Influence of human T lymphotrophic virus type I on diffuse pan-bronchiolitis

Abstract

Human T lymphotrophic virus type-I (HTLV-I), a human retrovirus, infects CD4(+) lymphocytes and is thought to modify their function and a possible association with pulmonary diseases has also been suggested. However, little is known about the influence of HTLV-I on diffuse pan-bronchiolitis (DPB), a chronic inflammatory lung disease with infiltration of lymphocytes and hyperplasia of the bronchus-associated lymphoid tissue. In this study, 35 DPB patients with and without HTLV-I infection were examined. HTLV-I positive DPB patients were likely to have a larger affected area with lower FEV(1). The CD3(+)/CD25(+) lymphocyte percentage was significantly higher in the BALF of HTLV-I positive patients than in negative patients. MIP-1 alpha, IP-10 and levels in BALF were also significantly higher in HTLV-I positive patients than in negative patients. The levels of MCP-1 and IL-8 were not significantly different. In HTLV-I positive patients, the MIP-1 alpha and IP-10 levels showed a significant positive correlation with the percentage of CD3(+)/CD25 lymphocytes. BALF cells of all HTLV-I positive DPB patients showed expression of p40(tax) mRNA. We suggest that HTLV-I infection may modify DPB pathogenesis via activation of T cells. We also found that the frequency of ATL development in HTLV-I positive DPB patients was significantly higher than in all HTLV-I positive patients (OR = 8.22, 95% CI = 2.61-25.9, P < 0.01). The levels of TGF-beta in patients who developed ATL were significantly lower than in patients who did not develop ATL. Sensitivity and specificity were 80% and 85.7%, respectively (cut-off = 20 pg/ml). We also propose that these features should be taken into consideration in the treatment of DPB in HTLV-I infected individuals.

Fig. 1

Comparison of cytokine levels in BALF between HTLV-I positive and negative DPB patients. MIP-1α and IP-10 levels were significantly higher in HTLV-I positive patients than in negative patients. The levels of TGF-β, MCP-1 and IL-8 were not significantly different. Bars represent standard deviations. *P < 0·01, **P < 0·05.

Fig. 2

Correlation between percentage of CD3⁺/CD25⁺ lymphocytes and cytokine levels in BALF of HTLV-I positive DPB patients. The levels of MIP-1α (r = 0·549, P < 0·05), IP-10 (r = 0·698, P < 0·01) and VS (r = 0·654, P < 0·01) showed significant positive correlations with the percentage of CD3⁺/CD25⁺ lymphocytes.

Fig. 3

(a) P40^tax mRNA expression in BALF cells of HTLV-I positive DPB patients. The lower band (145 bp) shows p40^tax and the upper band (508 bp) represents GAPDH. All patients’ BALF cells expressed p40^tax mRNA. M: marker. (b) Correlation of p40^tax mRNA expression level and CD3⁺/CD25⁺ lymphocytes in BALF. The percentage of CD3+/CD25⁺ lymphocytes increased with higher expression of p40^tax mRNA in BALF of HTLV-I positive patients. However, the correlation between the two parameters was not significant (r = 0·498, P = 0·059).

Fig. 4

(a) Comparison TGF-β levels in BALF between HTLV-I positive DPB patients who developed ATL and patients who did not develop ATL. TGF-β levels were significantly higher in HTLV-I positive DPB patients who developed ATL than those who did not develop ATL (*P < 0·01). (b) Comparison of MAP kinase protein phosphorylations. The JNK phosphorylation level of HTLV-I positive DPB patients who developed ATL (lane 3) was higher than those who did not develop ATL (lane 2) and HTLV-I negative DPB patients (lane 1). Data show the representative data of three different patients in each group. (c) Results of densitometry analysis of P-JNK/JNK. The JNK phosphorylation level of HTLV-I positive DPB patients who developed ATL (lane 3) was significantly higher than those who did not develop ATL (lane 2) and HTLV-I negative DPB patients (lane 1) (*P < 0·01, **P < 0·001, Bonferroni/Dunn with one-way factorial anova). Data are shown with mean ± standard deviation, n = 3 in each group).