human herpesvirus 6 and
human herpesvirus 7. New Microbiol 2007; 30:173-187
Rheumatoid arthritis
• The primary target for HHV-6 and HHV-7 replication is CD4+ T lymphocytes, pivotal cells in generation of humoral and cell-mediated adaptive immune response
• Both viruses have been shown to up-regulate TNF-alpha secretion by PBMC
• HHV-7 could also act as a trigger factor for HHV-6 activation
Lusso HHV-6 and the immune system:mechanisms of immunomodulation and viral escape. J Clin Virol 2006; Suppl 1:S4-10.
Wang F-Z, Pellet PE. HHV-6A, 6B and 7: immunobiology and host responce. Human Herpesviruses Biology. Arvin A, Campadelli-Fiume G, Mocarski E ed. Cambridge:Cambridge University Press, 2007.
Prober CG. Human herpesvirus 6. Adv Exp Med Biol 2011; 697:87-90.
through direct joint tropism through ability to activate immune response directed at joint tissue
The aim
To assess the relevance of viral infection in RA we evaluated the frequency of HHV-6 and
HHV-7 reactivation in RA and OA patients and changes in cytokine expression levels
Matherials and methods
• Patients and controls. – 35 patients with RA (27 females and 8 males) with mean age 56.1
years (range 38-76),
– 33 patients with OA (25 females and 8 males) with mean age 66.1 years (range 46-83)
– 31 apparently healthy persons (mean age 53.6 years, range 38-72).
• The clinical features and laboratory parameters (hemoglobin, C reactive protein, rheumatoid factor and anti-cyclic citrullinated peptide) and disease activity score DAS28 (only for RA patients) were examined for their potential relationship with HHV-6 and HHV-7 infections.
• The presence of HHV-6 and HHV-7 DNA in clinical samples was detected by nested PCR.
• Detection of viral DNA in cell-associated material – leucocytes and synovial tissues, has been used as a marker of latent/persistent infection while detection of viral DNA in cell-free plasma and synovial fluid as a marker of active infection (virus reactivation).
• Secretion level of IL-6, TNF-alpha, IL-1beta and IFN-gamma in peripheral blood was determined by quantitative ELISA (Immunotool, Germany).
• Statistical analysis. Data were analyzed by Fisher’s exact test. Values of p<0.05 were considered to be significant.
5.7 8.6
57.1
28.6
6.1 3
33.3
57.6
22.6
9.7
41.9
25.8
0
10
20
30
40
50
60
70
withoutinfection
HHV6 HHV-7 HHV6/7
Pre
vale
nce
of
late
nt/
pe
rsis
ten
t in
fect
ion
s (%
) Prevalence of latent/persistent HHV-6 and HHV-7
infections among RA and OA patients
RA
OA
HP
18.2 23.1
56.7
70
19.4
10
33.3
84.2 83.3
0 4.8
37.5
0
10
20
30
40
50
60
70
80
90
withoutactivation
HHV6 HHV-7 HHV-6/7
Inci
de
nce
of
acti
ve in
fect
ion
(%
)
Incidence of active HHV-6 and HHV-7 infection in RA and OA patients
RA
OA
HP
33.3 33.3
16.7
42,9
8.33
41.7 41.7
50
0
10
20
30
40
50
60
HHV-6 HHV-7 HHV6/7 HHV-6 in synovialtissues
Inci
de
nce
of
HH
V-6
an
d H
HV
-7 D
NA
(%
) Incidence of HHV-6 and HHV-7 DNA in synovial
fluid and sinovial tissues
RA
OA
Medium results of laboratory parameters
35.7
20.3
26.9
11.88
6.56 3.88 2.4
4.45 4.8 2.89
0
5
10
15
20
25
30
35
40
without infection latent persistentHHV-6 and/or
HHV-7
active HHV-6 active HHV-7 active HHV-6/HHV-7
C r
eact
ive
pro
tein
(m
g/L)
C reactive protein
RA
OA
4.72
5.61
4.46 4.51 4.77
0
1
2
3
4
5
6
withoutinfection
latentpersistent
HHV-6 and/orHHV-7
active HHV-6 active HHV-7 active HHV-6/HHV-7
DA
S28
DAS28 in RA patients
RA
117.4
347.27
171.7 142.56
249.5
6.64 7.7 3.5 8.73 9.63
0
50
100
150
200
250
300
350
400
withoutinfection
latentpersistent HHV-6 and/or HHV-7
active HHV-6 active HHV-7 active HHV-6/HHV-7
Rh
eum
ato
id f
acto
r (U
/ml)
Rheumatoid factor
RA
OA
1.8
136.27
49.7
83.2
217.9
7.64 5.17 7 8.2 7.72
0
50
100
150
200
250
withoutinfection
latentpersistent HHV-6 and/or HHV-7
active HHV-6 active HHV-7 active HHV-6/HHV-7
An
ti C
CP
(R
U/m
l)
Anti CCP
RA
OA
123 127.5 125.3 119.16
128.43
140.35 133
151
138.75 138.67
0
20
40
60
80
100
120
140
160
withoutinfection
latentpersistent HHV-6 and/or HHV-7
active HHV-6 active HHV-7 active HHV-6/HHV-7
He
mo
glo
bin
(g/
L)
Hemoglobin
RA
OA
16.2 29.7
158
0
20
40
60
80
100
120
140
160
180
without infection latent/persistentinfection
active infection
Leve
l of
TNF-
alp
ha
(pg/
ml)
Serum TNF-alpha level in RA patients
8
37.8
80.1
0
10
20
30
40
50
60
70
80
90
100
without infection latent/persistentinfection
active infection
Leve
l of
IL-1
be
ta (
pg/
ml)
Serum IL-1beta level In RA patients
14.8
8.9
18.8
0
5
10
15
20
25
without infection latent/persistentinfection
active infection
IL6
leve
l (p
g/m
l)
Serum IL-6 level in RA patients
12.2
40.9
239.5
0
50
100
150
200
250
300
without infection latent/persistentinfection
active infection
Leve
l of
IFN
-gam
ma
(pg/
ml)
Serum IFN-gamma level in RA patients
Conclusion
• Concurrent HHV-6 and HHV-7 reactivation may cause more aggressive progress of RA.
• Concurrent HHV-6 and HHV-7 reactivation in RA patients leads to significant increase of tumor necrosis factor alpha and interferon-gamma secretion.
• The role of HHV-6 and HHV-7 infection in the RA pathogenesis through immune dysregulation could not be excluded.
“Promotion of International Cooperation
Activities of Riga Stradiņš University in Science and Technologies”, agreement
No. 2010/0200/2DP/2.1.1.2.0/10/APIA/VIAA/006