Th1 polarization of the immune response in Beh�et's disease: A putative pathogenetic role of interleukin-12

Frassanito, Maria Antonia; Dammacco, Rosanna; Cafforio, Paola; Dammacco, Franco

doi:10.1002/1529-0131(199909)42:9<1967::aid-anr24>3.0.co;2-z

Cited by 205 publications

(115 citation statements)

References 47 publications

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“…The precise mechanisms of tissue destruction in BD have not been fully elucidated. Nevertheless, a growing number of reports have implicated T lymphocyte-mediated immune responses in the disease process (2)(3)(4)(5)(6).…”

Section: B Ehçet's Disease (Bd)mentioning

confidence: 99%

Characterization of the Divergent Wound-Healing Responses Occurring in the Pathergy Reaction and Normal Healthy Volunteers

Melikoğlu

Uysal

Krueger³

et al. 2006

The Journal of Immunology

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Behçet’s disease (BD) is a multisystem inflammatory disorder of unknown etiology characterized by recurrent oral and genital ulcerations and uveitis, with varying other manifestations associated with vascular inflammation. A unifying feature of BD inflammation is the skin pathergy reaction (SPR), a nonspecific tissue hyperreactivity to minor trauma involving epithelial disruption. This study compared skin responses to needle prick in BD patients and normal healthy volunteers. Two study groups, each consisting of 10 BD patients with SPR+ and 6 controls, were evaluated using either immunohistochemistry or quantitative real-time PCR to measure inflammatory cell and cytokine levels in biopsy specimens obtained serially from independent sites at 0, 8, and 48 h after needle prick. We found similar cellular infiltration patterns in response to needle prick in BD patients and controls between 0 and 8 h. Further development of this immune response was limited in skin of normal control subjects, with stable or decreased inflammatory mediators observed at 48 h. In contrast, in BD-derived skin specimens, increased influxes of mature dendritic cells, monocytes, and lymphocytes, including T regulatory cells, were noted by 48 h. Similarly, increases in cytokines (IFN-γ, IL-12 p40, IL-15), chemokines (MIP3-α, IP-10, Mig, and iTac), and adhesion molecules (ICAM-1, VCAM-1) were noted at 48 h in the skin of BD patients with SPR+ but not in the skin of normal controls. These results suggest that, in contrast to the self-limited inflammation associated with epithelial disruption of normal skin, BD patients experience marked cellular influxes into the injury site, leading to an exaggerated lymphoid Th1-type response.

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Section: B Ehçet's Disease (Bd)mentioning

confidence: 99%

Characterization of the Divergent Wound-Healing Responses Occurring in the Pathergy Reaction and Normal Healthy Volunteers

Melikoğlu

Uysal

Krueger³

et al. 2006

The Journal of Immunology

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“…Several humoral and cellular abnormalities have been described, such as the high serum levels of IL-2, IFN-, TNF- [8][9][10]. These cytokines detected in patients with active disease point to a polarized Th1 immune response, as suggested by in vitro and in vivo studies of experimental autoimmune uveoretinitis [11].…”

Section: Introductionmentioning

confidence: 99%

One year study of efficacy and safety of infliximab in the treatment of patients with ocular and neurological Behçet’s disease refractory to standard immunosuppressive drugs

Giardina

Ferrante²,

Ciccia³

et al. 2009

Rheumatol Int

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The aim of the study was to assess the long-term eYcacy and safety of InXiximab therapy in the treatment of patients with Behçet's disease refractory to standard immunosuppressive agents. Twenty-one patients that did not respond to corticosteroids and to at least one immunosuppressant (cyclosporin, methotrexate, azathioprine, cyclophosphamide) for the presence of ocular and/or CNS involvement were enrolled. Eighteen patients completed the study up to 54 weeks. Stable doses of prednisone (<10 mg/day) were permitted, immunosuppressants were discontinued at least 4 weeks prior baseline visit. The patients received three infusions of 5 mg/kg InXiximab (at weeks 0, 2 and 6) and then infusions of 5 mg/kg InXiximab every 8 weeks. At each visit data on clinical symptoms, response to therapy and adverse events were collected. The primary outcome of interest was to assess the clinical eYcacy (total or partial recovery) of inXiximab. Secondary end points were to evaluate quality of life and to monitor the safety of the drug. Eighteen patients achieved a total remission. Two patients achieved a partial remission and relapsed after 3 months from discontinuation of therapy. InXiximab was well tolerated throughout the study. A case of non-Hodgkin lymphoma was observed within 6 months.Minor side eVects were headache, dizziness, tachycardia that regressed spontaneously and did not entail interruption. Anti-nuclear antibodies were not detected during the period of observation.

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“…However, the immunomodulatory and antiinflammatory properties of this drug have been reported. IL-12 was demonstrated to be implicated in the pathogenesis of BD (6), preventing spontaneous and CD95-induced cell death in the peripheral blood leukocytes of patients with BD (8). Because IL-12 production in lipopolysaccharide-stimulated human monocytic cells is directly regulated by JNK, activator protein 1, and NF-B transcription factors (56), it is possible that thalidomide may also effectively decrease the production of IL-12 in patients with BD.…”

Section: Discussionmentioning

confidence: 99%

“…IL-12 prevents spontaneous and CD95-induced cell death, resulting in abnormal growth of autoreactive Th1 lymphocytes, which could be responsible for the prolonged state of inflammation observed in patients with BD (8).…”

mentioning

confidence: 99%

NF‐κB protects Behçet's disease T cells against CD95‐induced apoptosis up‐regulating antiapoptotic proteins

Todaro¹,

Zerilli²,

Triolo³

et al. 2005

Arthritis & Rheumatism

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Objective. To determine whether prolongation of the inflammatory reaction in patients with Behçet's disease (BD) is related to apoptosis resistance and is associated with the up-regulation of antiapoptotic factors.Methods. The percentage of cell death was evaluated by flow cytometry in peripheral blood mononuclear cells from 35 patients with BD and 30 healthy volunteers. The expression levels of antiapoptotic factors and NF-B regulatory proteins were measured using Western blotting and immunohistochemical analyses. To down-regulate NF-B nuclear translocation, BD T lymphocytes were exposed in vitro to thalidomide and subjected to transfection with NF-B small interfering RNA.Results. Although CD95 is highly expressed in BD T cells, the absence of sensitivity to CD95-induced apoptosis observed may be attributable to the inhibitory action of antiapoptotic genes. Immunoblot analysis for major antiapoptotic proteins showed considerable upregulation of the short form of cellular FLIP ( Conclusion. Taken together, these results indicate that NF-B contributes to the regulation of the apoptosis-related factors and death receptors leading to apoptosis resistance in BD T cell subsets. Our results suggest that NF-B plays a crucial role in the pathogenesis of BD, and that its pharmacologic control could represent a key strategy in modulating specific immunemediated disease.

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Th1 polarization of the immune response in Beh�et's disease: A putative pathogenetic role of interleukin-12

Cited by 205 publications

References 47 publications

Characterization of the Divergent Wound-Healing Responses Occurring in the Pathergy Reaction and Normal Healthy Volunteers

Characterization of the Divergent Wound-Healing Responses Occurring in the Pathergy Reaction and Normal Healthy Volunteers

One year study of efficacy and safety of infliximab in the treatment of patients with ocular and neurological Behçet’s disease refractory to standard immunosuppressive drugs

NF‐κB protects Behçet's disease T cells against CD95‐induced apoptosis up‐regulating antiapoptotic proteins

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