Pathophysiology of the Behçet's Disease

Table 1

Key stress protagonists in the BD.

Stress mediators, hormones, and cells	Main biological effect	In BD
Hormones of the HPA axis (CRH, ACTH, glucocorticoids)	Activate mast cells Upregulate production of IL-4, IL-6, IL-10, and IL-13 Inhibit the production of IL-12, IFN-γ, and TNF-α by antigen-presenting cells and T-helper 1 cells	Partial HPA axis dysfunction [10].
Prolactin	Participates in early and late T-cell activating events; contributes to a proinflammatory and apoptosis-prone environment	Increased, decreased, or normal [26–29].
Sex hormones	Immune modulation, affect HPA axis	Activation of neutrophils by testosterone, lower levels of DHEA-S (ocular BD), increased 17-OH-progesteron, testosterone, estradiol, FSH, LH, T3, T4, and normal TSH levels and androgen receptor density in scrotal skin, increased 21-hydroxylase gene mutations [30–32].
Substance P	Induces inflammation Induces lymphocyte proliferation Activates mast cells	Higher levels in active BD, strong immunoreactivity of SP in vasculitic skin lesions [39, 45].
CGRP	Inhibits proliferation and IL-2 release of T lymphocytes under immune challengesActivates mast cells, induces vascular permeability	Increased or decreased levels in BD [45, 52].
NGF, NEP, neuropeptide degrading enzyme	Promotes “crosstalk” between neuronal and immune cellsActs as autocrine and paracrine factor in the development and regulation of immune cellsPromotes monocyte and macrophage migration through vascular endotheliumActivates mast cells	Strong immunoreactivity in vasculitic skin lesions, Decreased NGF levels in inactive BD (Ocular-BD) [39, 52].
Natriuretic peptides	Endocrine-paracrine influence over many vascular parameters including fluid and electrolyte balance, vasodilatation, smooth muscle proliferation, and the reactivity of immune cells.	Lower ANP concentrations in active BD, higher serum BNP levels in BD, decreased CNP levels in active BD [56].
Heat shock proteins	Activates CD4 and γδ-T lymphocytes	Antibodies against bacterial or human HSP-60/65 are capable of cross-reacting with retinal antigensExposure to HSPs results in the proliferation of peripheral T lymphocytes of ocular BD patients Lesional skin of BD contains increased numbers of both HSP-60 and TCR γδ-T lymphocytesγδ-T lymphocyte is present in tissue specimens, whereas HSP-65 expression is abundantly upregulated in epidermal regions of active skin lesions Elevated HSPs upregulate the expression of the MICA locus in BD patients [68, 69].
Oxidative stress	Activate neutrophil function, chemotaxis, and phagocytosis	Excessive superoxide anion production, raised ADA activity, hydrogen peroxide-induced hydroxyl radical, and malondialdehyde productions [71, 75]
Antioxidative defense	Free radical scavenging	Decreased superoxide dismutase, glutathione peroxidase, and catalase levels [71].
Trace elements and vitamins	Cofactors to antioxidant enzymesNonenzymatic antioxidants	Decreased erythrocyte selenium, plasma iron, manganese, and zinc levels, increased plasma copper, erythrocyte zinc, and manganese levels, lower plasma concentrations of vitamins A, C, E, and β-carotene [77, 78].
Neutrophils, monocytes, and complements	Produce a number of proinflammatory cytokines, chemotaxis, active oxygen production, and phagocytosisInnate immune system activation	Hyperfunctions of neutrophils, leukocyte adhesion molecules including P and L selectins, Mac-1 and CD4 expression on peripheral leukocytes, increased plasma myeloperoxidase activity, elevated peripheral white blood cell count, activated monocytes, increased neutrophil motility, and circulating proteins including C3, C4, C5 [79].
Nitric oxide	Free oxygen radical	Decreased serum nitrite and nitrate concentrations, and Glu-Asp298 polymorphisms of endothelial NO synthase gene, increased NO concentration [85–90].
Psychological factors	Regulate the immune system at regional, local, and systemic levels	More depression and anxiety scores, affected quality of life [85–88].