Skewed Helper T-Cell Responses to IL-12 Family Cytokines Produced by Antigen-Presenting Cells and the Genetic Background in Behcet's Disease

Abstract

Behcet's disease (BD) is a multisystemic inflammatory disease and is characterized by recurrent attacks on eyes, brain, skin, and gut. There is evidence that skewed T-cell responses contributed to its pathophysiology in patients with BD. Recently, we found that Th17 cells, a new helper T (Th) cell subset, were increased in patients with BD, and both Th type 1 (Th1) and Th17 cell differentiation signaling pathways were overactivated. Several researches revealed that genetic polymorphisms in Th1/Th17 cell differentiation signaling pathways were associated with the onset of BD. Here, we summarize current findings on the Th cell subsets, their contribution to the pathogenesis of BD and the genetic backgrounds, especially in view of IL-12 family cytokine production and pattern recognition receptors of macrophages/monocytes.

Figure 1

Current view of helper T (Th) cell subsets in humans [12]. Naïve Th cells differentiate into several Th cell subsets in the presence of appropriate cytokines. In response to the cytokines, the corresponding signaling molecules and transcription factors are expressed to regulate lineage commitments. Th1 and Th17 cells require IL-12 and IL-23 for their expansion, respectively. TGFβ: transforming growth factor β, STAT: signal transducer and activator of transcription 3, GATA: GATA transcription factor, RORC: retinoic-acid-receptor-related orphan receptor c, and Foxp3: forkhead box P3.

Figure 2

A schematic representation of IL-12 family cytokines and the corresponding receptors and JAK-STAT signaling pathways [16]. IL-12, IL-23, IL-27, and IL-35 are heterodimeric and share the subunits. The 4 cytokines require each corresponding receptor which also shares components for the function. It is thought that the 4 cytokines have overlapping but distinct effect on T cells with corresponding Janus kinase (JAK)-STAT signaling pathway. The experimental data demonstrated a functional spectrum from proinflammatory to inhibitory in Th cell differentiation. IL-12 and IL-23 are produced by activated dendritic cells and macrophages and induce inflammation through Th1 and Th17 differentiation, respectively. IL-27 is secreted from antigen-presenting cells and produces IL-10 secreting Th cells. IL-35 is mainly produced by Treg cells, amplifies IL-35 producing Th cells, and induces T-cell arrest.

Figure 3

Th17 and Th1 cell differentiations and the phenotype plasticity [24, 25]. Th17 cell phenotype is not fixed in vitro and in vivo and Th17 cells can turn into IFNγ-expressing Th17 cells and subsequently into nonstandard Th1 cells. These two types of cells are thought to be more pathogenic and have higher affinity for inflammatory lesions than original Th17 cells.

Figure 4

Immunofluorescence of Th1, Th17, and IFNγ-expressing Th17 cells in a BD skin lesion. (a) Th1 cell, (b) Th17 cell, and (c) IFNγ-expressing Th17 cell were simultaneously observed in one skin specimen obtained from erythema-nodosum-like lesion of BD.

Figure 5

Two major TLR signaling pathways [48]. With TLR stimulation, except TLR3, APC produced proinflammatory cytokines through MyD88 and activated mitogen-activated protein kinases (MAPK). APC produced type 1 IFN by utilizing of TRIF through TLR3 stimulation, an intracellular TLR. TIRAP: Toll/interleukin 1 receptor (TIR) domain containing adaptor protein, MyD88: myeloid differentiation primary response protein 88, TRIF: TIR domain-containing adaptor-inducing IFNβ, MAPK: mitogen-activated protein kinases, and IFN: interferon.

Figure 6

IL-12-family-cytokine-related genetic polymorphisms were found to be associated with several human immune diseases [44]. Th17/Th1 cluster was related to the polymorphisms of IL-23R and IL-12B and affiliated with inflammatory bowel diseases, psoriasis, ankylosing spondylitis, and rheumatoid arthritis. Th1/IL-35 cluster was related to the polymorphisms of IL-12A and IL-12Rβ2, and affiliated with primary biliary cirrhosis and Graves's disease. Several studies suggest that celiac disease and multiple sclerosis show both clusters' polymorphisms. Several Genome-Wide Association Studies identified IL-23R-IL12RB2, STAT4, and IL-17A as BD susceptibility genes and indicated a possibility that BD was including in Th17/Th1 cluster.