RSS-Feed abonnieren
DOI: 10.1055/s-2008-1027452
© Georg Thieme Verlag KG Stuttgart · New York
Zytokine in der Diagnostik der Uveitis
The Role of Cytokines for the Diagnosis of UveitisPublikationsverlauf
Eingegangen: 6.2.2008
Angenommen: 28.3.2008
Publikationsdatum:
02. Juni 2008 (online)

Zusammenfassung
Nichtinfektiöse Formen der Uveitis sind durch einen Zusammenbruch der immunologischen Toleranz charakterisiert. In Tiermodellen konnten verschiedene Zytokine als lösliche Botenstoffe identifiziert werden, die entscheidend an der Regulation des Immunsystems während der Induktion, Progression und Remission der okulären Entzündung beteiligt sind. Diese Übersichtsarbeit analysiert den aktuellen Wissensstand über die Rolle der Zytokine für die Uveitis und dessen Relevanz für die klinische Diagnostik. Untersuchungen des Kammerwassers und des Serums von Uveitispatienten zeigen eine vermehrte Konzentration proinflammatorischer sowie eine Verminderung antiinflammatorischer Zytokine. Zusätzlich wurden Sequenzvarianten von Zytokingenen (single nucleotide polymorphisms) beschrieben, die das Expressionsniveau verändern und mit einem erhöhten Erkrankungsrisiko verbunden sind. Diese Studien wurden jedoch nur an kleinen oder heterogenen Patientengruppen durchgeführt. Zudem sind die Resultate teilweise widersprüchlich. Daher spielte die Analyse von Zytokinen bislang keine Rolle in der Routinediagnostik der Uveitis. Neue Multiplexverfahren der Zytokinanalyse liefern jedoch umfassendere Daten zum Verständnis der komplexen Regulation des Immunsystems im Verlaufe der intraokulären Entzündung. Dadurch kann es in Zukunft möglich werden, die für den einzelnen Patienten relevanten Mechanismen der Immunreaktion quantitativ zu beschreiben, um die individuelle Prognose einschätzen und gezielt die für den Patienten optimale Therapieform auswählen zu können.
Abstract
Non-infectious uveitis is characterised by a breakdown of immunological tolerance. Several cytokines could be identified as important regulators of the immune system during induction, progression and remission of ocular inflammation in animal models. This review analyses the current knowledge on cytokines in uveitis and their relevance for diagnostic purposes. Elevated levels of pro-inflammatory and decreased concentrations of anti-inflammatory cytokines were detected in the aqueous humor and serum of uveitis patients. In addition, single nucleotide polymorphisms of cytokine genes altering expression levels were found to be associated with an increased risk of uveitis. These studies, however, included only small or heterogenous patient populations. Moreover, the reported data are partially inconsistent. Thus, the analysis of cytokines does not play a role in the routine diagnostic process of uveitis so far. New multiplex techniques for cytokine analysis will provide comprehensive data for a better understanding of the complex regulation of the immune system during intraocular inflammation. This may lead to a quantitative description of the immunological mechanisms of uveitis in the individual patient to improve the prognostic evaluation and select the most efficient treatment.
Schlüsselwörter
Intraokulare Entzündungen - Zytokine - Diagnostik - Single nucleotide polymorphism
Key words
intraocular inflammation - cytokines - diagnosis - single nucleotide polymorphisms
Literatur
- 1
Krause C D, Pestka S.
Historical developments in the research of interferon receptors.
Cytokine Growth Factor Rev.
2007;
18 (5 - 6)
473-482
MissingFormLabel
- 2
Dinarello C A.
Historical insights into cytokines.
Eur J Immunol.
2007;
37 (Suppl 1)
S34-45
MissingFormLabel
- 3
O’Shea J J, Ma A, Lipsky P.
Cytokines and autoimmunity.
Nat Rev Immunol.
2002;
2 (1)
37-45
MissingFormLabel
- 4
Caspi R R.
Regulation, counter-regulation, and immunotherapy of autoimmune responses to immunologically
privileged retinal antigens.
Immunol Res.
2003;
27 (2 - 3)
149-160
MissingFormLabel
- 5
Egwuagu C E, Sztein J, Mahdi R M. et al .
IFN-gamma increases the severity and accelerates the onset of experimental autoimmune
uveitis in transgenic rats.
J Immunol.
1999;
162 (1)
510-517
MissingFormLabel
- 6
Frankenstein Z, Alon U, Cohen I R.
The immune-body cytokine network defines a social architecture of cell interactions.
Biol Direct.
2006;
1
32
MissingFormLabel
- 7
Gutcher I, Becher B.
APC-derived cytokines and T cell polarization in autoimmune inflammation.
J Clin Invest.
2007;
117 (5)
1119-1127
MissingFormLabel
- 8
McInnes I B, Schett G.
Cytokines in the pathogenesis of rheumatoid arthritis.
Nat Rev Immunol.
2007;
7 (6)
429-442
MissingFormLabel
- 9
Engel A, Mack E, Kern P. et al .
An analysis of interleukin-8, interleukin-6 and C-reactive protein serum concentrations
to predict fever, gram-negative bacteremia and complicated infection in neutropenic
cancer patients.
Infection.
1998;
26 (4)
213-221
MissingFormLabel
- 10
Dick A D.
Immune regulation of uveoretinal inflammation.
Int Ophthalmol.
1999;
30
187-202
MissingFormLabel
- 11 Caspi R R. The role of cytokines in induction and regulation of autoimmune uveitis. Kuchroo VK Contemporary Clinical Neurosciences: Cytokines and Autoimmune Diseases Totowa; Humana Press 2001 1. Aufl: 227-245
MissingFormLabel
- 12
Forrester J V.
Intermediate and posterior uveitis.
Chem Immunol Allergy.
2007;
92
228-243
MissingFormLabel
- 13
Dick A D, Carter D A.
Cytokines and immunopathogenesis of intraocular posterior segment inflammation.
Ocul Immunol Inflamm.
2003;
11 (1)
17-28
MissingFormLabel
- 14
Boyd S R, Young S, Lightman S.
Immunopathology of the noninfectious posterior and intermediate uveitides.
Surv Ophthalmol.
2001;
46 (3)
209-233
MissingFormLabel
- 15
Jones L S, Rizzo L V, Agarwal R K. et al .
IFN-gamma-deficient mice develop experimental autoimmune uveitis in the context of
a deviant effector response.
J Immunol.
1997;
158 (12)
5997-6005
MissingFormLabel
- 16
Streilein J W.
Immunoregulatory mechanisms of the eye.
Prog Retin Eye Res.
1999;
18 (3)
357-370
MissingFormLabel
- 17
Imrie F R, Dick A D.
Biologics in the treatment of uveitis.
Curr Opin Ophthalmol.
2007;
18 (6)
481-486
MissingFormLabel
- 18
Nussenblatt R B, Peterson J S, Foster C S. et al .
Initial evaluation of subcutaneous daclizumab treatments for noninfectious uveitis:
a multicenter noncomparative interventional case series.
Ophthalmology.
2005;
112 (5)
764-770
MissingFormLabel
- 19
Suhler E B, Smith J R, Wertheim M S. et al .
A prospective trial of infliximab therapy for refractory uveitis: preliminary safety
and efficacy outcomes.
Arch Ophthalmol.
2005;
123 (7)
903-912
MissingFormLabel
- 20
Dick A D, Duncan L, Hale G. et al .
Neutralizing TNF-alpha activity modulates T-cell phenotype and function in experimental
autoimmune uveoretinitis.
J Autoimmun.
1998;
11 (3)
255-264
MissingFormLabel
- 21
Murphy C C, Greiner K, Plskova J. et al .
Neutralizing tumor necrosis factor activity leads to remission in patients with refractory
noninfectious posterior uveitis.
Arch Ophthalmol.
2004;
122 (6)
845-851
MissingFormLabel
- 22
Franks W A, Limb G A, Stanford M R. et al .
Cytokines in human intraocular inflammation.
Curr Eye Res.
1992;
11 (Suppl)
187-191
MissingFormLabel
- 23
Smet M D, Chan C C.
Regulation of ocular inflammation - what experimental and human studies have taught
us.
Prog Retin Eye Res.
2001;
20 (6)
761-797
MissingFormLabel
- 24
Ooi K G, Galatowicz de G, Calder V L. et al .
Cytokines and chemokines in uveitis: is there a correlation with clinical phenotype?.
Clin Med Res.
2006;
4 (4)
294-309
MissingFormLabel
- 25
Murray P I, Clay C D, Mappin C. et al .
Molecular analysis of resolving immune responses in uveitis.
Clin Exp Immunol.
1999;
117 (3)
455-461
MissingFormLabel
- 26
Lacomba M S, Martin C M, Chamond R R. et al .
Aqueous and serum interferon gamma, interleukin (IL) 2, IL-4, and IL-10 in patients
with uveitis.
Arch Ophthalmol.
2000;
118 (6)
768-772
MissingFormLabel
- 27
Plskova J, Greiner K, Muckersie E. et al .
Interferon-alpha: a key factor in autoimmune disease?.
Invest Ophthalmol Vis Sci.
2006;
47 (9)
3946-3950
MissingFormLabel
- 28
Stübiger N, Kötter I, Deuter C. et al .
Behçet’s disease: uveitis-therapy with interferon alpha2a - prospective clinical study
in 33 patients.
Klin Monatsbl Augenheilkd.
2001;
218 (12)
768-773
MissingFormLabel
- 29
Plskova J, Greiner K, Forrester J V.
Interferon-alpha as an effective treatment for noninfectious posterior uveitis and
panuveitis.
Am J Ophthalmol.
2007;
144 (1)
55-61
MissingFormLabel
- 30
Ahn J K, Yu H G, Chung H. et al .
Intraocular cytokine environment in active Behçet uveitis.
Am J Ophthalmol.
2006;
142 (3)
429-434
MissingFormLabel
- 31
Kramer M, Monselise Y, Bahar I. et al .
Serum cytokine levels in active uveitis and remission.
Curr Eye Res.
2007;
32 (7 - 8)
669-675
MissingFormLabel
- 32
Lee M T, Hooper L C, Kump L. et al .
Interferon-beta and adhesion molecules (E-selectin and s-intracellular adhesion molecule-1)
are detected in sera from patients with retinal vasculitis and are induced in retinal
vascular endothelial cells by Toll-like receptor 3 signalling.
Clin Exp Immunol.
2007;
147 (1)
71-80
MissingFormLabel
- 33
Ooi K G, Galatowicz G, Towler H M. et al .
Multiplex cytokine detection versus ELISA for aqueous humor: IL-5, IL-10, and IFNgamma
profiles in uveitis.
Invest Ophthalmol Vis Sci.
2006;
47 (1)
272-277
MissingFormLabel
- 34
Sijssens K M, Rijkers G T, Rothova A. et al .
Cytokines, chemokines and soluble adhesion molecules in aqueous humor of children
with uveitis.
Exp Eye Res.
2007;
85 (4)
443-449
MissingFormLabel
- 35
Takase H, Futagami Y, Yoshida T. et al .
Cytokine profile in aqueous humor and sera of patients with infectious or noninfectious
uveitis.
Invest Ophthalmol Vis Sci.
2006;
47
1557-1561
MissingFormLabel
- 36
Kooij van B, Rothova A, Rijkers G T. et al .
Distinct Cytokine and Chemokine Profiles in the Aqueous of Patients With Uveitis and
Cystoid Macular Edema.
Am J Ophthalmol.
2006;
142 (2)
192-194
MissingFormLabel
- 37
Kaulen H.
Biomarker: Plausibilität und Korrelation allein reichen nicht aus.
Dtsch Arztebl.
2007;
104 (40)
2704-2705
MissingFormLabel
- 38
Fritzler M J.
Advances and applications of multiplexed diagnostic technologies in autoimmune diseases.
Lupus.
2006;
15 (7)
422-427
MissingFormLabel
- 39
Curnow S J, Murray P I.
Inflammatory mediators of uveitis: cytokines and chemokines.
Curr Opin Ophthalmol.
2006;
17 (6)
532-537
MissingFormLabel
- 40
Greiner K, Murphy C C, Willermain F. et al .
Anti-TNFalpha therapy modulates the phenotype of peripheral blood CD 4 + T cells in
patients with posterior segment intraocular inflammation.
Invest Ophthalmol Vis Sci.
2004;
45 (1)
170-176
MissingFormLabel
- 41
Murphy C C, Duncan L, Forrester J V. et al .
Systemic CD 4(+) T cell phenotype and activation status in intermediate uveitis.
Br J Ophthalmol.
2004;
88 (3)
412-416
MissingFormLabel
- 42
Chan C C, Wallace D J.
Intraocular lymphoma: update on diagnosis and management.
Cancer Control.
2004;
11 (5)
285-295
MissingFormLabel
- 43
Curnow S J, Falciani F, Durrani O M. et al .
Multiplex bead immunoassay analysis of aqueous humor reveals distinct cytokine profiles
in uveitis.
Invest Ophthalmol Vis Sci.
2005;
46 (11)
4251-4259
MissingFormLabel
- 44
Murphy C C, Greiner K, Plskova J. et al .
Cyclosporine vs tacrolimus therapy for posterior and intermediate uveitis.
Arch Ophthalmol.
2005;
123 (5)
634-641
MissingFormLabel
- 45
Aguillón J C, Cruzat A, Aravena O. et al .
Could single-nucleotide polymorphisms (SNPs) affecting the tumour necrosis factor
promoter be considered as part of rheumatoid arthritis evolution?.
Immunobiology.
2006;
211 (1 - 2)
75-84
MissingFormLabel
- 46
Hollegaard M V, Bidwell J L.
Cytokine gene polymorphism in human disease: on-line databases.
Genes Immun.
2006;
7
269-276
MissingFormLabel
- 47
Martinez A, Fernandez-Arquero M, Pascual-Salcedo D. et al .
Primary association of tumor necrosis factor-region genetic markers with susceptibility
to rheumatoid arthritis.
Arthritis Rheum.
2000;
43
1366-1370
MissingFormLabel
- 48
Wallace G R, Kondeatis E, Vaughan R W. et al .
IL-10 genotype analysis in patients with Behçet’s disease.
Hum Immunol.
2007;
68 (2)
122-127
MissingFormLabel
- 49
Stanford M R, Vaughan R W, Kondeatis E. et al .
Are cytokine gene polymorphisms associated with outcome in patients with idiopathic
intermediate uveitis in the United Kingdom?.
Br J Ophthalmol.
2005;
89 (8)
1013-1016
MissingFormLabel
- 50
El-Shabrawi Y, Wegscheider B J, Weger M. et al .
Polymorphisms within the tumor necrosis factor-alpha promoter region in patients with
HLA-B27-associated uveitis: association with susceptibility and clinical manifestations.
Ophthalmology.
2006;
113 (4)
695-700
MissingFormLabel
- 51
Atan D, Turner S J, Kilmartin D J. et al .
Cytokine gene polymorphism in sympathetic ophthalmia.
Invest Ophthalmol Vis Sci.
2005;
46 (11)
4245-4250
MissingFormLabel
- 52
Yeo T K, Ahad M A, Kuo N W. et al .
Chemokine gene polymorphisms in idiopathic anterior uveitis.
Cytokine.
2006;
35 (1 - 2)
29-35
MissingFormLabel
- 53
Maksymowych W P, Landewe R, Boers M. et al .
Development of draft validation criteria for a soluble biomarker to be regarded as
a valid biomarker reflecting structural damage endpoints in rheumatoid arthritis and
spondyloarthritis clinical trials.
J Rheumatol.
2007;
34 (3)
634-640
MissingFormLabel
Kathrin Greiner,MD, PhD
St. John Eye Hospital
P. O. Box 19960
97200 Jerusalem
Israel
Telefon: ++ 9 72/2/5 82 83 25
Fax: ++ 9 72/2/5 82 83 27
eMail: greiner@doctors.org.uk