title: Morphologic and immunohistochemical characterization of granulomas in the nucleotide oligomerization domain 2-related disorders Blau syndrome and Crohn disease.
abstract: 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.
  
  
  CONCLUSIONS
  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(H)17 axis might be involved in the pathogenesis of BS, whereas T(H)1 is important in both patients with BS and patients with CD.
authors.affiliation: Department of Pediatric Rheumatology, University Hospital Leuven, Leuven, Belgium.
authors.forename: Carl E I
authors.initials: CE
authors.lastname: Janssen
authors.forename: Carlos D
authors.initials: CD
authors.lastname: Rose
authors.forename: Gert
authors.initials: G
authors.lastname: De Hertogh
authors.forename: Tammy M
authors.initials: TM
authors.lastname: Martin
authors.forename: Brigitte
authors.initials: B
authors.lastname: Bader Meunier
authors.forename: Rolando
authors.initials: R
authors.lastname: Cimaz
authors.forename: Miroslav
authors.initials: M
authors.lastname: Harjacek
authors.forename: Pierre
authors.initials: P
authors.lastname: Quartier
authors.forename: Rebecca
authors.initials: R
authors.lastname: Ten Cate
authors.forename: Caroline
authors.initials: C
authors.lastname: Thomee
authors.forename: Valeer J
authors.initials: VJ
authors.lastname: Desmet
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.forename: Tania
authors.initials: T
authors.lastname: Roskams
authors.forename: Carine H
authors.initials: CH
authors.lastname: Wouters
mesh_terms: D000293:Adolescent; D001168:Arthritis; D002648:Child; D002675:Child, Preschool; D003389:Cranial Nerve Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D003424:Crohn Disease / Q000235:genetics* / Q000276:immunology / Q000473:pathology*; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006099:Granuloma / Q000235:genetics* / Q000276:immunology / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D008297:Male; D009154:Mutation; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics* / Q000276:immunology; D012507:Sarcoidosis; D013585:Synovitis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D014605:Uveitis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D056660:Hereditary Autoinflammatory Diseases
chemical_list: D016207:Cytokines; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein