Clonal expansions in selected TCR BV families of rheumatoid arthritis patients are reduced by treatment with the TNF[alpha] inhibitors etanercept and infliximab

Rheumatol Int (2011) 31:10231029 DOI 10.1007/s00296-010-1402-9

ORIGINAL ARTICLE

Clonal expansions in selected TCR BV families of rheumatoid arthritis patients are reduced by treatment with the TNFa inhibitors etanercept and iniximab

Matthias Pierer Manuela Rossol Sylke Kaltenhauser Sybille Arnold

Holm Hantzschel Christoph Baerwald Ulf Wagner

Received: 16 October 2009 / Accepted: 27 February 2010 / Published online: 20 March 2010 Springer-Verlag 2010

Abstract Clonal expansions of autoreactive CD4? T cells are frequently present in patients with rheumatoid arthritis (RA) and are stable over long periods of time. This study was undertaken to investigate the inuence of anti-TNFa treatment on such clonal expansions in the peripheral CD4? T-cell compartment. TNFa inhibiting therapies signicantly reduced the total number of expanded clono-types. This effect was mainly observed in clonal expansions in the BV6 family, while in clonal expansions of the BV14 family no such effect was seen. No change in the percentage of CD4? CD28 null T cells was observed. Serum concentrations of the pro-homeostatic cytokine IL-7 were found to increase in patients responding TNFa-inhibiting therapy. These data argue for a normalization of adaptive immune mechanisms under TNFa inhibiting therapies, which may be secondary to the control of inammation but contribute to the efcacy of cytokine blockade therapy.

Keywords Rheumatoid arthritis T lymphocytes

Clonal expansion TNFa IL-7 CD28

AbbreviationsTNF a Tumor necrosis factor a

CDR3 Complementarity determining region 3

RA Rheumatoid arthritisTCR T-cell receptorIL-7 Interleukin 7CMV CytomegalovirusBV Variable region of the T-cell receptor beta chain

Introduction

CD4? T cells are implicated in the pathogenesis of rheumatoid arthritis (RA), since disease susceptibility is inuenced by the presence of HLA class II alleles containing the shared epitope and of polymorphisms in the genes for PTPN22, STAT4 and CTLA4, all of which are relevant for T-cell activation and function [1]. The clinical efcacy of therapeutic blockade of T-cell costimulation by a CTLA4-Ig fusion protein (abatacept) adds further support to this pathogenic concept.

The most readily detectable pathologic nding in RA is massively expanded T-cell clones, which are present both in the peripheral circulation and in the synovial membrane of aficted patients, and which are characterized by phenotypical abnormalities, with the loss of the ubiquitous costimulatory molecule CD28 and the gain of certain NK cell receptors being most prominent. The expanded clones...