Ann Rheum Dis 66(6): 720-726

PMC: PMC1954653

PMID: 17223654

Ectopic lymphoid neogenesis in psoriatic arthritis

Beatriz Gil‐Torregrosa

Dominique Baeten

José Pablos

Begoña Santiago, José L Pablos, Servicio de Reumatología, Unidad de Investigación, Hospital 12 de Octubre, Madrid, Spain

Tineke Cantaert, Dominique Baeten, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands

Antonio Palacin, Servei de Anatomía Patológica, CDB, Hospital Clínic de Barcelona, Barcelona, Spain

Correspondence to: Dr J L Pablos
Servicio de Reumatología, Hospital 12 de Octubre, 28041 Madrid, Spain; jlpablos@h12o.es

Juan D Cañete, Raimon Sanmartí, Raquel Celis, Eduard Graell, Beatriz Gil‐Torregrosa, Unitat d'Artritis, Servei de Reumatología, Hospital Clínic de Barcelona and IDIBAPS, Barcelona, SpainBegoña Santiago, José L Pablos, Servicio de Reumatología, Unidad de Investigación, Hospital 12 de Octubre, Madrid, SpainTineke Cantaert, Dominique Baeten, Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, Amsterdam, The NetherlandsAntonio Palacin, Servei de Anatomía Patológica, CDB, Hospital Clínic de Barcelona, Barcelona, SpainCorrespondence to: Dr J L Pablos
Servicio de Reumatología, Hospital 12 de Octubre, 28041 Madrid, Spain; jlpablos@h12o.es

Accepted 2006 Dec 2.

Abstract

Background

Ectopic lymphoid neogenesis (LN) occurs in rheumatoid synovium, where it is thought to drive local antigen‐dependent B cell development and autoantibody production. This process involves the expression of specific homing chemokines and the development of high endothelial venules (HEV).

Objective

To investigate whether these mechanisms occur in psoriatic arthritis (PsA) synovium, where autoantibodies have not been described and the organisation and function of B cells is not clear, and to analyse their clinical correlates.

Methods

Arthroscopic synovial biopsy specimens from patients with PsA before and after tumour necrosis factor α blockade were characterised by immunohistochemical analysis for T/B cell segregation, peripheral lymph node addressin (PNAd)‐positive HEV, and the expression of CXCL13, CCL21 and CXCL12 chemokines in relation to the size of lymphoid aggregates.

Results

Lymphoid aggregates of variable sizes were observed in 25 of 27 PsA synovial tissues. T/B cell segregation was often observed, and was correlated with the size of lymphoid aggregates. A close relationship between the presence of large and highly organised aggregates, the development of PNAd+ HEV, and the expression of CXCL13 and CCL21 was found. Large organised aggregates with all LN features were found in 13 of 27 tissues. LN in PsA synovitis was not related to the duration, pattern or severity of the disease. The synovial LN pattern remained stable over time in persistent synovitis, but a complete response to treatment was associated with a regression of the LN features.

Conclusions

LN occurs frequently in inflamed PsA synovial tissues. Highly organised follicles display the characteristic features of PNAd+ HEV and CXCL13 and CCL21 expression, demonstrating that the microanatomical bases for germinal centre formation are present in PsA. The regression of LN on effective treatment indicates that the pathogenic and clinical relevance of these structures in PsA merits further investigation.

Abstract

Psoriatic arthritis (PsA) is a chronic inflammatory joint disease associated with skin psoriasis. It is usually included within the spondyloarthritis group of inflammatory joint diseases, with which it shares several phenotypic features.¹ However, although the peripheral joint involvement often displays a different distribution, the clinical and pathogenic features of PsA partially overlap those of rheumatoid arthritis (RA), and both diseases can lead to significant bone and cartilage destruction.²

Histopathological analyses of RA and PsA synovial tissues point to differential features that can be of potential value in the diagnostic classification of patients with undifferentiated arthritis, although the fundamental features are similar.³⁴⁵ Neovascularisation, infiltration by mononuclear cells (T and B lymphocytes, plasma cells and macrophages) and synovial lining hyperplasia are observed in both conditions. B cells and plasma cells are important components of inflammatory infiltrates in both diseases, and follicular aggregates of lymphocytes resembling lymphoid follicles have been well characterised in RA but only occasionally described in PsA.⁶⁷⁸⁹¹⁰¹¹

In RA, several studies have confirmed the presence of competent germinal centres (GCs) both at the structural and at the molecular level.⁶⁷⁸⁹¹² This process of organisation of T and B cells is called ectopic LN, and it is associated with the development of high endothelial venules (HEV) and the ectopic expression of a restricted set of homing chemokines, physiologically involved in the traffic and tissue compartmentalisation of T and B cells in secondary lymphoid organs.⁶⁸ The role of these factors in ectopic LN has been shown in relevant murine transgenic models. In such models, the process can be driven by enforced ectopic expression of lymphotoxin (LT)‐αβ or that of the homing chemokines CXCL13, CCL21 or CXCL12.¹³¹⁴¹⁵ Tumour necrosis factor (TNF) α, and particularly, lymphotoxin (LT)‐αβ play a potential role in the development of the HEV phenotype and the expression of homing chemokines, and in RA they seem to contribute to LN.⁶¹⁶¹⁷ The expression of TNFα and LTβ has also been demonstrated in PsA, but LN and GC formation has not been studied in PsA synovium.¹⁸¹⁹

On the basis of structural and molecular similarities between genuine GC in lymphoid tissues and LN in RA synovitis, it has been suggested that these structures may play a role in local antigen‐driven B cell development and autoantibody responses. They may also contribute to other processes such as antigen presentation and costimulation of T cells, and synthesis of soluble mediators, which could collectively explain the therapeutic efficacy of B cell depletion.²⁰ In PsA, clonal expansion of synovial B and T cells supporting a local antigen‐driven process has also been suggested but, in contrast with RA, the lack of detectable autoantibodies makes the role of B cells uncertain.²¹²²

We have searched for the presence of ectopic LN in PsA synovial tissues and its relationship to the expression of homing chemokines and the development of PNAd+ HEV. Our data demonstrate that a significant proportion of patients with PsA contain large and well‐organised T/B cell aggregates and that this phenomenon is closely related to the development of PNAd+ HEV and the expression of homing chemokines CXCL13 and CCL21. These features do not seem to indicate a particular clinical subset, but can disappear after full remission of the disease.

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Acknowledgements

JDC was supported by research grants from Fondo de investigación sanitaria (FIS 04/1023 and 1027, and FIS 05/0913), by a research award from the IDIBAPS and by a grant from Wyeth. JLP was supported by FIS 05/0060 and by a grant from Schering Plough, SA, TC and DB were supported by the European Community's FP6 funding. This publication reflects only the author's views. The European Community is not liable for any use that may be made of the information herein. We thank Dr Arenzana‐Seisdedos for kindly providing K15C the anti‐CXCL12 mAb.

Acknowledgements

Abbreviations

CCP - cyclic citrullinated peptide

CRP - C reactive protein

DAS - Disease Activity Score

ESR - erythrocyte sedimentation rate

GC - germinal centres

HEV - high endothelial venule

LN - lymphoid neogenesis

LT - lymphotoxin

PNAd - peripheral lymph node addressin

PsA - psoriatic arthritis

RA - rheumatoid arthritis

RF - rheumatoid factor

TNF - tumour necrosis factor

Abbreviations

Footnotes

Competing interests: None.

Supplementary table is available online at http://ard.bmj.com/supplemental

Footnotes

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