After peripheral nerve damage macrophages infiltrate the dorsal root ganglia (DRG) in which cell bodies of lesioned neurons are located. However, infiltration of macrophages into the DRGs was also reported in complete Freund's adjuvant (CFA)-induced inflammation raising the question whether CFA inflammation induces nerve cell damage or whether peripheral inflammation may also trigger macrophage infiltration into DRGs. Related questions are, first, which signals trigger macrophage infiltration into DRGs and, second, is macrophage infiltration correlated with pain-related behavior. Using the rat model of unilateral antigen-induced arthritis (AIA) in the knee we found a massive infiltration of ED1(+) macrophages into the ipsi- and contralateral lumbar DRGs but not into thoracic DRGs. At no time point of AIA DRG neurons showed expression of activating transcription factor-3 (ATF3) indicating that macrophage infiltration is not explainable by nerve cell lesions in this model. During AIA, lumbar but not thoracic DRGs exhibited a bilateral de novo expression of vascular cell adhesion molecule-1 (VCAM-1) which is known to be involved in macrophage infiltration. Tumor necrosis factor-alpha (TNF-alpha) neutralization with etanercept or infliximab treatment after induction of AIA significantly reduced both macrophage infiltration and VCAM-1 expression. It also decreased mechanical hyperalgesia at the inflamed joint although the joint inflammation itself was barely attenuated, and it reduced mechanical hyperalgesia at the non-inflamed contralateral knee joint. Thus, bilateral segment-specific infiltration of macrophages into DRGs is part of an unilateral inflammatory process in peripheral tissue and it may be involved in the generation of hyperalgesia in particular on the non-inflamed side.

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Hsp70 plays several roles in the adaptive immune response. Based on the ability to interact with diverse peptides, extracellular Hsp70:peptide complexes exert profound effects both in autoimmunity and in tumor rejection by evoking potent T cell responses to the chaperoned peptide. The interaction with receptors on APC represents the basis for the immunological functions of Hsp70 and a critical point where the immune response can be regulated. Various surface proteins (e.g. CD91, scavenger receptors (SR)) have been implicated in binding of Hsp70. In this study, antigenic peptides from tetanus toxin and influenza hemagglutinin complexed to human stress-inducible Hsp70 were found to enhance the proliferation and cytokine production of human antigen-specific CD4 1 T cells. This was demonstrated in proliferation experiments using human monocytes as APC. Proliferated antigen-specific cells were detected combining HLA-DRB1 Ã 0401 or HLA-DRB1 Ã 1101 tetramer and CFSE staining. Treating monocytes with CD91 siRNA diminished these effects. Additional blocking of SR by the SR ligand fucoidan completely abolished enhanced proliferation and production of Th1 and Th2 cytokines. Taken together, our data indicate that in the human system, CD91 and members of the SR family efficiently direct Hsp70:peptide complexes into the MHC class II presentation pathway and thus enhance antigen-specific CD4 1 T cell responses. IntroductionIt is well established that mammalian HSP such as the human stressinducible 70 kDa HSP (Hsp70) are able to form highly immunogenic HSP:peptide complexes that elicit antigen-specific CD8 1 T cell responses to the chaperoned peptides [1]. Moreover, a role of members of the Hsp70 and Hsp90 family in the MHC class II processing and presentation pathway has been shown in different studies [2][3][4][5][6][7]. However, most of these studies were performed in murine systems or with T cell hybridomas. Our group extended these findings by demonstrating that Hsp70:peptide complexes amplify the proliferation of human antigen-specific CD4 1 memory 986T cells [8]. According to these findings, HSP seem to play a role in the initiation of different autoimmune diseases [4,[9][10][11]. As shown earlier, a receptor-dependent internalization of the HSP:peptide complexes by the APC is a prerequisite for the initiation of an adaptive immune response [12]. Studies were thus focused on identifying these receptors. CD91 was the first HSP receptor identified [13]. Originally CD91 was described as a specific gp96 receptor [13] but further experiments showed that CD91 is also a receptor for other HSP such as Hsp70, Hsp90 and calreticulin [14]. The involvement of CD91 in the binding and internalization of HSP by APC was reported in several studies [9,15,16]. A clear interaction of Hsp70 with CD91 was shown by Delneste et al. on human macrophages. Nevertheless, apart from CD91, different members of the scavenger receptor (SR) family, including lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) [15,17,18], 19,20], 21], FEEL...

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