Presented by: M. Torabi (M.Sc.) Supervisor: Dr. Mahdi Mahmodi Supervisor: Dr. Mahdi Mahmodi 12/2/2013Rheumatology Research Center RRC (RRClab)

Behcet’s disease (BD) A recurrent systemic inflammatory disorder. Characterized by four major symptoms:  oral aphthous ulcers,  ocular lesions,  skin lesions,  genital aphthous Multiple systemic associations:  articular, gastrointestinal, cardiopulmonary, neurologic, and vascular involvement Rheumatology Research Center RRC (RRClab) 12/2/2013

Diagnostic : 1 Required Criteria and 2 Minor Criteria. Required Criteria:  Recurrent oral ulcerations: minor aphthous, major aphtous or herpetiform ulceration observed by physician or patient, which recurred at least 3 times in one 12 month period Minor Criteria:  Recurrent genital aphthous : aphthous ulceration or scarring observed by physician or patient  Eye lesion: anterior uveitis, posterior uveitis, or cells in vitreous on slit lamp examination or retinal vasculitis observed by ophthalmologist  Skin lesions : erythema nodosum observed by physician or patient, pseudofolliculitis or papulopustular lesions, or acneform nodules observed by physician in post-adolescent patients not on corticosteroid treatment  Positive pathergy test read by physician hours. 12/2/2013Rheumatology Research Center RRC (RRClab)

Etiopathogenesis The etiopathogenesis is uncertain. Some possible implications:  microbial agent triggers,  environmental factors,  genetic predisposition,  endothelial cell dysfunction,  immunological abnormalities 12/2/2013Rheumatology Research Center RRC (RRClab)

Immune system dysfunction Genetic predisposition Triggering factors Initiation of Behcet disease 12/2/2013Rheumatology Research Center RRC (RRClab)

Autoimmunity ??  It was postulated that Behcet’s disease is an autoimmune disease.  Through molecular mimicry or some other mechanism.  The disease is perpetuated by an abnormal immune response to an autoantigen in the absence of ongoing infection. 12/2/2013Rheumatology Research Center RRC (RRClab)

Immunological findings  Patients with active Behcet’s disease had significantly higher CD4(‏+)CD25(‏+) T cells compared with patients in remission and healthy controls.  Immunohistochemical analysis of BD inflammatory lesions showed vascular infiltrate of neutrophils and mononuclear cells with high predominance of T (CD3+) lymphocytes (mostly CD4+ cells), and few B lymphocytes, NK and macrophages cells.  High proportion of cytotoxic CD8+CD56+ NKT cells and CD8+CD56- T cell in intraocular infiltration of BD 12/2/2013Rheumatology Research Center RRC (RRClab)

Immunological findings Accumulation of cytotoxic γδ T cells in inflammation sites of BD Th1 cells infiltrates, (TNFα, INFγ, IL-8, IL12 and Th1 derived chemokines receptor CCR5, CXCR3 and MCP-1) producing cells were reported in lesions Increased expression of CCL5, CCR5, and CXCR3 was found in oral aphthous ulcers of BD compared to recurrent aphthous syndrome and healthy controls. Expansion of IL17 and IL21 producing cells in CSF and neuro-BD lesions was also evidenced 12/2/2013Rheumatology Research Center RRC (RRClab)

Understanding immunopathogenesis is important for control of the disease problem. 12/2/2013Rheumatology Research Center RRC (RRClab)

PATHERGY TEST  Non-specific hyperreactivity of the skin following minor trauma, which is specific to Behcet’s disease.  Intradermal injection of the skin with a 20-gauge needle under sterile conditions.  It is considered positive if an erythematous sterile papule develops within 48 hours.. 12/2/2013Rheumatology Research Center RRC (RRClab)

GENETIC SUSCEPTIBLITY 12/2/2013Rheumatology Research Center RRC (RRClab)

MHC complex genes  HLA-B5 or B51 –HLA-B51 is the most significant marker of BD: Two alleles of HLA-51, HLA-B5101 and HLA  Others MHC complex genes: HLA-A26, MIC-A and MIC-B, TNFα. 12/2/2013Rheumatology Research Center RRC (RRClab)

Non MHC complex genes  IL10  IL23R (IL12R) 12/2/2013Rheumatology Research Center RRC (RRClab)

Trigger Hypotgesis  Hypothesis: Various infectious agents may trigger an immune response. Initiation of immunological mechanisms leading to the onset of the diseas.  Evidences:  Turkish individuals who have emigrated to Germany have a significantly lower risk of disease.  The higher incidence of BD in British people who traveled to countries with a high incidence of disease. 12/2/2013Rheumatology Research Center RRC (RRClab)

Bacterial Trigger  The high frequency of oral ulcer.  Increased rate of oral ulcers after dental interventions.  Decrease of some symptoms with penicillin or minocycline.  Increased proportion of Streptococcus sanguis in the oral flora of BD.  Significant antibody responses to these streptococci.  Patients show skin tests hypersensitivity with streptococcal antigens.  Various other bacterial species: Mycoplasma fermentans, H. pylori, Mycobacteria or Borrelia burgdorferi. 12/2/2013Rheumatology Research Center RRC (RRClab)

Viral Trigger  Herpes simplex virus (HSV)  HSV-1 genome and serum antibodies against the virus.  HSV DNA can be detected in the genital and oral ulcers of patients with BD.  Inoculation of HSV into mice cause dlesions mimicking BD.  The role of Parvovirus B19, hepatitis viruses was evaluated with conflicting results. 12/2/2013Rheumatology Research Center RRC (RRClab)

HSPs  High homology between human HSP60 and the corresponding bacterial HSP65.  Autoantibodies against HSP65 and HSP60 have been reported in BD patients.  Cross-reactivity -----> proliferation of autoreactive T cells  Antigenic homology between HSP60 and retinal antigen. 12/2/2013Rheumatology Research Center RRC (RRClab)

HSPs HSP60 as a ligand to Toll like receptor (TLR) 2 and 4 could stimulate innate immunity acting like a danger signal >  Pro-inflammatory cytokines (IL6, IL12, IL15 and TNFα)  Expression of cell adhesion molecules (ICAM, VCAM)  Development of a Th1 immune response 12/2/2013Rheumatology Research Center RRC (RRClab)

Role of Cytokines and T cell subsets  Proinlammatory cytokines  Th1 type cytokines  Th2 type cytokines  Th17 type cytokines  Chemokines  Some other cytokines 12/2/2013Rheumatology Research Center RRC (RRClab)

Proinlammatory cytokines  IL1 comprises IL1α, IL1β, and IL1R.  Asignificantly higher level of IL1β in synovial fluid of BD patients as compared to that in OA patients.  A most recent SNPs of IL1 are associated with the onset of BD.  TNFα in disease onset.  IL-6 is associated with disease activity, a role in nervouse system involvement 12/2/2013Rheumatology Research Center RRC (RRClab)

Helper T cells 12/2/2013Rheumatology Research Center RRC (RRClab)

Th1 type Cytokines IL12 in vicseral organ involvement IFNγ IL18 12/2/2013Rheumatology Research Center RRC (RRClab)

Th2 Type Cytokines IL-10 No trusting report concerning the other Th2 type cytokines including IL4, IL5, IL13 in BD is available 12/2/2013Rheumatology Research Center RRC (RRClab)

Th17 type cytokines  T helper 17 cells (T h 17) are a subset of T helper celss producing IL-1 discovered in  play a key role in Autoimmune diseases 12/2/2013Rheumatology Research Center RRC (RRClab)

Th17 type Cytokines  IL-17  IL-23  IL > differentiation of Th17.  IL23, together with IL6, TGFβ leads to the differentiation of Th0 to Th17 cells.  Th17 cells carry out the function of secreting IL17A, IL17F, TNFα, IL1 leading to proinflammatory reaction. 12/2/2013Rheumatology Research Center RRC (RRClab)

Cells of the immune system in the pathogenesis of BD  T cells----> Th1, Th17, γδ T, Tregs, NKT cells  Neutrophils  Antigen presenting cells 12/2/2013Rheumatology Research Center RRC (RRClab)

Neutrophils  Hyperactivity of the neutrophils is seen in BD  Increased chemotaxis, phagocytosis, superoxide generation and myeloperoxidase expression, expression of CD11a, CD10, and CD14 on the cell surface  Activated neutrophils in BD patients produce significant quantities of IL-12 and IL-18====> priming of the neutrophils themselves as well as polarization of the immune response toward Th1 12/2/2013Rheumatology Research Center RRC (RRClab)

APCs Some researchers suggested that BD might probably be a disease of APCs, and that T cells may be ‘‘innocent bystanders’’.  Langerhans cells  Monocytes  IL-12, IL-18 ===> Th1 polarization 12/2/2013Rheumatology Research Center RRC (RRClab)

T cells:  Th1 T cell subpopulation  Th17 T cell subpopulation  Regulatory T cells (Tregs)  γδ T cells,  CD56+ CD3+ NKT cells 12/2/2013Rheumatology Research Center RRC (RRClab)

γδ+T-cells  γδ T lymphocytes play amajor role in mucosal immunity  γδ T cells are a strong Th1 and Th17 inducers in experimental models 12/2/2013Rheumatology Research Center RRC (RRClab)

γδ+T-cells  Increased proportion of activated γδ+T-cells was found in the circulation and mucosal lesions and was associated with disease activity.  Accumulation of γδ T cells in the sites of inflammation in BD has been reported  Polyclonal rather than oligoclonal expansion of γδ T cells  Role of Infliximab 12/2/2013Rheumatology Research Center RRC (RRClab)

NKT-cells 12/2/2013Rheumatology Research Center RRC (RRClab)

Tregs 12/2/2013Rheumatology Research Center RRC (RRClab)

Possible role of Th22 12/2/2013Rheumatology Research Center RRC (RRClab)

12/2/2013Rheumatology Research Center RRC (RRClab)

12/2/2013Rheumatology Research Center RRC (RRClab)