Behçet's disease is a complex vasculitis of unknown etiology. Abundant neutrophils suggest the involvement of innate immunity. Cytokines are skewed to the T-helper-1 pattern. Few sterile organs are easily accessible for analysis in Behçet's disease. Cañete and coworkers identify inflamed joints as a feasible model and suggest the involvement of innate immunity in Behçet's disease

Daele, P.L.A. (Paul) van

Hagen, P.M. (Martin) van

Kappen, J.H. (Jasper)

Laar, J.A.M. (Jan) van

Erasmus University Digital Repository

Available online http://arthritis-research.com/content/11/2/109Page 1 of 3(page number not for citation purposes)AbstractBehçet’s disease is a complex vasculitis of unknown etiology.Abundant neutrophils suggest the involvement of innate immunity.Cytokines are skewed to the T-helper-1 pattern. Few sterile organsare easily accessible for analysis in Behçet’s disease. Cañete andcoworkers identify inflamed joints as a feasible model and suggestthe involvement of innate immunity in Behçet’s disease.In a recent issue of Arthritis Research and Therapy, Cañeteand coworkers [1] describe a model for studying the immuno-pathology of Behçet’s disease (BD) by analyzing inflammatorycells, tissue, and cytokines in inflamed joints from BDpatients. The etiology of BD is obscure but it is considered tobe a complex systemic vasculitis, caused by T-helper-1 (Th1)cytokine skewed neutrophilic and lymphohistiocytic inflam-mation. Hence, an understanding of how cells and cytokinesfunction in inflamed tissues is important in terms of develop-ing therapeutic interventions [2]. A good example of howmechanistic insight can lead to effective treatment is that BDdisease symptoms can be effectively and rapidly reduced byblocking tumor necrosis factor (TNF)-α, a key cytokine in BD[3]. Activation of BD can be triggered by exogenous factorssuch as skin damage, introduction of bacterial components,viruses and stress subsequently leading to inflammation [4].A normal inflammatory response is rapid, non-specific, andself-limiting. It involves a carefully balanced reaction betweenactivated inflammatory cells and an exogenous trigger. Ininflammatory disorders such as BD, this response isunbalanced and causes excessive damage to the host. Theassociation of human leukocyte antigen (HLA)-B51 with BDand hyperactive neutrophils stresses the importance of innateimmunity in the pathogenesis of the disease [5]. Other factorssupporting participation of the innate immune system in BDinclude the following: prevalence of symptoms in body sitesin close contact with the outside environment (skin andmucosa); the presence of hypersensitive T cells; Toll-likereceptor expression in affected cells; and hyperactiveneutrophilic and CD8+ T-cell responses to heat shockproteins or bacterial cell wall fragments [2,4]. Cytokines thatare involved in BD are largely pro-inflammatory (IL-1β, IL-8, IL-10, TNF-α, and IFN-γ). Peripheral T cells in BD patientspredominantly exhibit a Th1-type pattern of cytokineexpression [6].How does the study of Cañete and coworkers [1] add to thebiomechanistic studies that have already been conducted inBD? First, in contrast to most of those studies, the analysesby Cañete and coworkers were conducted in untreatedpatients. In an uncommon disease such as BD, few studies innaïve patients are reported. In rheumatoid arthritis (RA), forexample, early and aggressive treatment is consideredmandatory if an optimal therapeutic outcome is to beachieved. It will therefore be of great therapeutic importanceto identify possible initiating factors in BD also by testingtherapy-naïve patients. This is especially important for theirreversible ophthalmic manifestations of the disease.Second, it is important that representative tissue is studied. InBD most mechanistic studies are conducted in bloodsamples; predominantly, testing of circulating cytokines or invitro peripheral blood mononuclear cells is done. Th1cytokines are involved, and hyperactive neutrophils andhyper-reactive T cells are held responsible for the symptomsobserved [7]. However, BD is an inflammatory disorderinvolving tissues such as skin, joint, eye, gut, brain, and oraland genital mucosa [2,4]. It is therefore mandatory to be surethat observations in blood are representative of bio-mechanisms at the tissue level.EditorialDo synovial biopsies help to support evidence for involvement ofinnate immunity in the immunopathology of Behçet’s disease?Jan AM van Laar, Jasper H Kappen, Paul LA van Daele and P Martin van HagenDepartment of Internal Medicine, Section of Clinical Immunology & Department of Immunology, Erasmus University Medical Center, PO Box 2040,3000 CA Rotterdam, The NetherlandsCorresponding author: Jan AM van Laar, j.vanlaar@erasmusmc.nlPublished: 30 April 2009 Arthritis Research & Therapy 2009, 11:109 (doi:10.1186/ar2657)This article is online at http://arthritis-research.com/content/11/2/109© 2009 BioMed Central LtdSee related research article by Cañete et al., http://arthritis-research.com/content/11/1/R17BD = Behçet’s disease; HLA = human leukocyte antigen; IFN = interferon; IL = interleukin; RA = rheumatoid arthritis; SF = synovial fluid; SpA =spondyloarthropathy; SPR = skin pathergy reaction; Th1 = T-helper-1.Arthritis Research & Therapy    Vol 11 No 2 van Laar et al.Page 2 of 3(page number not for citation purposes)Mucosal tissue is predominantly involved in BD, and micro-organisms from the external environment can readily influenceobservations in inflammatory cells. On the other hand, thosemicro-organisms are also capable of stimulating an immuneresponse in BD. Most tissue studies of the pathophysiologyof BD are conducted in skin. One of the unique and disease-specific features of BD is the occurrence of a positive skinpathergy reaction (SPR), which is observed in 30% to 75%of all BD patients [2,4]. Neutrophils and subsequentlylymphohistiocytic cells may be observed in sterile lesionsfollowing a sterile needle prick [8]. Representing endothelialinjury and functioning as leukocyte trafficking factors, celladhesion molecules (intercellular adhesion molecule-1 andvascular cell adhesion molecule-1) and endothelial growthfactor markers such as E-selectin, P-selectin, and endoglinare linked to SPR [9]. Infiltrating cells are mainly of theHLA-DR+/CD3+/CD4+/CD45RO+ type [10]. Other observa-tions include mature dendritic cells; monocytes; (regulatory)T cells; elevated levels of IFN-γ, IL-12-p40 and IL-15; MIP3-α(macrophage inflammatory protein-3α); IP-10 (IFN-inducibleprotein-10); Mig (monokine induced by IFN-γ); iTac(interferon-inducible T cell chemo-attractant); and adhesionmolecules [11].Studies of ocular BD show elevated Vγ9Vδ2 (CD4-/CD8-)and CD8brightCD56+ T cells, which are probably differentfrom those found infiltrating the SPR [12]. Cytokines found tobe elevated in ocular fluid from BD patients with active uveitisinclude IFN-γ, TNF-α, and IL-15 [13]. It must be stressed,however, that aqueous humor is seldom studied because it isdifficult to obtain samples; it is only evaluated in intensivelyand chronically treated BD patients.In contrast to most of the inflamed organs in BD, the joint issterile and frequently involved in BD. Cañete and coworkersexploit this readily accessible model, which has not oftenbeen studied in BD. Studies of BD arthropathy dating backmore than 30 years predominantly revealed neutrophillic infil-tration, depending on the stage and treatment of the disease.A more recent study of synovial fluid (SF) from BD patientsidentified increased levels of chemokines (C-X-C chemokineligand-9 and -10) related to Th1-directed inflammation [14].Cañete’s group has studied SF extensively in various otherarthropathies, such as spondyloarthropathy (SpA) and RA,and comparisons may be made with historical data.Comparing SF samples between SpA and other rheumaticdiseases (RA, juvenile SpA, juvenile polyarthritis, and juvenileoligoarthritis) revealed similarities only in terms of thepresence of CD3+, CD4+, and CD8+ cells [15].In the study presented Cañete and coworkers [1] concludethat psoriatic arthritis (PsA) resembles BD clinically; a furthersimilarity is the presence of neutrophils in SF from PsApatients. Increased levels of intra-articular CD15+ neutrophils,CD3+ T cells, and perforin were identified in SF from activeBD patients relative to SF from patients with PsA. Thisemphasizes that innate immunity is also involved in early BDand interacts with adaptive immunity, as reflected by thepresence of perforin, presumably secreted by CD3+ T cells. Itmight therefore be of interest to conduct further studies ofthese naïve T cells and cytokines in sterile SF in order torelate these observations to immunological patterns that havealready been described in tissues that are exposed toexogenous factors, or more intensively treated BD patients.These results can then be compared with various otherinflammatory diseases in order to obtain greater insight intothe immune-related etiology of BD and to develop morespecific, molecular based immunotherapies. Examples mayinclude targeting cytokines (IL-1, IL-10, or IL-6) and use ofagents that interfere with lymphocyte action.Competing interestsThe authors declare that they have no competing interests.Authors’ informationThe authors of this editorial include a PhD resident (JK) andinternist-immunologists (JVL, PVD, and PVH), representingthe staff of the clinical immunological section of the internalmedicine department of the largest Dutch university hospital.Their work concentrates on (auto)immune diseases andimmune deficiencies. An outpatient population of more than110 BD patients represents the largest Dutch population andprovides a basis for both immunopathophysiologic, genetic,and therapeutic studies and reports.References1 Cañete JD, Celis R, Noordenbos T, Moll C, Gómez-Puerta JA,Pizcueta P, Palacin A, Tak PP, Sanmartí R, Baeten D: Distinctsynovial immunopathology in Behçet disease and psoriaticarthritis. Arthritis Res Ther 2009, 11:R17.2 Sakane T, Takeno M, Suzuki N, Inaba G: Behçet’s disease. NEngl J Med 1999, 341:1284-1291.3 van Laar JA, Missotten T, van Daele PL, Jamnitski A, Baarsma GS,van Hagen PM: Adalimumab: a new modality for Behçet’sdisease? Ann Rheum Dis 2007, 66:565-566.4 Yazici H, Fresko I, Yurdakul S: Behçet’s syndrome: diseasemanifestations, management, and advances in treatment. NatClin Pract Rheumatol 2007, 3:148-155.5 Takeno M, Kariyone A, Yamashita N, Takiguchi M, Mizushima Y,Kaneoka H, Sakane T: Excessive function of peripheral bloodneutrophils from patients with Behçet’s disease and fromHLA-B51 transgenic mice. Arthritis Rheum 1995, 38:426-433.6 Suzuki N, Nara K, Suzuki T: Skewed Th1 responses caused byexcessive expression of Txk, a member of the Tec family oftyrosine kinases, in patients with Behcet’s disease. Clin MedRes 2006, 4:147-151.7 Accardo-Palumbo A, Triolo G, Carbone MC, Ferrante A, Ciccia F,Giardina E, Triolo G: Polymorphonuclear leukocyte myeloper-oxidase levels in patients with Behçet’s disease. Clin ExpRheumatol 2000, 18:495-498.8 Ergun T, Gürbüz O, Harvell J, Jorizzo J, White W: Thehistopathology of pathergy: a chronologic study of skin hyper-reactivity in Behçet’s disease. Int J Dermatol 1998, 37:929-933.9 Inaloz HS, Evereklioglu C, Unal B, Kirtak N, Eralp A, Inaloz SS:The significance of immunohistochemistry in the skinpathergy reaction of patients with Behçet’s syndrome. J EurAcad Dermatol Venereol 2004, 18:56-61.10 Gül A, Esin S, Dilsen N, Koniçe M, Wigzell H, Biberfeld P:Immunohistology of skin pathergy reaction in Behçet’sdisease. Br J Dermatol 1995, 132:901-907.11 Melikoglu M, Uysal S, Krueger JG, Kaplan G, Gogus F, Yazici H,Oliver S: Characterization of the divergent wound-healingresponses occurring in the pathergy reaction and normalhealthy volunteers. J Immunol 2006, 177:6415-6421.12 Verjans GM, van Hagen PM, van der Kooi A, Osterhaus AD,Baarsma GS: Vgamma9Vdelta2 T cells recovered from eyes ofpatients with Behçet’s disease recognize non-peptide prenylpyrophosphate antigens. J Neuroimmunol 2002, 130:46-54.13 Ahn JK, Yu HG, Chung H, Park YG. Intraocular cytokine envi-ronment in active Behçet uveitis. Am J Ophthalmol 2006, 142:429-434.14 Erdem H, Pay S, Musabak U, Simsek I, Dinc A, Pekel A, Sengul A:Synovial angiostatic non-ELR CXC chemokines in inflamma-tory arthritides: does CXCL4 designate chronicity of synovi-tis? Rheumatol Int 2007, 27:969-973.15 Kruithof E, Van den Bossche V, De Rycke L, Vandooren B, Joos R,Cañete JD, Tak PP, Boots AM, Veys EM, Baeten D: Distinct syn-ovial immunopathologic characteristics of juvenile-onsetspondylarthritis and other forms of juvenile idiopathic arthri-tis. Arthritis Rheum 2006, 54:2594-2604.Available online http://arthritis-research.com/content/11/2/109Page 3 of 3(page number not for citation purposes)

Do synovial biopsies help to support evidence for involvement of innate immunity in the immunopathology of Behçet's disease?

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Do synovial biopsies help to support evidence for involvement of innate immunity in the immunopathology of Behçet's disease?

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