Dendritic cells from spondylarthritis‐prone HLA–B27–transgenic rats display altered cytoskeletal dynamics, class II major histocompatibility complex expression, and viability

Abstract

Objective. Spondylarthritis (SpA) is characterized by spinal and peripheral joint inflammation, frequently combined with extraarticular manifestations. Despite the well-established association of SpA with the class I major histocompatibility complex (MHC) allele HLA-B27, there are still different, parallel hypotheses on the relationship between HLA-B27 and disease mechanisms. The present study was undertaken to investigate several characteristics of mature dendritic cells (DCs), which are believed to be essential for triggering disease in a model of SpA in HLA-B27-transgenic rats.Methods. We combined different whole-proteome approaches (2-dimensional polyacrylamide gel electrophoresis and iTRAQ) to define the most aberrant molecular processes occurring in spleen DCs. Videomicroscopy and flow cytometry were used to confirm both cytoskeletal and class II MHC expression deficiencies.Results. Our proteome studies provided evidence of up-regulation of proteins involved in class I MHC loading, and unfolded protein response, along with a striking down-regulation of several cytoskeletonreorganizing proteins. The latter result was corroborated by findings of deficient motility, altered morphology, and decreased immunologic synapse formation. Furthermore, class II MHC surface expression was reduced in DCs from B27-transgenic rats, and this could be linked to differences in class II MHC-induced apoptotic sensitivity. Finally, we found reduced viability of the CD103؉CD4؊ DC subpopulation, which likely exerts tolerogenic function.Conclusion. Taken together, our findings have different important implications regarding the physiology of B27-transgenic rat DCs, which have a putative role in spontaneous disease in these rats. In particular, the reduced motility and viability of putatively tolerogenic CD4؉ DCs could play an important role in initiating the inflammatory process, resulting in SpA.The class I major histocompatibility complex (MHC) allele HLA-B27 confers susceptibility to spondylarthritis (SpA) (1,2). Different hypotheses on the role of this allele in disease mechanism exist in parallel. Classic hypotheses refer to aberrant recognition of putative arthritogenic peptide by CD8ϩ T cells, whereas the more recent hypotheses involve speculation on the slow folding of the HLA-B27 heavy chain during its synthesis in the endoplasmic reticulum (ER), which may be responsible for an unfolded protein response (UPR),

Phenotype of Resting and Activated Monocyte-Derived Dendritic Cells Grown from Peripheral Blood of Patients with Ankylosing Spondylitis

“…Recent research on HLA-B27 transgenic rats has pointed to the functional impairment of DCs in this model of AS and questioned the contribution of this dysfunction to the mechanisms of spondyloarthritis-like disease development in these animals [5,6]. In these experiments, DCs demonstrated both impaired immunologic synapse formation by interfering with the engagement of co-stimulatory molecules and altered class II MHC expression.…”

“…In these experiments, DCs demonstrated both impaired immunologic synapse formation by interfering with the engagement of co-stimulatory molecules and altered class II MHC expression. The mechanisms of dependence of these effects on the HLA-B27 positivity are still unknown, but down-regulation of several cytoskeletonreorganizing proteins, which was also demonstrated, may be responsible or, at least contribute, to the lower class II MHC surface expression by DCs in HLA-B27 transgenic animals [6].…”

“…The other, non antigen presenting functions of HLA-B27 and their potential impact on the development of AS are now under investigation [2]. A collection of findings such as: disease dependence on the presence of the commensal bacteria [3]; the leading role of CD4 cells in the adoptive transfer studies in HLA B27 transgenic rats [4]; as well as the recent data on defective co-stimulation and decreased expression of class II major histocompatibility complex (MHC) expression by dendritic cells (DCs) from the same animal model [5,6] indicate that dysfunction of antigen presenting cells may be involved in the early stages of the pathogenesis of AS.…”

Essential role for CD103+ cells in the pathogenesis of spondyloarthritides

“…A characteristic of the HLA-B27 rat model is a deficient function of these dendritic cells (including the CD103+ cells). Dendritic cells exhibit decreased vitality and mobility in this model, with loss of their ability to migrate toward the lymph nodes [6] and to induce naive T cell differentiation toward the Treg pathway [7,8]. This fact contributes to orient the T cell response toward the Th17 profile [9].…”

Dendritic cells and regulatory T cells in spondyloarthritis

“…For example, splenic dendritic cells from B27-TG rats exhibit a reduced capability to induce proliferation of allogeneic T cells [58], perhaps because they form fewer and shorter-lasting conjugates with T cells [59]. HLA-B27 þ dendritic cells also have deficient cytoskeletal dynamics, reducing their mobility, affecting their interactions with T cells, decreasing expression of MHC class II, and increasing their death by apoptosis [60]. Furthermore, HLA-B27 þ dendritic cells may contribute to inflammation in B27-TG rats by promoting a pathogenic Th17 response [61]; splenic dendritic cells from B27-TG animals induce more IL-17-producing T cells than their wild-type counterparts [31].…”