Elsevier

Human Immunology

Volume 60, Issue 6, June 1999, Pages 479-491
Human Immunology

Original Articles
Clonal characteristics of T cell infiltrates in skin and synovium of patients with psoriatic arthritis1

https://doi.org/10.1016/S0198-8859(99)00034-8Get rights and content

Abstract

Psoriasis is a chronic inflammatory skin disease that is often complicated by an inflammatory arthritis. Considerable evidence implicates cellular immune responses in psoriatic skin lesions, but the pathogenesis of the associated arthritis has not been elucidated. We analyzed T cell antigen receptor beta chain variable (TCRβV) gene repertoires among peripheral blood lymphocytes, skin and synovium of nine patients with psoriatic arthritis. RNase protection assays were used to quantitate the expression levels of 25 TCRβV genes, and CDR3 region sequencing was used to further characterize selected expansions. All patients exhibited significant TCRβV biases in the peripheral blood and moreover, all had expansions common to both skin and synovium. CDR3 sequencing demonstrated these expansions frequently consisted of oligo- or monoclonal populations. Although no ubiquitous CDR3 nucleotide sequences were identified, two patients shared identical sequences and several highly homologous amino acid motifs were present in skin and synovium among and between individual patients. Findings of common TCRβV expansions in diverse inflammatory sites, among multiple afflicted individuals, suggest that these T cell proliferations are driven by engagements with a limited set of conventional antigens. These findings demonstrate an important role for cognate T cell responses in the pathogenesis of psoriatic arthritis, and further suggest the inciting antigen(s) is identical or homologous between afflicted skin and synovium.

Introduction

Psoriasis is a complex inflammatory skin disorder with a prevalence of approximately 2% in Caucasians [1]. Arthropathies with protean manifestations, ranging from asymmetrical mono- or oligoarthritis to symmetric polyarthritis resembling rheumatoid arthritis, occur in 5–15% of the patients afflicted with characteristic psoriatic skin lesions [2]. Spinal and sacroiliac disease, a feature of the seronegative spondyloarthropathies (reactive arthritis and ankylosing spondylitis), can also occur but usually are found in combination with peripheral arthritis. Rheumatoid factor is typically absent in patients with psoriatic arthritis. Furthermore, epidemiologic, genetic, clinical and radiographic studies suggest that psoriatic arthritis is distinct from other inflammatory arthritides [2].

The histopathologic changes in psoriatic skin are remarkably similar to those observed in the synovium and entheses with hyperproliferation of epithelial cells (keratinocytes and synovial cells), accumulation of inflammatory cells (T cells, monocytes B cells and neutrophils) and elongation and increased tortuosity of blood vessels [3]. Streptococcal superantigens (SAg) have been implicated in the pathogenesis of the guttate form of psoriasis [4], although direct evidence supporting this causality is somewhat more tenuous, particularly in studies of patients with psoriasis vulgaris 5, 6.

Compelling data suggest that T cells play a pathogenic role in the skin manifestations of this disease 1, 2, 6, 7. Infiltration of activated T cells precedes the eruption of psoriatic skin lesions [8], and exacerbations of the disease can be triggered by systemic administration of IL-2 [9], IFN-γ [10] or IFN-α [11]. Keratinocyte proliferation, the sine qua non of psoriasis, can be induced in vitro by T cell clones isolated from skin lesions [12]. The response of lesions to immunosuppressive therapies, including mAb CD4 13, 14, lymphocyte selective toxin composed of IL-2 and fragments of diphtheria toxin (DAB389IL-2) [15] and cyclosporine A [16], further demonstrate the importance of activated T cells in this disorder. In addition, orthotopic human skin grafts in SCID mouse undergo development [17] or persistence [18] of psoriatic lesions after injection of autologous immunocytes from afflicted patients.

In contrast to skin lesions of psoriasis, the role of T cells in the pathogenesis of the associated arthritis is less clearly established and, to our knowledge, there has not previously been a detailed molecular characterization of synovial lesions. In general, analyses of T cell receptor repertoires and clonal characteristics have proven to be useful for evaluating the dynamics and specificity of immune responses 19, 20. In particular, evidence of restricted T cell expansions occurring at sites of inflammation, especially if oligoclonal, delineate cognate immune responses that are directed against conventional antigenic epitopes, and these findings have important implications for understanding disease pathogenesis and eventual development of specific treatments.

Accordingly, we analyzed T cell antigen receptor beta chain variable gene (TCRβV) repertoires of peripheral blood lymphocytes (PBL), skin and synovial membrane of nine patients with psoriatic arthritis. Common TCRβV gene expansions were found in the skin and synovium of the patients, and these biases were demonstrated to be composed in large part by oligoclonal or monoclonal proliferations. In addition, identical or highly homologous CDR3 peptide sequences were found among inflammatory loci of individual patients, as well as between individuals with shared MHC. These findings suggest that the T cell accumulations in synovium and skin of patients with psoriatic arthritis are strongly focused by a relatively limited number of common immunodominant epitopes.

Section snippets

Patients and tissue samples

Peripheral blood, skin and synovial biopsies were obtained from nine patients with psoriatic arthritis. Informed consent was obtained in a protocol approved by the NIDDK/NIAMS Institutional Review Board. The diagnosis of psoriatic arthritis was based on the following criteria: (a) presence of typical psoriatic rash; (b) inflammatory arthritis involving peripheral joints (with or without axial involvement); and (c) negative test for rheumatoid factor in the serum. Glucocorticoids and

Patients

Nine patients with mild to moderate skin involvement (lesions over less than 30% of body surface area), and moderate to severe arthritis were studied (Table 1). All patients examined had one or more HLA alleles known to be associated with psoriasis (e.g., HLA-A2, B13, B27, Bw57, Cw2, Cw6, and DR7) [24] (Table 2). None of the patients had the shared epitope alleles (DRB1∗0101,∗0404,∗0405, and ∗1402) that have been associated with rheumatoid arthritis [25].

Peripheral blood

In general, TCRβV profiles of PBLs

Discussion

These data implicate an important role for T cell responses in the etiopathogenesis of psoriatic arthritis. By the use of stringent criteria (>3 SD from normal values), the TCRβV repertoires among PBL of the psoriatic arthritis patients here were markedly biased relative to normal controls, a finding qualitatively similar to those in diverse populations with chronic exposures to other potent conventional antigens 23, 26. These findings per se are novel in that previous assays of PBL repertoires

Acknowledgements

We would like to thank Dr. J. Davis and Mrs. C. Yarboro, R.N. for their help with the evaluation and biopsy of patients, and Drs. J. H. Klippel, P. H. Plotz, and R. L. Wilder for critical review of the manuscript.

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    These authors contributed equally to this paper.

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