Th17 cells reflect colon submucosal pathologic changes in active eosinophilic granulomatosis with polyangiitis

Abstract

Background: Chronic eosinophilic pneumonia (CEP) or eosinophilic gastroenteritis (EG), or both, with asthma precede the onset of eosinophilic granulomatosis with polyangiitis (EGPA) in half of all EGPA patients. It is not known what determines whether patients with CEP or with EG following asthma will develop EGPA.

Methods: We studied 17 EGPA patients and 12 patients with CEP but without EGPA. We assayed serum ICAM-1, VCAM-1, and VEGF, and the percentage of peripheral blood CD4(+) T cells producing IL-17 (Th17 cells), at both onset and remission. We also examined the numbers of submucosal eosinophils and the basement membrane-to-crypt and crypt-to-crypt distance to evaluate edema in the colon submucosa at onset and remission in EGPA and at onset in CEP.

Results: Nine of 12 (75.0%) CEP patients had symptoms or endoscopic findings. Colonic submucosal eosinophil counts and edema in EGPA at onset were greater than at remission or in CEP at onset. Th17 cells (%) and serum ICAM-1 levels at onset were greater in EGPA than in CEP. In EGPA, peripheral blood Th17 cells (%) were significantly correlated with serum ICAM-1 level, colonic submucosal eosinophil count, and degree of edematous change; inversely correlated with serum VEGF level; but not correlated with VCAM-1 level.

Conclusions: Eosinophilia and colonic submucosal edematous change were greater in EGPA than in CEP. The mechanism of vasculitis in EGPA appears related to increases in serum Th17 cell numbers and ICAM-1 levels and decreases in VEGF levels.

Fig. 1

Endoscopic findings in the large intestine in patients with eosinophilic granulomatosis with polyangiitis (EGPA) (a–c) or chronic eosinophilic pneumonia (CEP) (d–f). Arrows show ulcer (A), erosion (B), dark red sign (C), and various red flares (D, E, F). The number in bright green indicated a region biopsied. EGPA patients had subjective symptoms related to the endoscopic findings in the lower digestive organs (e.g. abdominal pain, diarrhea, and blood in the stool), but there were no subjective symptoms in patients with CEP

Fig. 2

Pathological findings in the large intestine in patients with eosinophilic granulomatosis with polyangiitis (EGPA) (a–c) or chronic eosinophilic pneumonia (CEP) (d–f). Evidence of bleeding was present in the submucosa (a). The number of eosinophils in the submucosa was higher in patients with EGPA (a–c) than in those with CEP (d–f). Edematous changes (expressed as the width of the basement membrane-to-crypt distance or the crypt-to-crypt distance) were more severe in patients with EGPA than in those with CEP

Fig. 3

Assessment of number of eosinophils and edema in colonic submucosa in a pathology specimen from a patient with eosinophilic granulomatosis with polyangiitis. Blue arrows indicate eosinophils. Red arrows show crypt-to-crypt distance. Yellow arrows show basement membrane-to-crypt distance. All values are expressed as means ± SD in Table 2

Fig. 4

Correlations between eosinophils count (per microliter) in the colonic submucosa and eosinophil count in the peripheral blood (a) or the basement membrane-to-crypt distance (b) in patients with eosinophilic granulomatosis with polyangiitis (EGPA). The basement membrane-to-crypt distance reflected edema in the colonic submucosa. Closed circles: mucous membrane of colon biopsied at the onset of EGPA. Open circles: mucous membrane of colon biopsied in remission after treatment with corticosteroids with or without immunosuppressants. Correlation coefficients (r values) and P values were calculated by using Spearman’s rank correlation test

Fig. 5

Correlations between the percentage of CD4⁺ T cells producing IL-17 in peripheral blood and eosinophil count in the colonic submucosa (a); the crypt-to-crypt distance (b); the basement membrane-to-crypt distance (c), the ICAM-1 level (d); the VCAM-1 level (e); and the VEGF level (f) in the sera of patients with eosinophilic granulomatosis with polyangiitis (EGPA). Closed circles: mucous membrane of colon biopsied at onset of EGPA. Open circles: mucous membrane of colon biopsied in remission after treatment with corticosteroids with or without immunosuppressants. Correlation coefficients (r values) and P values were calculated by using Spearman’s rank correlation test