Morphologic and immunohistochemical characterization of granulomas in the nucleotide oligomerization domain 2-related disorders Blau syndrome and Crohn disease

Carl E.I. Janssen, Carlos D. Rose, Gert De Hertogh, Tammy M. Martin, Brigitte Bader Meunier, Rolando Cimaz, Miroslav Harjacek, Pierre Quartier, Rebecca Ten Cate, Caroline Thomee, Valeer J. Desmet, Alain Fischer, Tania Roskams, Carine H. Wouters

Research output: Contribution to journalArticlepeer-review

59 Scopus citations


Background: Blau syndrome (BS) and Crohn disease (CD) are both characterized by granulomatous inflammation and related to nucleotide oligomerization domain 2 (NOD2) mutations. Objective: This study aimed to define the morphologic and immunohistochemical characteristics of granulomas in patients with NOD2-related BS and CD. Methods: Granuloma-containing biopsy specimens from 6 patients with BS and 7 pediatric patients with CD carrying NOD2 mutations or single nucleotide polymorphisms were studied for morphology, cellular composition, and cytokine expression by using hematoxylin and eosin staining and immunohistochemistry. Results: Biopsy specimens from patients with BS typically showed polycyclic granulomas with large lymphocytic coronas, extensive emperipolesis of lymphocytes within multinucleated giant cells (MGCs), MGC death, and fibrinoid necrosis and fibrosis. In contrast, biopsy specimens from patients with CD showed simple granulomas with subtle/absent lymphocytic coronas, sclerosis of the surrounding tissue, and polymorphonuclear cells. Findings found to be similar in all granulomas were as follows: CD68 and HLA-DR expression by epithelioid cells, monocyte-macrophage lineage cells and MGCs, increased lymphocytic HLA-DR expression, increased CD4 +/CD8 + T-cell ratio, and CD20 + B lymphocytes evenly distributed within and around granulomas. In both patient groups prominent IFN-γ expression was found in and around granulomas, and TNF-α and IL-23 receptor expression was moderate. IL-6, IL-17, and TGF-β expression was prominent in granulomas from patients with BS but sporadic in granulomas from patients with CD. IL-10 expression was absent. Conclusion: Granulomas from patients with BS and granulomas from patients with NOD2-associated CD show distinct morphologic features and cytokine expression patterns, suggesting that the T H17 axis might be involved in the pathogenesis of BS, whereas T H1 is important in both patients with BS and patients with CD.

Original languageEnglish (US)
Pages (from-to)1076-1084
Number of pages9
JournalJournal of Allergy and Clinical Immunology
Issue number4
StatePublished - Apr 2012


  • Blau syndrome
  • Crohn disease
  • Nucleotide oligomerization domain 2
  • T 17 cell
  • granuloma
  • monocyte macrophage lineage
  • multinucleated giant cell

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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