Erdheim-Chester disease: report on a case and new insights on its immunopathogenesis

Sir, Erdheim–Chester disease (ECD) is a rare (approximately 350 published cases worldwide) non-Langerhans cell histiocytosis (LCH) characterized by tissue infiltration with CD68+, CD1a− foamy histiocytes. The disease almost invariably affects bones, causing the nearly pathognomonic osteosclerosis of the limbs. In addition, ECD patients frequently have extra-skeletal manifestations, including exophthalmos, xanthelasma, interstitial lung disease, retroperitoneal fibrosis, pituitary and hypothalamic infiltration and central nervous system and cardiovascular involvements [1–3]. IFN-α represents the best available treatment [4], but response to therapy varies among patients and according to the sites of involvement [5]. The aetiology is unknown. Similar to LCH [6], ECD lesions express a wide array of cyto-chemokines, which may orchestrate histiocyte recruitment and activation [7]. We describe here the release of cyto-chemokines potentially relevant to ECD pathogenesis by intra-lesional cells from a patient with skeletal and multi-organ involvements. A 45-year-old man with a 10-year history of chronic renal failure due to renal polycystosis was admitted for worsening renal function. An MRI of the abdomen demonstrated inflammatory infiltration of the perirenal adipose tissue, causing urinary flow obstruction (Fig. 1A). A similar mass surrounded the abdominal aorta. A chest CT scan documented bilateral pulmonary infiltrates (Fig. 1B). A 99mtechnetium methylene diphosphonate (99mTc MDP) bone scan showed symmetrical uptake of the diaphyses of tibiae and the large joints of upper and lower limbs, highly suggestive of ECD (Fig. 1C). A bone biopsy showed clusters of foamy CD68+ histiocytes lacking markers of Langerhans cells (LC) (CD1a and S-100 protein) [1] (Fig. 1D and E; and data not shown). Diagnosis was made based on clinical, radiological and pathological findings, according to previously published criteria [2]. MNCs from an ECD bone lesion release cytokines and chemokines. MNCs were isolated from a bone lesion of a patient diagnosed with ECD based on clinical, radiological and pathological findings. (A) MRI of the abdomen showed an inflammatory infiltrate surrounding the kidney and determining dilatation of pelvises (T2-weighted MRI); (B) a chest CT scan documented bilateral pulmonary infiltrates; (C) a 99mTc MDP bone scan showed symmetric uptake of the diaphyses of tibiae and the large joints of the limbs. A bone biopsy showed clusters of foamy histiocytes (haematoxylin and eosin, D) positive for CD68 (E) (magnification: ×400). (F) Supernatants collected from 2 × 105 MNCs, either unstimulated (white bars) or stimulated with PMA plus ionomycin (dashed bars) were assessed for cyto-chemokine concentration. Mononuclear cells (MNCs) were obtained from biopsy fragments upon enzymatic digestion and Ficoll density gradient centrifugation, and then assessed for spontaneous and stimulated [Phorbol Myristate Acetate (PMA) plus ionomycin] cytokine production [8], which was determined by multiplex bead-based cytokine assays (Bio-Plex, Bio-Rad). In particular, we selected TNF-α and IL-6, which we have already shown in ECD specimens [7], and CXCL8/IL-8, a chemoattractant for polymorphonuclears and monocytes associated with other forms of histiocytosis [6, 9]. As a control, we tested the production of VEGF, a key player in angiogenesis, which is not a prominent pathological process in ECD. As shown in Fig. 1F, TNF-α was secreted only upon stimulation. IL-6 and particularly CXCL8/IL-8 were instead spontaneously released and mildly affected by PMA plus ionomycin stimulation. As expected, VEGF production was not detectable in MNC-derived supernatants. The present data, which are, to the best of our knowledge, the first obtained from viable cells from ECD lesions, demonstrate that inflammatory cytokines and chemokines are released by infiltrating MNCs. TNF-α and IL-6 production is in agreement with our previous results [7], showing strong expression of both cytokines by ECD histiocytes; in addition, IL-6 was found in endothelial cells of vessels inside the lesion and of the healthy peri-lesional tissue [7]. IL-6 is a pro-inflammatory cytokine responsible for macrophage activation and bone resorption. TNF-α is implicated in the up-regulation of inflammatory chemokines [10], which we have previously found in ECD lesions and may contribute to histiocyte recruitment [7]. The remarkable production of CXCL8/IL-8 instead represents a novel finding. CXCL8/IL-8 increase was reported in other forms of histiocytosis, i.e. in the sera of haemophagocytic lymphohistiocytosis patients [9] and in LCH lesions [6], where it might contribute to an autocrine loop of LC recruitment [6]. A similar significance can be envisaged in ECD, albeit the cellular source of CXCL8/IL-8, as well as the expression of the counter-receptor, is presently unknown. Altogether, the present data demonstrate the feasibility of deriving viable MNC from ECD lesions, which may prove a new useful tool for dissecting the pathogenetic mechanisms of the disease. Moreover, we confirm and extend our previous findings of a complex cytokine and chemokine network inside ECD lesions by showing the actual spontaneous and stimulated secretion of relevant molecules by isolated cells. The identification of new specific targets may provide a rationale for therapeutic approaches of the disease based on cytokine neutralization. We thank Dr Elisabetta Ferrero for helpful discussion, Prof. Alessandro Del Maschio and Prof. Ferruccio Fazio for radiological and nuclear medicine studies. Disclosure statement: The authors have declared no conflicts of interest.