Review Article A New Diagnostic Way for Behcet s Disease ...downloads.hindawi.com/journals/gri/2014/581468.pdf · Review Article A New Diagnostic Way for Behcet s Disease: Skin Prick

Review ArticleA New Diagnostic Way for Behcetrsquos DiseaseSkin Prick with Self-Saliva

Fumio Kaneko1 Ari Togashi1 Erika Nomura1 and Koichiro Nakamura2

1 Institute of Dermato-Immunology and -Allergy Southern TOHOKU Research Institute for Neuroscience 7-115 YatsuyamadaKoriyama Fukushima 963-8563 Japan

2Department of Dermatology Saitama Medical University 38 Hongo Moroyama Iruma-gun Saitama 350-0495 Japan

Correspondence should be addressed to Fumio Kaneko fkanekomtstrinsorjp

Received 11 September 2013 Accepted 18 November 2013 Published 23 January 2014

Academic Editor Haner Direskeneli

Copyright copy 2014 Fumio Kaneko et alThis is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Behcetrsquos disease (BD) is a mysterious multisystemic disorder characterized by recurrent involvement of mucocutaneous (includingrecurrent aphthous stomatitis RAS) ocular intestinal vascular andor nervous system organs Previously the positivity ofldquopathergy testrdquo which is one of the diagnostic examinations was reported to be related to the possession of HLA-B51 gene inBD patients even though the positivity is low and different from the countries Here instead of the ordinal pathergy test wewould like to propose the prick with self-saliva as a new diagnostic way for patients with RAS of BD based on the genetic intrinsicfactors including HLA-B51 and extrinsic triggering factors BD patients are considered to acquire the hypersensitivity against oralstreptococci through the innate immune mechanism in the oral cavity Bes-1 gene and 65 kD of heat shock protein (HSP-65) derivedfrom oral S sanguinis are supposed to play important roles as extrinsic factors in BD pathogenesis Although the prick positivitywas not related to the possession of HLA-B51 gene the method is suggested to be a significant way for BD diagnosis The resultsalso suggest that BD symptoms are due to the vascular immune responses by monocytes expressed oral streptococcal agents of thepatients

1 Introduction

Behcetrsquos disease (BD) [1] is a chronic multisystematic inflam-matory disorder characterized by the recurrent involve-ment of mucocutaneous [oral and genital ulceration ery-thema nodosum (EN)-like eruption acne-like eruption etc]ocular vascular digestive andor nervous system organsAlthough the actual etiology of BD is still unclear thepathogenesis has been generally clearer by the etiologi-cal research based on the genetic intrinsic factors andimmunological reactions to the extrinsic triggering factorsin an environmental agent [2ndash14] As one of the triggeringfactors the oral unhygienic condition may be suspectedbecause periodontitis decayed teeth chronic tonsillitis andso forth are frequently noted in the oral cavity of BDpatients [9 10] The infectious triggering factors are sus-pected to be many organisms including streptococci herpessimplex viruses (HSVs) Saccharomyces fermentans Borreliaburgdorferi Helicobacter pylori Escherichia coli Staphylococ-cus aureus Mycoplasma fermentans andmycobacterium [11]

The proportion of Streptococcus sanguinis (S sanguinis)which was previously recognized as species of the genusStreptococcus named ldquoS sanguisrdquo was significantly high inthe oral bacterial flora of BD patients in comparison withthose of healthy controls [12ndash14] Most of the patients tend toacquire hypersensitivity against streptococci in their oral bac-terial flora as previously demonstrated that much strongercutaneous reactions were seen by the prick with strepto-coccal antigen than those by ldquoPathergy testrdquo [8 9 15 16]Non-BD patients with recurrent aphthous stomatitis (non-BD-RAS) were also having the hyperreactivity as reportedby Graykowski et al in the 1960s [17] In vitro systeminflammatory cytokines interleukin (IL)-6 and interferon(IFN)-120574 were produced from peripheral blood mononuclearcells (PBMCs) of BD patients which were stimulated bystreptococcal antigen [18] and the serum-antibody titersagainst streptococci were also elevated in BD patients [19]The peptides of 65 kD of heat shock protein (HSP-65) derivedfrom streptococci show considerable homology with those

Hindawi Publishing CorporationGenetics Research InternationalVolume 2014 Article ID 581468 10 pageshttpdxdoiorg1011552014581468

2 Genetics Research International

(a) (b)

Figure 1 Oral aphtha and genital ulcerations seen in a male BD patient with neuropathy (55 M YY in Table 1) (a) Oral ulcer round andpunched-out shaped on the tongue (b) Genital ulcer shaped like oral ulcer

of the human HSP-60 which appeared as counterpart afterstreptococcal infection [20ndash22]

Here an attempt to review on the mucocutaneous man-ifestations clinically seen in BD patients was done in theconnection with the genetic intrinsic and extrinsic triggeringfactorsWewould like to take up a new diagnostic way for BDusing self-saliva prick instead of the ordinal ldquoPathergy testrdquowhich seems to be low positive in BD patients

2 Mucocutaneous Involvements

21 Aphthous Ulceration RAS generally starts as an initialsymptom in BD patients since their childhood andor youthand other mucocutaneous symptoms follow after RAS [23ndash25] (Figures 1(a) and 1(b)) The oral aphthous ulcerationpunch-out shaped occurs with pain on the tongue buccalmucosa gingival and lip and it continues around a weekin BD patients The clinical features of the oral ulcers isdivided as minor major herpetiform and the combinedtypes depending on the lesional size and shapes Non-BD-RAS is a very common disorder due to trauma some viralandor bacterial infections except for patients with BD andother autoimmune diseases because it is known that 20of the general population is affected in the world [26] Onthe other hand nearly 100 of BD patients are associatedwith RAS as the initial symptom as aphthous ulcerationThe biopsy specimen of aphthous ulcer lesion from a BDpatient revealed a reactionmdashlike the antibody dependent cellmediated cytotoxicity that the epithelial cells surrounded byneutrophils and lymphoid cells look like leaves falling downfrom the mucous epithelial layer (Figures 2(a) and 2(b))These epithelial cells are stained with IgM and HLA-DR andare surrounded by T cells in the immunohistological findingsand in addition antistreptococcal antibody was also stainedon the cell membrane of the epithelium [15 27] However itis histologically difficult to differentiate aphthous ulcerationof BD patient from non-BD-RAS patients

22 Genital Ulcer The clinical features of genital ulcerationare generally shaped as similar to oral aphthous ulceration

in BD patients (Figure 1(b)) and in young female a genitalulceration suddenly occurs as the initial symptom of BDas Lipschutz ulceration [28] although it was reported to berelated to Epstein-Barr viral infection [29] About more than50 of BD patients are found to be associated with genitalulceration (female 555 male 587) that is ulcers occuron vulva (661) vaginalmucosa (357) anus (96) cervix(41) and groin area (08) in female patients and on thepenis (465) scrotum (385) anus (92) and groin area(50) in male patients [23 25]

23 EN-Like Eruption More than 50 of BD patients isreported to be associated with EN-like eruption on thelegs [23ndash25 30] which relatively looks smaller indulationthan that of non-BD patients (Figure 3(a)) The histologyis generally vascular reaction infiltrated by lymphoid cellsso-called lymphocytic vasculitis in the dermis and septalpanniculitis in the subcutaneous fatty tissue (Figure 3(b)) Inacute phase however vasculitis surrounded by neutrophilsis also able to be recognized Immunofluorescence techniquerevealed deposits of IgA IgM and complement in the vas-cular walls and the similar findings can be seen in thereactive site by pathergy test [31ndash33] Streptococcal relatedmaterials can also be detected in the vascular walls byuse of antistreptococcal antibody (Figure 3(c)) [9 15 27]Recently Cho et al [34 35] have demonstrated that IgA andIgM deposited at the lesional vascular walls targeted againsthuman nuclear ribonucleoprotein (hnRNP) A2B1 of theendothelial cells in BD patients whose serum IgA and IgMalso reacted with S sanguinis and HSP-6560

24 Other Cutaneous Disorders Acne-like eruption due toperifolliculitis repeatedly appears on the upper body ofBD patients and subcutaneous thrombophlebitis so-calledldquothrombophlebitismigransrdquo is suddenly noticed on the lowerextremities Rarely the follicular lesions may develop to alarge ulceration like ldquopyoderma gangrenosumrdquo on the ex-tremities Some male BD patients may have a sudden painand edema of the scrotum due to epididymitis

Genetics Research International 3

(a) (b)

Figure 2Histology of aphthous ulceration of a BDpatient (a)Aphthous ulcer of the lip defecting the epithelial layer (HEtimes100) (b)Magnifiedfeature of the ulcer edge of the epithelial layer The epithelial cells are surrounded by inflammatory infiltrates like ldquoRosetta formationrdquo

Histology and immunohistology by antistreptococcal group D antibody in the lesions of

Fukushima Medical University School of Medicine Department of Dermatology

(a) (b) (c)

Behcetrsquos disease (Kaneko et al Br J Dermatol 1985)

Figure 3 EN-like eruption and the histology and immunohistology (a) EN-like eruption on the lower legs of a BD patient (b) Vasculitisinfiltrated by lymphoid cells and neutrophils (HE 400x) (c) Deposits of streptococcal antigen adhering to the vascular wall (directimmunofluorescence times400)

3 Pathergy Test and Oral Streptococci

The diagnosis of BD is not thought to be difficult for theclinically typical cases who are based on the diagnosticcriteria by Japanese andor International Study Group [2436] except for the atypical cases without the main muco-cutaneous symptoms including RAS Pathergy test whichis a nonspecific cutaneous hypersensitive reaction showingaround 2mm pustule 24ndash48 h after 20G syringe needle stickhas been thought to be helpful for making a diagnosis of BD

for long time because the phenomenon has been believedas a unique feature for BD The reactive conditions seem tobe varied by the technical method and generally the highpositivity is found in Mediterranean and Middle East coun-tries [30] The reactivity of the ldquopathergy testrdquo is suggestedto be correlated with HLA-B51 in Mediterranean countries[37] and it is one of diagnostic criteria by International StudyGroup of BD [36] On the other hand in the Japanese BDdiagnostic criteria ldquopathergy testrdquo is considered as one of thediagnostic references [23 24] However its positivity in BD


Table 1 Self-salivary prick test in patients with aphthous ulceration and controls

Patients Age sex (initials) Prick test Small pustule SS-prick CS-prick(after 48 h)

Neuro BD 55 M YY 11 times 15mm + nd ndash

Incomplete

33 F ATlowast 22 times 22 minus ndash ndash26 F MNlowast 10 times 10 + + dot ndash27 M TG 11 times 12 + + dot ndash47 M YT 10 times 13 + + dot ndash36 F ANlowast 5 times 10 minus nd ndash46 M KH 10 times 10 minus ndash ndash17 F YT 5 times 5 minus ndash ndash

Complete 23 M OOlowast 10 times 10 + ndash ndash

Recurrent aphthous stomatitis(non-BD RAS)

24 F YN 8 times 10mm minus ndash ndash28 F YS 8 times 4 minus ndash ndash32 F YN ndash minus nd ndash29 M ON ndash minus nd ndash28 F MS 3 times 5 minus ndash ndash

Disease controlsnon-BD EN

39 F KY ndash minus nd ndash61 F MF ndash minus mdash ndash

Viral aphthosis (3) ndash minus nd ndashHealthy controls (6) ndash minus ndash ndashBD Behcetrsquos disease EN erythema nodosum F female M male dot small spot + positive minusnegative S-prick prick with self-saliva SS-prick prick withsterilized self-saliva CS prick with saline nd not done The clinical type of BD is followed by the Japanese BD classification lowastSame cases in Table 2

patients seems to be chronologically lower to less than 40of BD patients seen in 2007s though more than 70 of thepatients exhibited positive to the pathergy test in 1970s Thepositivity by the test is also different from the prevalence inthe countries as mentioned [38ndash40] It is of interest that thesurgical cleaning of the forearm before needle prick reducedthe prevalence of the ldquopathergy reactionrdquo [41] suggestingthat the positive reaction might be a cutaneous response tosome bacteria living on the surface of the skin In our allcases shown in Tables 1 and 2 none of cutaneous reactionswere found 24ndash48 hours after venipuncture for the clinicalexaminations using syringe with 22G needle because beforethe venipuncture their forearm was cleaned

As it is known that many kinds of bacteria are containedin our saliva we tried to incubate saliva form a BD patientusingMitis-Salivarius (MS) agarwhich streptococci are selec-tively grown The result showed many oral streptococci grewup from pure saliva (Figure 4(a)) and that no bacteria grewfrom the sterilized saliva by use of a syringe micromembranefilter (Figure 4(b)) Then instead of conventional ldquopathergytestrdquo we tried to prick with self-saliva in which oral bacteriaincluding streptococci are ordinary contained to the fore-arms of BD patients for diagnosis using a Lancetter witha tiny stick (OY ALGO AB EspooEsbo Sweden) becausethe patients have hypersensitivity to oral streptococci asdescribed previously The results revealed more than 90 of10 BD patients showed erythematous reaction by stick withself-saliva and that a tiny spot or no reaction was seen bythe prick with microfilter-sterilized saliva and control saline(Figure 5 Table 1) [42] The results also suggest that oral

streptococci are playing an important role in the pathogenesisof the RAS of BD patients and that the salivary prick is ableto make a differentiation of BD from non-BD disorders Thereaction and severity to self-saliva prick was not related to thepossession of the HLA-B51 gene in BD patients (Table 2)

4 HLA Genotyping of BDand Streptococcal Infection

HLA-B51 is supposed to be a highly associated geneticmarker of BD patients from many different ethnic groupsincluding European Mediterranean and Asian people andBD has several unique epidemiologic features from SouthernEurope to Japan along ldquothe old silk routerdquo [2 4 5 44]The appearance of BD lesions is not directly correlated withHLA-B51 in the immunological background of the patientsbut it was recently found that HLA-B51-restricted cytotoxicT lymphocytes (CTLs) and 120574120575T cells played some roles incorrelation with the stressed target tissues expressing majorhistocompatibility complex class I-related gene A (MICA) inBD pathogenesis When the transmembrane-MICA locatednearly at the HLA-B51 gene is expressed preferentially onepithelial and endothelial cells by stress they seem to be thecandidates for the HLA-B51-restricted CTLs response andMICA expressed on the stressed epithelium and endotheliumwhich are considered to be the ligand for activating naturalkiller (NK) cells with NKG2Dmolecule 120574120575T cells and CD8+T cells as CTLs [45] Regarding NK cell activation inhibitoryCD34NKG2A and activating CD94NKG2C molecules are


Table 2 Self-salivary prick test in BD patients with or without HLA-B51

Type of BD (Japanese classification) Patients (initials) Prick test (mm) HLA-B51S SS CS

Complete type 23 M OOlowast 10 mdash ndash + (B51)

Incomplete type

40 M HG 10 7 ndash + (B51 01 01)31 F MA 30 7 ndash + (B51 40)42 F MK 7 4 ndash + (B51 46 DR4 8)34 F MY 26 5 ndash minus (B35 48)36 F ANlowast 10 ndash ndash minus (B44 03 01)33 F YK 10 ndash ndash ndash37 F ATlowast 22 ndash ndash minus (B40 48)30 F MNlowast 10 ndash ndash ndash35 M YI 10 nd ndash minus (B15 35)37 F HT 4 ndash ndash minus (B40 44)36 MMK 4 3 ndash minus (B35 44)35 M KF 7 2 ndash minus (B46 54)35 F YO 14 ndash ndash minus (B07 02 01)

F female M male S self-saliva SS filtered sterilized saliva CS control saline + positive minus negative nd not done lowastSame cases in Table 1

alternatively expressed on NK CD4+CD8+ T cells as indi-cating an imbalance in cytotoxic activity in BD patients [46]although the function of NK cells is supposed to be down-regulated in the active stage and to be up-regulated in theremission of BD patients [47] The excessive CD4+ T cellsactivated by inflammatory cytokines including interferon(IFN)-120574 IL-12 and IL-23 were altered to Th17 cells and IL-17 which might be released from them in the BD lesions [48]

It is considered that HSP-6560 derived from microor-ganism including S sanguinis and fromhuman tissues whichis detected in the oral mucosal and skin lesions of BD patients[20 21] also becomes a stress-inducible factor in connectionwith MICAlowast009 expression Generally antigen presentingcells (APCs) which produce IL-12 in correlation with Th1type immune-reaction are thought to be activated in BDpatientswithHLA-B51 in active stage as indicated byYasuokaet al [45] However we have obtained the results that PBMCsfrom BD patients without HLA-B51 gene can be significantlystimulated by S sanguinis antigen in the expression of IL-12p40 mRNA and increasing of protein level in connectionwith IL-12p70 (70 kDa composed of p35 and p40 subunits)rather than those of the patients with HLA-B51 [51] It hasbeen suggested that antibacterial host response in T cell typeimmunity mediated by IL-12 is much stronger in HLA-B51-negative BD patients The skin response severity by the prickwith oral streptococci of self-saliva seemed to be unrelated tothe HLA-B51 gene as seen in Table 2

5 Hypersensitivity against S sanguinis

Generally the oral health is impaired in BD patients [8ndash13]which seems to be associated with the disease severity [10]Although there are a number of the triggering factors forBD in environmental agent the predisposition of BD patientsmay be correlated with streptococcal infection as one of thefactors because the uncommon serotype oral S sanguinis is

(a)

(b)

Figure 4 Incubation of saliva of a BD patient using MS (mitis andsalivarius) agar in which oral streptococci are selectively grown (a)Oral streptococci grew from saliva in 5 day (b) Area of sterilizedsaliva using syringe micromembrane filter

Figure 5 Prick test with self-saliva using Lancetter (33 F AT inTable 1) The skin reactions were observed 48 hours after prick Sself-saliva SS sterilized saliva using syringe-filter with 02 120583mporesCS control saline


(a) (b)

Patients

4 BD

BD

BD

BD

7

8

9

22

PCR

PCR in situ hybridization

Bes-1 DNA fragment encoding Streptococcus sanguinisin the mucocutaneous lesions

29 yM genital ulcer

49 yF EN-like eruption

Oral aphtha

23 yF Cellulitis by streptococcalinfection (control)


No

Figure 6 Bes-1 gene expression in the mucocutaneous lesions of patients with Behcetrsquos disease (BD) [43] (a) Three of 11 BD patientswere positive for Bes-1 DNA in the lesions including aphthous and genital ulcerations and erythema nodosum (EN)-like eruptionby amplified polymerase chain reaction (PCR) using the primers Bes-1-1 (51015840-TAATAACCCTGACCAAGCCTA-31015840) and Bes-1-2 (51015840-CCCTTTCAAAAGTCATAAATC-31015840) encoding S sanguinis (b) In these positive lesions Bes-1 DNA was also detected in the cytoplasmof monocytes adhering to the vascular walls and infiltrated around the vessels by PCR in situ hybridization

significantly increased in BD patients compared with healthyand disease controls [11ndash15]The antibodies against S sangui-nis in sera from BD patients showed cross reactivity with thesome synthetic peptides of HSP-65 derived from S sanguinis[52ndash54] The patients show strong delayed type cutaneoushypersensitivity reactions against streptococcal antigens inskin tests [8 9 15] and sometimes the BD symptoms wereprovoked by skin injection of the antigens [16] Becauseaphthous ulceration can be also induced by a prick withstreptococcal antigen on the oral mucous membrane of aBD patient [9] the appearance of aphthous ulceration isconsidered to be based on the hypersensitive reaction againstS sanguinis which may be traumatically penetrated into theoral membrane of BD patients Isogai et al [53] demonstratedthat the symptoms mimicking BD appeared in germ-freemice when S sanguinis from BD patients was inoculated intotheir oral tissue damaged by heat shock andor mechanicalstress This report suggests that the immunization with Ssanguinis through the oral membrane route elicits BD-likesymptoms in the animal model as seen in BD patients whocarry S sanguinis as the pathogenic microorganism in theiroral cavity In order to find polymerase chain reaction (PCR)targeting Bes-1 gene in BD lesions using 2 distinct primersets (peptides 229ndash243 and 373ndash385) encoding S sanguinis(serotype KTH-1) which was prepared by Yoshikawa et al[54] we recognized that Bes-1 DNA was present in variousmucocutaneous lesions including oral and genital ulcerationsand EN-like lesions The PCR in situ hybridization alsorevealed that Bes-1 DNA was expressed in the cytoplasm ofinflammatory infiltrated monocytes adhering the vascular

walls in mucocutaneous lesions (Figure 6) [43] In contrastwe failed to detect DNAs of HSV-1 HSV-2 cytomegalovirushuman herpes virus (HHV)-6 and HHV-7 in the lesionsby PCR [55] although HSV infection has been speculatedas etiologically important since the report of Behcet [1]Interestingly the amino acid sequence of the peptides of Bes-1 (229ndash243 and 373ndash385) shows more than 60 similarity tothe human intraocular ganglion peptide Brn-3b which is asubfamily of POU (pit-Oct Unc) domain factors containingBrn-3a and Brn-3c [56] The peptide of Bes-1 (229ndash243) wasalso found to be correlated with the peptide of HSP-60 (336ndash351) [54] Recently it has been found that the peptide ofBes-1 (337ndash385) stimulated PBMCs of BD patients whichproduced IFN-120574 and IL-12 though the cellular proliferationof the stimulated PBMCswas not observed [57]These resultssuggest that Bes-1 derived from oral S sanguinismight be aninducer for the possible retinal and neural involvement in BDpatients

6 HSPs and BD Pathogenesis

Antibodies against the HSP peptides derived from bacteriaincluding S sanguinis are found in aphthous ulceration andserum of BD patients [58] though HSP specific antibodiesand T cells are considered to play a complicated role in thepathogenesis of human autoimmune diseases [59] It is spec-ulated that HSPs trigger both innate and adaptive immunemechanisms in BD On the other hand the therapeuticapproaches involvingHSP immunomodulationmay be avail-able as ldquooral tolerationrdquo using the peptide of HSP (336ndash351)


Damaged oral mucous membrane(aphthous ulceration)

S sanguinis

geneTLRs 2 4 6 9

HSP-60

IL-12120572120573T 120574120575T

Bes-1

Hsp-65

(a)

Peripheral vessel (vascular reaction)

Hsp-6560

Hsp-6560

Adhesion molecules

PMNs

IL-12

Localinflammation

T T

T

IL-1 6 8

TNF-120572

TNF-120574

120574120575CD8

120574120575CD8

120572120573CD4

Bes-1

Bes-1

Kaneko et al Eur J Dermatol 2008

(b)

Figure 7 Hypothesis of the mechanisms in the appearance of various lesions of BD patients [49 50] (a)The antigen presenting cells (APCs)(macrophages andor dendritic cells) immunized by S sanguinis agents though TLRs in the oral cavity might be carried to the peripheralregions (b) If the APCs in the blood flow adhered to the impaired andor MICA and adhesion molecules expressed endothelial cells ofvascular wall the immunological reaction might be appeared as BD lesion

linked to recombinant cholera toxin B for BD patients withadvanced uveitis as demonstrated by Stanford et al [60]In order to understand the suppressive mechanisms of thecytokine production in PBMCs from active BD patients wetried to find the binding sites of the peptides onmonocytes bycDNA chips (Gene Chip Human Genome) using NOMO-1cells (human macrophage cell line) activated by S sanguinisantigen and they were incubated with the peptides It wasfound that although the expression of IL-8 IL-16 IL-13Rand IL-17R was decreased after incubation with HSP-65peptides (LO1 and UK) respectively LO2 (480ndash499) didnot decrease IL-8 production CD58 (lymphocyte function-associated antigen-3) molecule andor FK506 binding pro-tein were highly expressed on the cell membrane by LO1(249ndash264) and UK (311ndash326) [61 62]

7 Toll-Like Receptor (TLR) Expression inthe Innate Immunity

Regarding the recognition system for the microorganismantigens in humans 10 numbers of TLR family are supposedto act as innate immune receptors by binding of particularstructures present on bacteria viruses fungi and so forth

[63] Although generally TLRs are weakly detectable in var-ious human tissues with varying levels the TLR expressionof the organs involved in immune response and exposed toenvironment is found to be significantly stronger [64] TLR-3[ds RNA] and TLR-6 [mycoplasma staphylococci etc] arealso reported to be enhanced in expression on neutrophilsand monocytes of BD patients when stimulated by HSP-60 and S sanguinis antigen [65] In the oral ulcer lesionexpression of TLR-9 [unmethylated CpG DNA bacteria andvirus] has been found recently [66] These findings suggestthat innate immune system contributes the acquisition ofhypersensitivity against oral S sanguinis as the extrinsicfactor in the pathogenesis of BD

8 Oral Aphthous Ulcerationand Systemic Symptoms

BD symptoms are characterized by vascular involvementsshowing swollen endothelial cells of the microarteries infil-trated by inflammatory monocytes and a few neutrophilshistologically as so-called ldquovascular reactionrdquo seen in EN-like eruption and other lesions [15 31 67 68] The stronghypersensitivity reaction against S sanguinis agents [8 9 1516 18] whichmight be gained by antigen present cells (APCs)


through the innate immune mechanism can be suspected asthe extrinsic triggering factor in the pathogenesis of BD Inthe treatment by antibiotics for the involvement of oral Ssanguinis especially minocycline which not only reduces thegrowth of streptococci but also suppresses IL-1120573 and IL-6production from T cells inflamed was clinically effective foraphthous ulceration acne-like eruption and EN-like lesion inBD patients [9] Other study also showed that combinationtherapy colchicine and benzathine penicillin was effective tosuppress BD symptoms compared to colchicinemonotherapy[69 70] Although Kaneko et al [49] and others [5ndash7] havealready reviewed on the role of infectious agents in BDpathogenesis we also dare to propose the hypothesis thatafter Bes-1 gene taken in the cytoplasm of APCs through theTLRs in the oral cavity the APCs which are expressing thestreptococcal antigen produce HSP-6560 as demonstratedby Deniz et al [58] If these APCs are curried in the bloodflow to the impaired andor MICA expressed endothelium ofthe vessels in correlation with HSP-6560 VEGF adhesionmolecules and so forth BD lesions might be induced bythe ldquovascular reactionrdquo andor ldquolymphocytic vasculitisrdquo as theimmunological reaction by the APCs expressing S sanguinisantigen Then the relationship between oral ulceration andthe systemic symptoms might be considered as illustratedin Figure 7 From the viewpoint it is considerable that thepositivity of the prick with self-saliva is high for BD patients[49 50 62] So we would like to propose a new diagnosticway for BD and differentiation from non-BD patients andornon-BD RAS patients

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

We deeply appreciate that our studies were supported by theGrants from Japanese Behcetrsquos Disease Research Committeeof the Ministry of Health Labor and Welfare

References

[1] H Behcet ldquoUber rezidivierende aphthous durch ein Virusverursachte Geschwuere amMund am Auge und an den Geni-talienrdquo Dermatologische Wochenschrift vol 105 pp 1152ndash11571937

[2] A Altenburg N Papoutsis H Orawa P Martus L KrauseandC C Zouboulis ldquoEpidemiology and clinical manifestationsof Adamantiades-Behcet disease in Germanymdashcurrent patho-genetic concepts and therapeutic possibilitiesrdquo Journal of theGerman Society of Dermatology vol 4 no 1 pp 49ndash66 2006

[3] E Alpsoy C Zouboulis and G E Ehrlich ldquoMucocutaneouslesions of Behcetrsquos diseaserdquo Yonsei Medical Journal vol 48 no4 pp 573ndash585 2007

[4] S Ohno M Onguchi S Hirose H Matsuda A Wakisakaand M Aizawa ldquoClose association of HLA-Bw51 with Behcetrsquosdiseaserdquo Archives of Ophthalmology vol 100 no 9 pp 1455ndash1458 1982

[5] C C Zouboulis and T May ldquoPathogenesis of Adamantiades-Behcetrsquos diseaserdquo Medical Microbiology and Immunology vol192 no 3 pp 149ndash155 2003

[6] A Karaycian and C C Zouboulis ldquoAn update on Behcetrsquosdiseaserdquo Journal of the European Academy of Dermatology andVenereology vol 21 pp 1ndash10 2007

[7] I Krause and A Weinberger ldquoBehcetrsquos diseaserdquo Current Opin-ion in Rheumatology vol 20 pp 82ndash87 2008

[8] F Kaneko T Kaneda O Ohnishi et al ldquoInfection allergy inBehcetrsquos diseaserdquo Japanese Journal of Allergology vol 27 pp440ndash450 1978

[9] F Kaneko N Oyama and A Nishibu ldquoStreptococcal infectionin the pathogenesis of Behcetrsquos disease and clinical effects ofminocycline on the disease symptomsrdquo Yonsei Medical Journalvol 38 no 6 pp 444ndash454 1997

[10] G Mumcu T Ergun N Inanc et al ldquoOral health is impairedin Behcetrsquos disease and is associated with disease severityrdquoRheumatology vol 43 no 8 pp 1028ndash1033 2004

[11] M Galeone R Colucci A M DrsquoErme S Moretti and T LottildquoPotential infectious etiology of Behcetrsquos diseaserdquo PathologyResearch International vol 2012 Article ID 595380 4 pages2012

[12] K Yokota S Hayashi Y Araki et al ldquoCharacterization of Strep-tococcus sanguis isolated from patients with Behcetrsquos diseaserdquoMicrobiology and Immunology vol 39 no 9 pp 729ndash732 1995

[13] E Isogai S Ohno K Takashi et al ldquoClose association of Strep-tococcus sanguis uncommon serotypes with Behcetrsquos diseaserdquoBifidobacteria Microflora vol 9 pp 27ndash41 1990

[14] E Isogai S Ohno S Kotake et al ldquoChemiluminescence ofneutrophils from patients with Behcetrsquos disease and its corre-lation with an increased proportion of uncommon serotypes ofStreptococcus sanguis in the oral florardquo Archives of Oral Biologyvol 35 no 1 pp 43ndash48 1990

[15] F Kaneko Y Takahashi Y Muramatsu and Y Miura ldquoImmu-nological studies on aphthous ulcer and erythema nodosum-like eruptions in Behcetrsquos diseaserdquo The British Journal of Der-matology vol 113 no 3 pp 303ndash312 1985

[16] Y Mizushima T Matsuda K Hoshi and S Ohno ldquoInductionof Behcetrsquos disease symptoms after dental treatment and strep-tococcal antigen skin testrdquo Journal of Rheumatology vol 15 no6 pp 1029ndash1030 1988

[17] E A Graykowski M F Barile W B Lee and H R Stan-ley Jr ldquoRecurrent aphthous stomatitis Clinical therapeutichistopathologic and hypersensitivity aspectsrdquoThe Journal of theAmericanMedical Association vol 196 no 7 pp 637ndash644 1966

[18] S Hirohata H Oka and Y Mizushima ldquoStreptococcal-relatedantigens stimulate production of IL6 and interferon-120574 by T cellsfrom patients with Behcetrsquos diseaserdquo Cellular Immunology vol140 no 2 pp 410ndash419 1992

[19] K Yokota S Hayashi N Fuji et al ldquoAntibody response to oralStreptococci in Behcetrsquos diseaserdquoMicrobiology and Immunologyvol 36 no 8 pp 815ndash822 1992

[20] T Lehner ldquoThe role of heat shock protein microbial and auto-immune agents in the etiology of Behcetrsquos diseaserdquo InternationalReviews of Immunology vol 14 no 1 pp 21ndash32 1997

[21] S Kaneko N Suzuki N Yamashita et al ldquoCharacterization of Tcells specific for an epitope of human 60-kD heat shock protein(hsp) in patients with Behcetrsquos disease (BD) in Japanrdquo Clinicaland Experimental Immunology vol 108 no 2 pp 204ndash212 1997

[22] A Kibaroglu E Eksioglu-Demiralp T Akoglu and H Dire-skeneli ldquoT and NK cell subset changes with microbial extracts


and human HSP60-derived peptides in Behcetrsquos diseaserdquo Clini-cal and Experimental Rheumatology vol 22 no 4 supplement34 pp S59ndashS63 2004

[23] T Sakane M Takeno N Suzuki and G Inaba ldquoBehcetrsquosdiseaserdquo The New England Journal of Medicine vol 341 no 17pp 1284ndash1291 1999

[24] M Suzuki-Krokawa and N Suzuki ldquoBehcetrsquos diseaserdquo Clinicaland Experimental Medicine vol 3 pp 10ndash20 2004

[25] D Bang K H Yoon H G Chung E H Choi E S Lee and SLee ldquoEpidemiological and clinical features of Behcetrsquos disease inKoreardquo Yonsei Medical Journal vol 38 no 6 pp 428ndash436 1997

[26] J A Ship ldquoRecurrent aphthous stomatitis An updaterdquo OralSurgery Oral Medicine Oral Pathology Oral Radiology andEndodontics vol 81 no 2 pp 141ndash147 1996

[27] F Kaneko ldquoBehcetrsquos diseaserdquo in A Color Atlas of Dermato-Immunohistology H Ueki and H Yaoita Eds pp 84ndash85WolfeMedical Publication London UK 1989

[28] B Lipschutz ldquoUlcer vulvae acutumrdquo inHandbuch der Haut undGeschl J Jadassohn Ed vol 21 pp 392ndash414 Spriger BerlinGermany 1927

[29] A Lampert H Assier-Bonnet B Chevallier T Clerici andP Saiag ldquoLipschutzrsquos genital ulceration a manifestation ofEpstein-Barr virus primary infectionrdquo The British Journal ofDermatology vol 135 no 4 pp 663ndash665 1996

[30] S Lee D Bang and E S Lee ldquoBehcetrsquos diseaserdquo inThe 3rd Listof Publication on Behcetrsquos Disease 1995ndash2002 pp 27ndash49 YonseiUniversity College of Medicine Seoul Republic of Korea AjouUniversity School ofMedicine Suwon Republic of Korea 2003

[31] S Haim J D Sobel R Friedman Birnbaum and C LichtigldquoHistological and direct immunofluorescence study of cuta-neous hyperreactivity in Behcetrsquos diseaserdquo The British Journalof Dermatology vol 95 no 6 pp 631ndash636 1976

[32] J L Jorizzo J L AbernethyW LWhite et al ldquoMucocutaneouscriteria for the diagnosis of Behcetrsquos disease an analysis ofclinicopathologic data from multiple international centersrdquoJournal of the American Academy of Dermatology vol 32 no6 pp 968ndash976 1995

[33] H Serhat Inaloz C Evereklioglu B Unal N Kirtak A Eralpand S S Inaloz ldquoThe significance of immunohistochemistry inthe skin pathergy reaction of patients with Behcetrsquos syndromerdquoJournal of the European Academy of Dermatology and Venereol-ogy vol 18 no 1 pp 56ndash61 2004

[34] S Cho Z Zheng S Cho et al ldquoBoth the sera of patients withBehcetrsquos disease and Streptococcus sanguis stimulatemembraneexpression of hnRNP A2B1 in endothelial cellsrdquo ScandinavianJournal of Rheumatology vol 42 no 3 pp 241ndash246 2013

[35] S B Cho Z Zheng K J Ahn et al ldquoSerum IgA reactivityagainst GroEL of Streptococcus sanguinis and human heteroge-neous nuclear ribonucleoproteinA2B1 in patientswith Behcetrsquosdiseaserdquo The British Journal of Dermatology vol 168 no 5 pp977ndash983 2013

[36] International Study Group for Behcetrsquos Disease ldquoCriteria fordiagnosis of Behcetrsquos diseaserdquoThe Lancet vol 335 no 8697 pp1078ndash1080 1990

[37] H Yazici Y Tuzun H Pazarli B Yalcin S Yurdakul and AMuftuoglu ldquoThe combined use ofHLA-B5 and the pathergy testas diagnostic markers of Behcetrsquos disease in Turkeyrdquo Journal ofRheumatology vol 7 no 2 pp 206ndash210 1980

[38] F Davatchi C Chams-Davatchi F Shahram et al ldquoPathergytest in Behcetrsquos disease change in incidence over the timerdquoAPLAR Journal of Rheumatology vol 10 no 4 pp 333ndash3352007

[39] P G Davies J N Fordham J R Kirwan C G Barnes andW JDinning ldquoThe pathergy test and Behcetrsquos syndrome in BritainrdquoAnnals of the Rheumatic Diseases vol 43 no 1 pp 70ndash73 1984

[40] R Friedman-Birnbaum R Bergman and E Aizen ldquoSensitivityand specificity of pathergy test results in Israeli patients withBehcetrsquos diseaserdquo Cutis vol 45 no 4 pp 261ndash264 1990

[41] I Fresko H Yazici M Bayramicli S Yurdakul and C MatldquoEffect of surgical cleaning of the skin on the pathergy phe-nomenon in Behcetrsquos syndromerdquo Annals of the RheumaticDiseases vol 52 no 8 pp 619ndash620 1993

[42] A Togashi S Saito F Kaneko K Nakamura and N OyamaldquoSkin prick test with self-saliva in patients with oral aphthosesa new diagnostic pathergy for behcetrsquos disease and recurrentaphthosisrdquo Inflammation and AllergymdashDrug Targets vol 10 no3 pp 164ndash170 2011

[43] M Tojo H Yanagihori X Zheng et al ldquoBes-1 DNA fragmentencoding streptococcal antigen in skin lesions from patientswith Behcetrsquos diseaserdquo Journal of Applied Research vol 3 no 3pp 232ndash238 2003

[44] N Mizuki H Inoko and S Ohno ldquoMolecular genetics (HLA)of Behcetrsquos diseaserdquo in Behcetrsquos DiseasemdashA Guide to Its ClinicalUnderstanding S Lee D Bang E-S Lee and S Sohn Eds pp87ndash100 Springer New York NY USA 2001

[45] H Yasuoka Y Okazaki Y Kawakami et al ldquoAutoreactive CD8+cytotoxic T lymphocytes to major histocompatibility complexclass I chain-related gene A in patients with Behcetrsquos diseaserdquoArthritis and Rheumatism vol 50 no 11 pp 3658ndash3662 2004

[46] J Seo J S Park J H Nam et al ldquoAssociation of CD94NKG2ACD94NKG2C and its ligand HLA-E polymorphisms withBehcetrsquos diseaserdquo Tissue Antigens vol 70 no 4 pp 307ndash3132007

[47] F Kaneko Y Takahashi and R Muramatsu ldquoNatural killer cellnumbers and function in peripheral lymphoid cells in Behcetrsquosdiseaserdquo The British Journal of Dermatology vol 113 no 3 pp313ndash318 1985

[48] J Shimizu K Takai N Fujiwara et al ldquoExcessive CD4+ T cellsco-expressing interleukin-17 and interferon-120574 in patients withBehcetrsquos diseaserdquo Clinical and Experimental Immunology vol168 no 1 pp 68ndash74 2012

[49] F Kaneko N Oyama H Yanagihori E Isogai K Yokotaand K Oguma ldquoThe role of streptococcal hypersensitivityin the pathogenesis of Behcetrsquos diseaserdquo European Journal ofDermatology vol 18 no 5 pp 489ndash498 2008

[50] F Kaneko A Togashi S Saito et al ldquoBehcetrsquos disease (Ada-mantiades-Behcetrsquos disease)rdquo Clinical and DevelopmentalImmunology vol 2011 Article ID 681956 7 pages 2011

[51] H Yanagihori N Oyama K Nakamura N Mizuki K Ogumaand F Kaneko ldquoRole of IL-12B promoter polymorphism inAdamantiades-Behcetrsquos disease susceptibility an involvementof Th1 immunoreactivity against Streptococcus sanguinis anti-genrdquo Journal of Investigative Dermatology vol 126 no 7 pp1534ndash1540 2006

[52] E Isogai H Isogai S Kotake et al ldquoAntibody cross reactivityfrom sera of patients with behcetrsquos disease with syntheticpeptides that have homologies with proteins from Streptococcussanguisrdquo Journal of Applied Research vol 2 no 3 pp 1ndash7 2002

[53] E Isogai H Isogai S Kotake S Ohno K Kimura and KOguma ldquoRole of Streptococcus sanguis and traumatic factors inBehcetrsquos diseaserdquo Journal of Applied Research vol 3 no 1 pp64ndash75 2003

[54] K Yoshikawa S Kotake T Kubota K Kimura E Isogai andN Fujii ldquoCloning and sequencing of BES-1 gene encoding the


immunogenic antigen of Streptococcus sanguis KTH-1 isolatedfrom the patients with Behcetrsquos diseaserdquo Zentralblatt fur Bakte-riologie vol 287 no 4 pp 449ndash460 1998

[55] M Tojo X Zheng H Yanagihori et al ldquoDetection of herpesvirus genomes in skin lesions from patients with Behcetrsquos dis-ease and other related inflammatory diseasesrdquo Acta Dermato-Venereologica vol 83 no 2 pp 124ndash127 2003

[56] M Xiang L Zhou Y Peng R L Eddy T B Shows and JNathans ldquoBrn-3b a POU domain gene expressed in a subset ofretinal ganglion cellsrdquo Neuron vol 11 no 4 pp 689ndash701 1993

[57] A Kulaber I Tugal-Tutkun S P Yentur et al ldquoPro-inflam-matory cellular immune response in Behcetrsquos diseaserdquo Rheuma-tology International vol 27 no 12 pp 1113ndash1118 2007

[58] E Deniz U Guc N Buyukbabani and A Gul ldquoHSP 60expression in recurrent oral ulcerations of Behetrsquos diseaserdquoOralSurgery Oral Medicine Oral Pathology Oral Radiology andEndodontology vol 110 no 2 pp 196ndash200 2010

[59] U Zugel and H E Kaufman ldquoRole of heat shock proteinsin protection from and pathogenesis of infectious diseasesrdquoClinical Microbiology Reviews vol 12 pp 19ndash39 1999

[60] M Stanford T Whittall L A Bergmeier et al ldquoOral toleriza-tion with peptide 336-351 linked to cholera toxin B subunit inpreventing relapses of uveitis in Behcetrsquos diseaserdquo Clinical andExperimental Immunology vol 137 no 1 pp 201ndash208 2004

[61] K Oguma R Shin and K Yokota ldquoStudies on immunologicalresponses by bacterial antigens in Behcetrsquos diseaserdquo in Reportof the Research Group for Behcetrsquos Disesae Organized by theJapanese Ministry of Health Lavour and Welfare 2006-2007 pp31ndash33 2008 (Japanese)

[62] F Kaneko A Togashi E Nomura et al ldquoRole of heat shock pro-tein derived from Streptococcus sanguinis in Behcetrsquos diseaserdquoJournal of Medical Microbiology and Diagnosis S2 2012

[63] K A Zarember and P J Godowski ldquoTissue expression ofhuman toll-like receptors and differential regulation of toll-likereceptor mRNAs in leukocytes in response to microbes theirproducts and cytokinesrdquo Journal of Immunology vol 168 no 2pp 554ndash561 2002

[64] V Hornung S Rothenfusser S Britsch et al ldquoQuantitativeexpression of toll-like receptor 1ndash10 mRNA in cellular subsetsof human peripheral bloodmononuclear cells and sensitivity toCpG oligodeoxynucleotidesrdquo Journal of Immunology vol 168no 9 pp 4531ndash4537 2002

[65] S Yavuz Y Elbir A Tulunay E Eksioglu-Demiralp and HDireskeneli ldquoDifferential expression of toll-like receptor 6 ongranulocytes and monocytes implicates the role of microor-ganisms in Behcetrsquos disease etiopathogenesisrdquo RheumatologyInternational vol 28 no 5 pp 401ndash406 2008

[66] O Durranni G R Wallace J Hamburger et al ldquoToll-likereceptors (TLRs) expression in oral ulcer biopsies from Behcetrsquosdisease (BD) patients a role for the innate immune system inBDrdquo Clinical and Experimental Rheumatology vol 22 supple-ment 34 p S-93 2004

[67] S W Yi E H Kim H Y Kang Y C Kim and E S Lee ldquoEry-thema nodosum clinicopathologic correlations and their use indifferential diagnosisrdquo Yonsei Medical Journal vol 48 no 4 pp601ndash608 2007

[68] T Iikunur U Pabuccuoglu C Akin B Lebe and A T GunesldquoHistopathologic and direct immunofluorescence findings ofthe papulopustular lesions in Behcetrsquos disesaserdquo European Jour-nal of Dermatology vol 16 pp 146ndash150 2006

[69] M Calguneri I Ertenli S Kiraz M Erman and I CelikldquoEffect of prophylactic benzathine penicillin onmucocutaneous

symptoms of Behcetrsquos diseaserdquo Dermatology vol 192 no 2 pp125ndash128 1996

[70] G Mumcu N Inanc S Yavuz and H Direskeneli ldquoThe roleof infectious agents in the pathogenesis clinical manifestationsand treatment strategies in Behcetrsquos diseaserdquo Clinical andExperimental Rheumatology vol 25 no 4 pp S27ndashS33 2007

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of


Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology


Molecular Biology International

GenomicsInternational Journal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014


BioinformaticsAdvances in

Marine BiologyJournal of



Signal TransductionJournal of


BioMed Research International

Evolutionary BiologyInternational Journal of



Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


Genetics Research International


Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational



Enzyme Research



Microbiology


(a) (b)

Figure 1 Oral aphtha and genital ulcerations seen in a male BD patient with neuropathy (55 M YY in Table 1) (a) Oral ulcer round andpunched-out shaped on the tongue (b) Genital ulcer shaped like oral ulcer

of the human HSP-60 which appeared as counterpart afterstreptococcal infection [20ndash22]

Here an attempt to review on the mucocutaneous man-ifestations clinically seen in BD patients was done in theconnection with the genetic intrinsic and extrinsic triggeringfactorsWewould like to take up a new diagnostic way for BDusing self-saliva prick instead of the ordinal ldquoPathergy testrdquowhich seems to be low positive in BD patients

2 Mucocutaneous Involvements

21 Aphthous Ulceration RAS generally starts as an initialsymptom in BD patients since their childhood andor youthand other mucocutaneous symptoms follow after RAS [23ndash25] (Figures 1(a) and 1(b)) The oral aphthous ulcerationpunch-out shaped occurs with pain on the tongue buccalmucosa gingival and lip and it continues around a weekin BD patients The clinical features of the oral ulcers isdivided as minor major herpetiform and the combinedtypes depending on the lesional size and shapes Non-BD-RAS is a very common disorder due to trauma some viralandor bacterial infections except for patients with BD andother autoimmune diseases because it is known that 20of the general population is affected in the world [26] Onthe other hand nearly 100 of BD patients are associatedwith RAS as the initial symptom as aphthous ulcerationThe biopsy specimen of aphthous ulcer lesion from a BDpatient revealed a reactionmdashlike the antibody dependent cellmediated cytotoxicity that the epithelial cells surrounded byneutrophils and lymphoid cells look like leaves falling downfrom the mucous epithelial layer (Figures 2(a) and 2(b))These epithelial cells are stained with IgM and HLA-DR andare surrounded by T cells in the immunohistological findingsand in addition antistreptococcal antibody was also stainedon the cell membrane of the epithelium [15 27] However itis histologically difficult to differentiate aphthous ulcerationof BD patient from non-BD-RAS patients

22 Genital Ulcer The clinical features of genital ulcerationare generally shaped as similar to oral aphthous ulceration

in BD patients (Figure 1(b)) and in young female a genitalulceration suddenly occurs as the initial symptom of BDas Lipschutz ulceration [28] although it was reported to berelated to Epstein-Barr viral infection [29] About more than50 of BD patients are found to be associated with genitalulceration (female 555 male 587) that is ulcers occuron vulva (661) vaginalmucosa (357) anus (96) cervix(41) and groin area (08) in female patients and on thepenis (465) scrotum (385) anus (92) and groin area(50) in male patients [23 25]

23 EN-Like Eruption More than 50 of BD patients isreported to be associated with EN-like eruption on thelegs [23ndash25 30] which relatively looks smaller indulationthan that of non-BD patients (Figure 3(a)) The histologyis generally vascular reaction infiltrated by lymphoid cellsso-called lymphocytic vasculitis in the dermis and septalpanniculitis in the subcutaneous fatty tissue (Figure 3(b)) Inacute phase however vasculitis surrounded by neutrophilsis also able to be recognized Immunofluorescence techniquerevealed deposits of IgA IgM and complement in the vas-cular walls and the similar findings can be seen in thereactive site by pathergy test [31ndash33] Streptococcal relatedmaterials can also be detected in the vascular walls byuse of antistreptococcal antibody (Figure 3(c)) [9 15 27]Recently Cho et al [34 35] have demonstrated that IgA andIgM deposited at the lesional vascular walls targeted againsthuman nuclear ribonucleoprotein (hnRNP) A2B1 of theendothelial cells in BD patients whose serum IgA and IgMalso reacted with S sanguinis and HSP-6560

24 Other Cutaneous Disorders Acne-like eruption due toperifolliculitis repeatedly appears on the upper body ofBD patients and subcutaneous thrombophlebitis so-calledldquothrombophlebitismigransrdquo is suddenly noticed on the lowerextremities Rarely the follicular lesions may develop to alarge ulceration like ldquopyoderma gangrenosumrdquo on the ex-tremities Some male BD patients may have a sudden painand edema of the scrotum due to epididymitis


(a) (b)




(a) (b) (c)










Incomplete

















Incomplete type







(a)

(b)




(a) (b)

Patients

4 BD

BD

BD

BD

7

8

9

22

PCR



29 yM genital ulcer


Oral aphtha



No








S sanguinis

geneTLRs 2 4 6 9

HSP-60

IL-12120572120573T 120574120575T

Bes-1

Hsp-65

(a)


Hsp-6560

Hsp-6560

Adhesion molecules

PMNs

IL-12

Localinflammation

T T

T

IL-1 6 8

TNF-120572

TNF-120574

120574120575CD8

120574120575CD8

120572120573CD4

Bes-1

Bes-1


(b)












Acknowledgments


References



















































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology


(a) (b)




(a) (b) (c)










Incomplete

















Incomplete type







(a)

(b)




(a) (b)

Patients

4 BD

BD

BD

BD

7

8

9

22

PCR



29 yM genital ulcer


Oral aphtha



No








S sanguinis

geneTLRs 2 4 6 9

HSP-60

IL-12120572120573T 120574120575T

Bes-1

Hsp-65

(a)


Hsp-6560

Hsp-6560

Adhesion molecules

PMNs

IL-12

Localinflammation

T T

T

IL-1 6 8

TNF-120572

TNF-120574

120574120575CD8

120574120575CD8

120572120573CD4

Bes-1

Bes-1


(b)












Acknowledgments


References



















































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology





Incomplete

















Incomplete type







(a)

(b)




(a) (b)

Patients

4 BD

BD

BD

BD

7

8

9

22

PCR



29 yM genital ulcer


Oral aphtha



No








S sanguinis

geneTLRs 2 4 6 9

HSP-60

IL-12120572120573T 120574120575T

Bes-1

Hsp-65

(a)


Hsp-6560

Hsp-6560

Adhesion molecules

PMNs

IL-12

Localinflammation

T T

T

IL-1 6 8

TNF-120572

TNF-120574

120574120575CD8

120574120575CD8

120572120573CD4

Bes-1

Bes-1


(b)












Acknowledgments


References



















































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology





Incomplete type







(a)

(b)




(a) (b)

Patients

4 BD

BD

BD

BD

7

8

9

22

PCR



29 yM genital ulcer


Oral aphtha



No








S sanguinis

geneTLRs 2 4 6 9

HSP-60

IL-12120572120573T 120574120575T

Bes-1

Hsp-65

(a)


Hsp-6560

Hsp-6560

Adhesion molecules

PMNs

IL-12

Localinflammation

T T

T

IL-1 6 8

TNF-120572

TNF-120574

120574120575CD8

120574120575CD8

120572120573CD4

Bes-1

Bes-1


(b)












Acknowledgments


References



















































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology


(a) (b)

Patients

4 BD

BD

BD

BD

7

8

9

22

PCR



29 yM genital ulcer


Oral aphtha



No








S sanguinis

geneTLRs 2 4 6 9

HSP-60

IL-12120572120573T 120574120575T

Bes-1

Hsp-65

(a)


Hsp-6560

Hsp-6560

Adhesion molecules

PMNs

IL-12

Localinflammation

T T

T

IL-1 6 8

TNF-120572

TNF-120574

120574120575CD8

120574120575CD8

120572120573CD4

Bes-1

Bes-1


(b)












Acknowledgments


References



















































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology



S sanguinis

geneTLRs 2 4 6 9

HSP-60

IL-12120572120573T 120574120575T

Bes-1

Hsp-65

(a)


Hsp-6560

Hsp-6560

Adhesion molecules

PMNs

IL-12

Localinflammation

T T

T

IL-1 6 8

TNF-120572

TNF-120574

120574120575CD8

120574120575CD8

120572120573CD4

Bes-1

Bes-1


(b)












Acknowledgments


References



















































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology





Acknowledgments


References



















































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology





























































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology



























Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology








Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology

Documents

Review Article A New Diagnostic Way for Behcet s Disease ...downloads.hindawi.com/journals/gri/2014/581468.pdf · Review Article A New Diagnostic Way for Behcet s Disease: Skin Prick