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

Abstract

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.

The exaggerated inflammatory response in Behçet's syndrome: identification of dysfunctional post-transcriptional regulation of the IFN-γ/CXCL10 IP-10 pathway

“…The IFN-g-CXCL10 pathway is of interest to us, as IFN-g appears to be an important cytokine in BS and CXCL10 has been found in excess in uveitis, CSF and histological samples of BS [10][11][12][13][14][15]. We found increased CXCL10 protein expression by IFN-g-stimulated monocytes in repeated experiments comparing BS and HC.…”

“…CXCR3 receptors (the receptors for CXCL9/10/11) have been shown to be highly expressed in BS biopsies of oral ulcers [13]. Moreover, the pathology of pathergy reactions shows increased mRNA transcripts for CXCR3, CXCL10 and CXCL11 [14,15]. Given the probable importance of CXCL10 in BS, this project investigated the generation of CXCL10 in response to IFN-g in CD14…”

Th17 Trafficking Cells in Behcet's Disease Skin Lesions

“…CD3 + IL-17 + T cells (Th17) are postulated to play a role in inflammatory/autoimmune pathogenesis [Wilson et al, 2007;Zaba et al, 2007;Murphy et al, 2003;Aggarwal et al, 2003]. Recent data from Melikoglu et al [Melikoglu et al, 2006] reported increased cytokines (IFN-, IL-12 p40, IL-15), chemokines (MIP3-, IP-10, Mig, and iTac), and adhesion molecules (ICAM-1, VCAM-1) in the skin of BD patients with SPR + but not in the skin of normal controls. These results suggested that BD patients experience marked cellular influx into the injury site, leading to an exaggerated lymphoid Th1-type response.…”

“…Regarding the contribution of epidermal CD8 + IL-17 + cells to the pathogenesis of BD skin lesions, we have proved that CD4 + IL-17 + and CD8 + IL-17 + proliferate and secrete cytokines efficiently in response to CD3/TCR-mediated stimulation and to certain mediators. In Behcet's disease, high mRNA levels of IL-8, IFN-, IL-12, IL-10, and MCP-1were found in lesional skin and pathergy sites [Melikoglu et al, 2006]. CD4 + CD25 + regulatory T (Treg) cells were found increased in the peripheral circulation of BD patients [Hamzaoui, 2007].…”

“…We studied skin lesions from BD patients. Previous studies implicated Th1 cells promoting cytokine in skin lesions from BD patients [Melikoglu et al, 2006]. In the current investigation, we explored the phenotype and function of IL-17 -secreting T cells in BD and healthy skin, and the factors supporting their trafficking to and induction in lesional skin.…”