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Comparative Study
. 2007 Sep;75(9):4621-8.
doi: 10.1128/IAI.00263-07. Epub 2007 Jul 2.

Chemokine Signatures in the Skin Disorders of Lyme Borreliosis in Europe: Predominance of CXCL9 and CXCL10 in Erythema Migrans and Acrodermatitis and CXCL13 in Lymphocytoma

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Free PMC article
Comparative Study

Chemokine Signatures in the Skin Disorders of Lyme Borreliosis in Europe: Predominance of CXCL9 and CXCL10 in Erythema Migrans and Acrodermatitis and CXCL13 in Lymphocytoma

Robert R Müllegger et al. Infect Immun. .
Free PMC article

Abstract

The three skin disorders of Lyme borreliosis in Europe include erythema migrans, an acute, self-limited lesion; borrelial lymphocytoma, a subacute lesion; and acrodermatitis chronica atrophicans, a chronic lesion. Using quantitative reverse transcription-PCR, we determined mRNA expression of selected chemokines, cytokines, and leukocyte markers in skin samples from 100 patients with erythema migrans, borrelial lymphocytoma, or acrodermatitis chronica atrophicans and from 25 control subjects. Chemokine patterns in lesional skin in each of the three skin disorders included low but significant mRNA levels of the neutrophil chemoattractant CXCL1 and the dendritic cell chemoattractant CCL20 and intermediate levels of the macrophage chemoattractant CCL2. Erythema migrans and particularly acrodermatitis lesions had high mRNA expression of the T-cell-active chemokines CXCL9 and CXCL10 and low levels of the B-cell-active chemokine CXCL13, whereas lymphocytoma lesions had high levels of CXCL13 and lower levels of CXCL9 and CXCL10. This pattern of chemokine expression was consistent with leukocyte marker mRNA in lesional skin. Moreover, using immunohistologic methods, CD3(+) T cells and CXCL9 were visualized in erythema migrans and acrodermatitis lesions, and CD20(+) B cells and CXCL13 were seen in lymphocytoma lesions. Thus, erythema migrans and acrodermatitis chronica atrophicans have high levels of the T-cell-active chemokines CXCL9 and CXCL10, whereas borrelial lymphocytoma has high levels of the B-cell-active chemokine CXCL13.

Figures

FIG. 1.
FIG. 1.
mRNA expression of neutrophil, dendritic cell, and macrophage chemoattractants and their cell markers in 64 EM lesions, 11 BL lesions, 25 ACA lesions, and 25 normal skin samples relative to the GAPDH gene. Data are shown in box plots in which the boxes represent the 25th and 75th percentiles, the lines within the boxes represent the median values, and the lines outside the boxes represent the 5th and 95th percentiles. A difference between normal and lesional skin (*), between EM and BL or EM and ACA lesions (**), or between BL and ACA lesions (§) at the 0.05 level is indicated above the bars. Low mRNA levels of neutrophil and dendritic cell chemoattractants and moderate mRNA levels of macrophage chemoattractants, primarily CCL2, were found.
FIG. 2.
FIG. 2.
mRNA expression of T- and B-cell chemoattractants and their cell markers in 64 EM lesions, 11 BL lesions, 25 ACA lesions, and 25 normal skin samples relative to the GAPDH gene. Data are shown in box plots in which the boxes represent the 25th and 75th percentiles, the lines within the boxes represent the median values, and the lines outside the boxes represent the 5th and 95th percentiles. A difference between normal and lesional skin (*), between EM and BL or EM and ACA lesions (**), or between BL and ACA lesions (§) at the 0.05 level is indicated above the bars. High levels of the CD8+ and Th1-type CD4+ T-cell chemoattractants CXCL9 and CXCL10 were found in EM and ACA lesions, whereas BL lesions had high levels of the B-cell chemoattractant CXCL13 and proportionally lower levels of CXCL9 and CXCL10.
FIG. 3.
FIG. 3.
Immunohistochemistry of skin biopsy samples from a representative patient with EM (A to D) or BL (E to H). At low power (A), infiltrating CD3+ T cells are seen around sweat glands in the reticular dermis of the EM lesion, and at higher power (B), they are seen in perivascular locations in the papillary dermis. In panel C, with the microscope centered on the same location, staining for CXCL9 is visualized in the area of the T-cell infiltrate, and in panel D, the same area is stained without primary antibody. In the biopsy of the central portion of a BL lesion, intense staining of CD20+ B-cell clusters is seen at low power, particularly within the mid- and deeper dermis (E), and at higher power (F), a single aggregate of B cells is seen. In panel G, with the microscope centered on the same location, staining for CXCL13 is visualized in the area of the B-cell aggregate, and in panel H, the same area is stained without primary antibody. In each section, the specific stain is diaminobenzidine (brown) and the nonspecific background stain is hematoxylin (purple). Magnifications, ×100 (A and E) and ×400 (B to D and F to H).
FIG. 4.
FIG. 4.
mRNA expression of proinflammatory and anti-inflammatory cytokines in 64 EM lesions, 11 BL lesions, 25 ACA lesions, and 25 normal skin samples relative to the GAPDH gene. Data are shown in box plots in which the boxes represent the 25th and 75th percentiles, the lines within the boxes represent the median values, and the lines outside the boxes represent the 5th and 95th percentiles. A difference between normal and lesional skin (*) or between EM and ACA lesions (**) at the 0.05 level is indicated above the bars. mRNA expression of the proinflammatory cytokines IFN-γ, IL-1β, and TNF-α was greater than of the anti-inflammatory cytokines IL-10, IL-4, IL-5, and TGF-β.

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