Systemic perturbation of cytokine and chemokine networks in Erdheim-Chester disease: a single-center series of 37 patients

Abstract

Immunopathogenesis of Erdheim-Chester disease (ECD), a rare non-Langerhans cell histiocytosis, is poorly known. In previous studies, various cytokines were detected in ECD lesions, presumably orchestrating lesional histiocyte recruitment. Because ECD lesions are frequently associated with systemic symptoms, we postulated that underlying global immune perturbations might also be revealed. We quantitatively analyzed 23 cytokines in serum samples obtained from a large single-center cohort of 37 patients with ECD, and studied the impact of treatment on cytokine production. IL-6, IL-12, interferon-α (IFN-α), and monocyte chemotactic protein-1 (MCP-1) levels were significantly higher in untreated patients than in controls, whereas interferon-γ (IFN-γ) inducible protein 10, IL-12, MCP-1, and IL-1 receptor antagonist were found significantly increased in IFN-α-treated patients. A biomathematical approach was used to rationalize multiparameter data, to generate new hypotheses, and identify global control pathways. Interestingly, cytokine profiles proved to be particularly stable at the individual level, and an "ECD signature" further distinguished patients from controls, based on their production of IFN-α, IL-12, MCP-1, IL-4, and IL-7. Altogether, our data underline the systemic immune Th-1-oriented perturbation associated with this condition and provide clues for the choice of more focused therapeutic agents in this rare disease with noncodified therapeutic management.

Immunotherapy using IL-2 and GM-CSF is a potential treatment for multidrug-resistant Mycobacterium tuberculosis

“…Disorders of cytokine networks are closely associated with disease [26,27]. Cytokines produced by immune cells can influence the outcome of mycobacterial infection.…”

Tocilizumab in patients with multisystem Erdheim–Chester disease

“…In Patients 1 and 2, treatment was associated with a stabilization or reduction of the circulating levels of CXCL8, CXCL10, CCL2, CCL4, and CCL5, all pro-inflammatory mediators typically increased in ECD patients 13,14 (Fig. 3).…”

“…13,14 Interleukin (IL)-6, a pleiotropic cytokine involved in the regulation of immune responses and bone metabolism, may be central to this inflammatory network. In fact, IL-6 is abundantly produced by foamy histiocytes in ECD lesions, and serum levels correlate with disease severity.…”

“…In fact, IL-6 is abundantly produced by foamy histiocytes in ECD lesions, and serum levels correlate with disease severity. [13][14][15] Tocilizumab, a monoclonal antibody blocking the IL-6 receptor, is an effective treatment option for rheumatoid arthritis. In this study, we evaluated IL-6 blockade with tocilizumab in ECD.…”

Erdheim-Chester: beyond the lesion

“…3 In this issue of Blood, Arnaud and colleagues quantitatively analyze 23 cytokines, chemokines, and growth factors in serum samples from 37 patients with ECD. 1 They found many significant differences in cytokine/chemokine levels in ECD patients compared with controls, with principal component analysis identifying an ECD-specific signature based on increased expression of IFN-␣, IL-12, monocyte chemotactic protein-1, and decreased expression of IL-4 and IL-7. Compared with controls, untreated patients had For personal use only.…”