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Observational Study
. 2013 Sep 6;8(9):e74651.
doi: 10.1371/journal.pone.0074651. eCollection 2013.

Angiogenesis and lymphangiogenesis in the spectrum of leprosy and its reactional forms

Cleverson Teixeira Soares  1 , Patrícia Sammarco Rosa, Ana Paula Fávaro Trombone, Luciana Raquel Vicenzi Fachin, Cássio César Ghidella, Somei Ura, Jaison Antonio Barreto, Andréa de Faria Fernandes Belone
Affiliations
Observational Study

Angiogenesis and lymphangiogenesis in the spectrum of leprosy and its reactional forms

Cleverson Teixeira Soares et al. PLoS One. .

Abstract

Background: Angiogenesis and lymphangiogenesis are the processes of neovascularization that evolve from preexisting blood and lymphatic vessels. There are few studies on angiogenesis and none on lymphangiogenesis in leprosy. Thus, the role of neovascularization in the pathophysiological mechanisms of the disease was studied across the spectrum of leprosy, its reactional states and its residual lesions.

Methodology/principal findings: Seventy-six biopsies of leprosy skin lesions and seven healthy controls were selected. Fifty-five serum samples were used for the detection of CD105 by ELISA. Histological sections were stained with antibodies against CD31 (blood and lymphatic vessels), D2-40/podoplanin (lymphatic vessels), and CD105/endoglin (neovessels). Microvessels were counted in 100 high-power fields (400x) and the number of vessels was evaluated in relation to the extension of the inflammatory infiltrate (0-3), to the bacillary index (0-6) and to the clinical forms. Angiogenesis, as marked by CD31 and CD105, was observed across the leprosy spectrum, compared with the controls. Additionally, there was a positive correlation between these markers with extension of the infiltrate (p <0.0001). For D2/40, lymphangiogenesis was observed in the tuberculoid form (p <0.0001). There was no statistical significance for values of CD105 detected in plasma by ELISA.

Conclusions/significance: Angiogenesis is present across the spectrum of leprosy and in its reactional forms. The increase in the number of vessels, as detected by CD31 and CD105 staining, is related to the extension of the inflammatory infiltrate. Samples from reactional lesions have a higher number of CD31+ and CD105+ stained vessels, which indicates their involvement in the pathophysiological mechanisms of the reactional states. The regression of lesions is accompanied by the regression of neovascularization. Drugs inhibiting angiogenesis may be relevant in the treatment of leprosy, in addition to multidrugtherapy, and in the prevention of the development of reactions.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Experimental design.
(A) Seventy-six paraffin blocks were selected. The samples constituted punch biopsies of patients in the leprosy spectrum, reactional cases, residual leprosy and controls (n=76). (B) The sections (4µm) were stained by HE and Fite-Faraco (R&J histopathological classification) and (C) immunohistochemistry using antibodies against CD31, D2-40 and CD105 for the counting of microvessels. (D) For each marker, the microvessels were counted in 100 hpf, within the entire thickness of the dermis and part of the subcutaneous tissue. (E) A field immunostained for CD105 in ENL lesion. (*) 46 patients, six TT, six BT, six BB, seven BL, seven LL, seven RR and seven ENL, also had blood samples taken. Nine healthy controls (C) were included in the ELISA test for serum detection of CD105.
Figure 2
Figure 2. Histopathological pictures.
(A) A normal capillary vessel in the papillary dermis, comprising endothelial cells with fusiform shape and showing elongated nuclei (HE, 1000x). (B) The endothelium of an ENL skin lesion, comprising endothelial cells with large and vacuolated cytoplasm, large nuclei, one or more nucleoli and mitoses. The lumen of the capillaries and the interstitium are filled by neutrophils, macrophages, lymphocytes and plasma cells, among other cells (HE-1000x). (C) Capillaries positive for CD31 inside and surrounding the tuberculoid granuloma (IHC, CD31- 200x). (D) Capillaries positive for CD105 inside and surrounding the tuberculoid granuloma (IHC, CD105- 200x). (E) A lepromatous lesion showing multivacuolated histiocytes permeated by capillary vessels (HE- 400x). (F) A residual lesion showing regressive granulomas with a few histiocytes with multivacuolated cytoplasm (HE- 400x). (G) A tuberculoid leprosy case showing a granuloma comprised of epithelioid macrophages in the center and lymphocytes in the periphery (HE- 400x). (H) Lymphatic vessels around the tuberculoid granuloma containing multinucleated giant cells (IHC, D2-40, 200x).
Figure 3
Figure 3. Microvessels counting.
Evaluation of positive staining for the three markers (CD31, D2-40 and CD105) in comparison with polar forms of the leprosy spectrum, reactional groups (RR and ENL) and the clinical forms of the reactional groups (A-I). Different letters indicate statistical significance (P<0,05), equal letters indicate no significance.
Figure 4
Figure 4. Anti-CD105 serum levels detected by ELISA.
Detection of antibodies against CD105 in sera of leprosy patients across the spectrum, in reactional groups and controls. Data reported as means ± SD absorbance. Results show that absorbance was not significantly different between the evaluated groups.
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This study was supported by the Lauro de Souza Lima Institute funding and FAPESP. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.