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Increased serum IL-6, TNF-alpha and IL-10 levels in patients with bullous pemphigoid: relationships with disease activity
Journal of the European Academy of Dermatology and Venereology 12 (1999) 11–15
Increased serum IL-6, TNF-alpha and IL-10 levels in patients with bullous pemphigoid: relationships with disease activity L. D’Auria a, A. Mussi a, C. Bonifati a, A. Mastroianni b, B. Giacalone b, F. Ameglio a,* a
Laboratory of Clinical Pathology, Institute S.Gallicano IRCCS, Rome, Italy b Department of Dermatology, Institute S.Gallicano IRCCS, Rome, Italy
Abstract Aim The present report analyzes the serum levels of three cytokines, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) in 15 patients with bullous pemphigoid (BP) (compared with 20 healthy controls) to evaluate a possible involvement of these biological modulators in the clinical expression of this disease. Background BP is a rare, bullous disease of autoimmune origin with evidence of inflammatory processes that cause skin lesions with local increase of various pro-inflammatory mediators. Methods Determination of cytokine concentrations were obtained employing commercially available ELISA kits. Results The sera of BP patients showed increased levels of these three cytokines (P , 0.01). When the number of skin lesions (blisters and/or erosion) of each patient, employed as a marker of disease activity, was correlated with the serum levels of IL-6 and TNF-alpha, significant correlations were found (IL-6: P , 0.01 and TNF-alpha: P , 0.01, respectively), suggesting a possible role of these mediators in the development of BP blisters. The serum levels of IL-6 also correlated (P = 0.01) with those of serum C reactive protein (CRP), an acute-phase protein induced by IL-6 in hepatocytes. In addition, serum TNFalpha and sE-selectin (an adhesion molecule previously reported to be increased by this cytokine) levels were also correlated (P , 0.05). Conclusions On the basis of these data, it may be indicated that at least IL-6 and TNF-alpha are associated with the clinical expression of BP and that the endothelial activation (possibly induced by the TNF-alpha activity), seems to be an important phase of this dermatosis. 1999 Elsevier Science B.V. All rights reserved. Keywords: Cytokines; Bullous pemphigoid; Serum; Blister fluid
1. Introduction Bullous pemphigoid (BP) is a rare, autoimmune dermatosis characterized by blisters appearing on erythematous/edematous skin, and more rarely on normal skin. Blister cleavage is localized between the epidermis and the lamina lucida and is caused by autoantibodies directed against the 230 and 180 kDa (major antigen) proteins [1]. Several pathogenetic steps are necessary between the autoantibody * Corresponding author. Fax: +39-6-58543747.
0926-9959/99/$ - see front matter PII: S09 26-9959(98)001 26-3
induction and the clinical expression of the disease, including the release of various cytokines. Interleukin-6 (IL-6) is one of the most important pro-inflammatory cytokines and is produced by various cell types, including keratinocytes, monocytes/ macrophages, T-lymphocytes, endothelial cells. It stimulates B-cells to differentiation and antibody secretion [2] and the production of acute phase proteins by hepatocytes [3]. IL-6 seems to play a role in autoimmune diseases: high levels of this molecule have been reported in arthritis, Castelman’s disease, psoriasis and other diseases [4].
1999 Elsevier Science B.V. All rights reserved.
12
L. D’Auria et al. / J. Eur. Acad. Dermatol. Venereol. 12 (1999) 11–15
Tumor necrosis factor-alpha (TNF-alpha) is another pro-inflammatory modulator; it is produced by a wide spectrum of cells and acts on most cells types including eosinophils and neutrophils, T-cells, keratinocytes, etc. This molecule also induces the expression of E-selectin on endothelial cells, known to be involved in all inflammatory processes [5]. In contrast, interleukin-10 (IL-10), a so called TH2 cytokine, is described to exert anti-inflammatory activities. CD4+ T-cells, activated monocytes and peripheral blood cells are sources of IL-10. This cytokine can inhibit the antigen-presenting function of macrophages and can down-regulate class II MHC expression on macrophages [6]. In addition, it is a growth co-stimulator of mast-cells [7,8] and activates endothelial cells [9]. The aim of the present report was therefore to compare the serum levels of IL-6, TNF-alpha and IL-10 with those observed in healthy subjects and establish possible correlations between these levels and disease activity, in order to better evaluate the role of these cytokines in BP.
days, showed disease relapse. The serum titers of antibody anti-basement-membrane-zone (ABMZ) were determined in all patients. Diagnosis was made on the basis of histological examination and direct immunofluorescent assay on biopsies of lesional and perilesional skin. At the time of enrollment, the serum cytokine and sE-selectin levels were assayed using commercially available ELISA kits (R & D Systems, 614 McKinley Place, NE Minneapolis, MN 55413 USA) according to the manufacturer’s instructions. The kit sensitivities were 0.09 pg/ml (IL-6), 2.0 pg/ ml (IL-10), 4.4 pg/ml (TNF-alpha) and 0.1 ng/ml (sEselectin), respectively. Cytokine determinations were also made on the sera of 20 healthy control subjects, matched for age and sex with the BP patients (median age: 73 years, range 42–87 years, sex: nine males, six females). The serum levels of the C-reactive protein (CRP) were determined by nephelometry (Beckman, Array 360, CRP reagent, Galway, Ireland).
3. Statistical analysis 2. Materials and methods Fifteen consecutive patients with BP (sex: 10 males, five females; median age: 82 years, range 33–88 years; median disease duration: 0 years, range 0–12 years) were enrolled in this study. Because of the lack of a standard parameter to gauge disease activity, the number of skin lesions (blisters and/or erosions) of each patient at the time of enrollment was counted (median number: 16, range 3–70). Ten patients were diagnosed for the first time, while the remaining subjects, untreated for at least 15
Because of the lack of knowledge on the type of the data distribution, comparisons between the groups were made with the Mann–Whitney non-parametric test. The Spearman rank correlation test was used to analyze the correlations between the different variables [10].
4. Results Table 1 reports the median serum levels and ranges of IL-6, TNF-alpha and IL-10 in both the BP patients
Table 1 Medians, ranges and number of detectable samples in the sera of subjects with bullous pemphigoid and in healthy controls Cytokine
IL-6 TNF-alpha IL-10
BPS
CTRS
P
Det/n
Median
Range
Det/n
Median
Range
15/15 9/15 8/15
17.8 5.3 2.7
0.1–138.1 ,4.4–32.4 ,2.0–81.0
15/20 1/20 3/20
1.6 ,4.4 ,2.0
0.3–4.7 ,4.4–6.0 ,2.0–5.1
PBS, bullous pemphigoid sera; CTRS, controls sera; Det, number of detectable samples; n, number of subjects. All the values are expressed in pg/ml. Comparisons were calculated using the Mann–Whitney test.
,0.01 ,0.01 ,0.01
L. D’Auria et al. / J. Eur. Acad. Dermatol. Venereol. 12 (1999) 11–15
Fig. 1. Correlation between the serum levels of IL-6 (pg/ml) and the number of skin lesions of 15 BP patients.
and controls; those of the patient group were significantly increased (P , 0.01). When the number of skin lesions of each patient was correlated with the serum cytokine levels, significant correlations were found between disease activity and either IL-6 (R = 0.72, P , 0.01) (Fig. 1) or TNF-alpha (R = 0.76, P , 0.01) (Fig. 2). In contrast, no significant correlation was observed with IL-10. In addition, the serum levels of TNF-alpha significantly correlated (R = 0.64, P , 0.05) with those of sE-selectin. As expected, because the CRP is specifically induced by IL-6, a significant correlation between these two molecule concentrations was observed in BP patients (R = 0.60, P = 0.01); the median serum CRP level was 1.25 mg/100 ml, range 0.1–18.0).
13
The results obtained are in agreement with the histological and laboratory findings on BP. In fact, IL-6 and TNF-alpha are produced by keratinocytes and other cells that constitute the cell infiltrates of BP lesions (including monocytes/macrophages, T-cells, eosinophils and mastocytes) [16]. Both TNF-alpha and interleukin-5 (IL-5) [17] are also known to activate eosinophils which in turn have been suggested to mediate, at least in part, the blistering processes, while IL-6 stimulates B-cell differentiation and subsequent autoantibody production [2]. As an indirect suggestion of IL-6 activity, the serum levels of CRP are not only often increased in BP patients [3] but there was a significant correlation with the serum IL-6 levels in this study. In a previous report, we observed increased sEselectin (an endothelial activation marker) levels in the sera of BP patients [18]. TNF-alpha induces the expression of E-selectin, which may therefore represent a marker of TNF-alpha activity and, as expected, a statistically significant correlation between these two molecules was found, suggesting that the former might mediate the endothelial activation in BP. Also IL-10 showed increased serum levels in BP patients and has been reported to induce E-selectin molecules on the endothelial cells [19]. IL-10 exerts stimulatory functions on mast cell growth [7,8], another cell known to play a role in the development of BP lesions [20], and inhibits CD4 + T-cell
5. Discussion Elevated concentrations of IL-4, IL-6 and IL-10 at the local level (blister fluid) have already been described in patients with BP [11]; in agreement with these data, high levels of these cytokines and other anti- and pro-inflammatory modulators in BP blister fluids were reported [12–15], pointing to a local production of these molecules. In the present study, increased levels of IL-6, TNF-alpha and IL10 are also described for the first time in the sera of BP patients.
Fig. 2. Correlation between the serum levels of TNF-alpha (pg/ml) and the number of skin lesions of 15 BP patients.
14
L. D’Auria et al. / J. Eur. Acad. Dermatol. Venereol. 12 (1999) 11–15
functions mediated by the cytokines released by monocyte/macrophage cells [21]. Together with IL4, IL-10 is considered the most representative biological modulator of a Th2 response, characterizing pregnancy, chronic infections and inflammatory or allergic diseases [22]. The data presented in this report stress the relationship between the serum increases of those cytokines already shown to be elevated in blister fluids [11,12] and indicates that local production conditions the serum concentrations. The correlations between the serum levels of IL-6 and TNF-alpha with the number of the skin lesions (blisters and/or erosions) of each patient, a par-ameter of disease activity, further emphasizes the role of these molecules as mediators of the pathogenetic steps leading to the development of blisters in BP.
[7]
[8]
[9]
[10] [11]
[12]
Acknowledgements This work was partially supported by the ‘Pemphigus’ Project of the Italian Ministry of Health.
[13]
[14]
References [15] [1] Stanley JR. Bullous pemphigoid, cicatritial pemphigoid and chronic bullous diseases of childhood. In: Fitzpatrick TB, Eiden AZ, Wolff K, Freedberg IM, Austen KF, editors. Dermatology in general medicine, fourth ed., Chp. 53. New York: McGraw-Hill, 1993, pp. 615–625. [2] Kikutami H, Tetsuya T, Akira S, et al. Effect of B cell differentiation factor (BCDF) on biosynthesis and secretion of immunoglobulin molecules in human B cell lines. J Immunol 1985;134:990–995. [3] Baumann H, Jahreis GP, Sauder DN, Koj A. Human keratinocytes and monocytes release factors which regulate the synthesis of major acute phase plasma proteins in hepatic cells from man, rat and mouse. J Biol Chem 1984;259: 7331–7342. [4] Hirano T. Interleukin-6 and its relation to inflammation and disease. Clin Immunol Immunopathol 1992;62:S60– 65. [5] Aggarwal BB, Natarajan K. Tumor necrosis factors: developments during the last decade. Eur Cyt Netw 1996;7:93– 124. [6] de Waal Malefyt R, Haanen J, Spits H, et al. Interleukin-10 (IL-10) and viral IL-10 strongly reduce antigen -specific human T cell proliferation by diminishing the antigen-pre-
[16]
[17]
[18]
[19]
[20]
senting capacity of monocytes via downregulation of class II major histocompatibility complex expression. J Exp Med 1991;174:915–924. Rennik D, Hunte B, Dang W, Thompson-Snipes W, Hudak S. Interleukin-10 promotes the growth of megakaryocyte, mastcells, and multilineage colonies: analysis with committed progenitors and Thy10Sca1 + stem cells. Exp Hematol 1994;22: 136–141. Thompson-Snipes L, Dhar V, Bond MW, Mosmann TR, Moore KW, Rennik DM. Interleukin-10: a novel stimulatory factor for mast cells and their progenitors. J Exp Med 1991;173:507–510. Sironi M, Mun˜oz C, Pollicino T, et al. Divergents effects of interleukin-10 on cytokine production by mononuclear phagocytes and endothelial cells. Eur J Immunol 1993;23:2692– 2695. Snedcor GW, Cochran WG. Statistical methods, sixth ed. Ames, IA: IOWA State University Press, 1967. Schmidt E, Bastian B, Dummer R, Tony HP, Bro¨cker EB, Zillikens D. Detection of elevated levels of IL-4, IL-6, and IL-10 in blister fluid of bullous pemphigoid. Arch Dermatol Res 1996;288:353–357. Ameglio F, D’Auria L, Bonifati C, et al. Blister fluids and serum concentrations of different cytokines in patients with bullous pemphigoid. Int J Immunopath Pharm 1997;10:97– 98. Ameglio F, D’Auria L, Bonifati C, Ferraro C, Mastroianni A, Giacalone B. Cytokine pattern in blister fluids and serum of patients with bullous pemphigoid; relationships with disease intensity. Br J Dermatol 1998;138:611–614. Caproni M, Bianchi B, Amato LE, Fabbri P. Th2-like and fibrogenic cytokines expression in cicatritial pemphigoid. Int J Immunopath Pharm 1997;10:99–102. D’Auria L, Pietravalle M, Mastroianni A, et al. IL-5 levels in the serum and blister fluid of patients with bullous pemphigoid: correlations with eosinophilic cationic protein, RANTES, IgE and disease severity. Arch Dermatol Res 1998;290:25–27. Nestor MS, Cochran AJ, Ahmed AR. Mononuclear cell infiltrate in bullous disease. J Invest Dermatol 1987;88:172– 175. Terr AI. Inflammation. In: Stites DP, Terr AI, Parslow TG, editors. Basic and clinical immunology, eight ed., Chp. 11. Appleton and Lange, Norwalk, CT, USA, 1994, p. 139. D’Auria L, Cordiali-Fei P, Pietravalle M, et al. The serum levels of sE-selectin are increased in patients with bullous pemphigoid or pemphigus vulgaris. Correlation with the number of skin lesions and recovery after corticosteroid therapy. Br J Dermatol 1997;137:59–64. Palmetshofer A, Schwarz A, Mahnke K, Bhardwaj R, Luger TA, Schwarz T. Interleukin-10 affects the expression of adhesion molecules on human dermal microvascular endothelial cells. Abstracts of the Sixth Immunodermatology Symposium of European Immunodermatology Society, Mu¨nster, Germany, 24–26 June, 1994. Wintroub BU, Mihm MC, Goetzl EJ, Soter NA, Austen KF. Morphologic and functional evidence for release of mast-cell
L. D’Auria et al. / J. Eur. Acad. Dermatol. Venereol. 12 (1999) 11–15 products in bullous pemphigoid. N Engl J Med 1978;298: 417–421. [21] Oppenheim JJ, Ruscetti FW, Faltynek C. Cytokines. In: Stites DP, Terr AI, Parslow TG, editors. Basic and clinical immunology, eight ed., Chp. 9. Appleton and Lange, Norwalk, CT, USA, 1994, p. 105.
15
[22] De Pita’ O, Frezzolini A, Cianchini G, Ruffelli M, Teofoli P, Puddu P. T-helper 2 involvement in the pathogenesis of bullous pemphigoid: role of soluble CD30 (sCD30). Arch Dermatol Res 1997;289:667–670.
Increased serum IL-6, TNF-alpha and IL-10 levels in patients with bullous pemphigoid: relationships with disease activity L. D’Auria a, A. Mussi a, C. Bonifati a, A. Mastroianni b, B. Giacalone b, F. Ameglio a,* a
Laboratory of Clinical Pathology, Institute S.Gallicano IRCCS, Rome, Italy b Department of Dermatology, Institute S.Gallicano IRCCS, Rome, Italy
Abstract Aim The present report analyzes the serum levels of three cytokines, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) in 15 patients with bullous pemphigoid (BP) (compared with 20 healthy controls) to evaluate a possible involvement of these biological modulators in the clinical expression of this disease. Background BP is a rare, bullous disease of autoimmune origin with evidence of inflammatory processes that cause skin lesions with local increase of various pro-inflammatory mediators. Methods Determination of cytokine concentrations were obtained employing commercially available ELISA kits. Results The sera of BP patients showed increased levels of these three cytokines (P , 0.01). When the number of skin lesions (blisters and/or erosion) of each patient, employed as a marker of disease activity, was correlated with the serum levels of IL-6 and TNF-alpha, significant correlations were found (IL-6: P , 0.01 and TNF-alpha: P , 0.01, respectively), suggesting a possible role of these mediators in the development of BP blisters. The serum levels of IL-6 also correlated (P = 0.01) with those of serum C reactive protein (CRP), an acute-phase protein induced by IL-6 in hepatocytes. In addition, serum TNFalpha and sE-selectin (an adhesion molecule previously reported to be increased by this cytokine) levels were also correlated (P , 0.05). Conclusions On the basis of these data, it may be indicated that at least IL-6 and TNF-alpha are associated with the clinical expression of BP and that the endothelial activation (possibly induced by the TNF-alpha activity), seems to be an important phase of this dermatosis. 1999 Elsevier Science B.V. All rights reserved. Keywords: Cytokines; Bullous pemphigoid; Serum; Blister fluid
1. Introduction Bullous pemphigoid (BP) is a rare, autoimmune dermatosis characterized by blisters appearing on erythematous/edematous skin, and more rarely on normal skin. Blister cleavage is localized between the epidermis and the lamina lucida and is caused by autoantibodies directed against the 230 and 180 kDa (major antigen) proteins [1]. Several pathogenetic steps are necessary between the autoantibody * Corresponding author. Fax: +39-6-58543747.
0926-9959/99/$ - see front matter PII: S09 26-9959(98)001 26-3
induction and the clinical expression of the disease, including the release of various cytokines. Interleukin-6 (IL-6) is one of the most important pro-inflammatory cytokines and is produced by various cell types, including keratinocytes, monocytes/ macrophages, T-lymphocytes, endothelial cells. It stimulates B-cells to differentiation and antibody secretion [2] and the production of acute phase proteins by hepatocytes [3]. IL-6 seems to play a role in autoimmune diseases: high levels of this molecule have been reported in arthritis, Castelman’s disease, psoriasis and other diseases [4].
1999 Elsevier Science B.V. All rights reserved.
12
L. D’Auria et al. / J. Eur. Acad. Dermatol. Venereol. 12 (1999) 11–15
Tumor necrosis factor-alpha (TNF-alpha) is another pro-inflammatory modulator; it is produced by a wide spectrum of cells and acts on most cells types including eosinophils and neutrophils, T-cells, keratinocytes, etc. This molecule also induces the expression of E-selectin on endothelial cells, known to be involved in all inflammatory processes [5]. In contrast, interleukin-10 (IL-10), a so called TH2 cytokine, is described to exert anti-inflammatory activities. CD4+ T-cells, activated monocytes and peripheral blood cells are sources of IL-10. This cytokine can inhibit the antigen-presenting function of macrophages and can down-regulate class II MHC expression on macrophages [6]. In addition, it is a growth co-stimulator of mast-cells [7,8] and activates endothelial cells [9]. The aim of the present report was therefore to compare the serum levels of IL-6, TNF-alpha and IL-10 with those observed in healthy subjects and establish possible correlations between these levels and disease activity, in order to better evaluate the role of these cytokines in BP.
days, showed disease relapse. The serum titers of antibody anti-basement-membrane-zone (ABMZ) were determined in all patients. Diagnosis was made on the basis of histological examination and direct immunofluorescent assay on biopsies of lesional and perilesional skin. At the time of enrollment, the serum cytokine and sE-selectin levels were assayed using commercially available ELISA kits (R & D Systems, 614 McKinley Place, NE Minneapolis, MN 55413 USA) according to the manufacturer’s instructions. The kit sensitivities were 0.09 pg/ml (IL-6), 2.0 pg/ ml (IL-10), 4.4 pg/ml (TNF-alpha) and 0.1 ng/ml (sEselectin), respectively. Cytokine determinations were also made on the sera of 20 healthy control subjects, matched for age and sex with the BP patients (median age: 73 years, range 42–87 years, sex: nine males, six females). The serum levels of the C-reactive protein (CRP) were determined by nephelometry (Beckman, Array 360, CRP reagent, Galway, Ireland).
3. Statistical analysis 2. Materials and methods Fifteen consecutive patients with BP (sex: 10 males, five females; median age: 82 years, range 33–88 years; median disease duration: 0 years, range 0–12 years) were enrolled in this study. Because of the lack of a standard parameter to gauge disease activity, the number of skin lesions (blisters and/or erosions) of each patient at the time of enrollment was counted (median number: 16, range 3–70). Ten patients were diagnosed for the first time, while the remaining subjects, untreated for at least 15
Because of the lack of knowledge on the type of the data distribution, comparisons between the groups were made with the Mann–Whitney non-parametric test. The Spearman rank correlation test was used to analyze the correlations between the different variables [10].
4. Results Table 1 reports the median serum levels and ranges of IL-6, TNF-alpha and IL-10 in both the BP patients
Table 1 Medians, ranges and number of detectable samples in the sera of subjects with bullous pemphigoid and in healthy controls Cytokine
IL-6 TNF-alpha IL-10
BPS
CTRS
P
Det/n
Median
Range
Det/n
Median
Range
15/15 9/15 8/15
17.8 5.3 2.7
0.1–138.1 ,4.4–32.4 ,2.0–81.0
15/20 1/20 3/20
1.6 ,4.4 ,2.0
0.3–4.7 ,4.4–6.0 ,2.0–5.1
PBS, bullous pemphigoid sera; CTRS, controls sera; Det, number of detectable samples; n, number of subjects. All the values are expressed in pg/ml. Comparisons were calculated using the Mann–Whitney test.
,0.01 ,0.01 ,0.01
L. D’Auria et al. / J. Eur. Acad. Dermatol. Venereol. 12 (1999) 11–15
Fig. 1. Correlation between the serum levels of IL-6 (pg/ml) and the number of skin lesions of 15 BP patients.
and controls; those of the patient group were significantly increased (P , 0.01). When the number of skin lesions of each patient was correlated with the serum cytokine levels, significant correlations were found between disease activity and either IL-6 (R = 0.72, P , 0.01) (Fig. 1) or TNF-alpha (R = 0.76, P , 0.01) (Fig. 2). In contrast, no significant correlation was observed with IL-10. In addition, the serum levels of TNF-alpha significantly correlated (R = 0.64, P , 0.05) with those of sE-selectin. As expected, because the CRP is specifically induced by IL-6, a significant correlation between these two molecule concentrations was observed in BP patients (R = 0.60, P = 0.01); the median serum CRP level was 1.25 mg/100 ml, range 0.1–18.0).
13
The results obtained are in agreement with the histological and laboratory findings on BP. In fact, IL-6 and TNF-alpha are produced by keratinocytes and other cells that constitute the cell infiltrates of BP lesions (including monocytes/macrophages, T-cells, eosinophils and mastocytes) [16]. Both TNF-alpha and interleukin-5 (IL-5) [17] are also known to activate eosinophils which in turn have been suggested to mediate, at least in part, the blistering processes, while IL-6 stimulates B-cell differentiation and subsequent autoantibody production [2]. As an indirect suggestion of IL-6 activity, the serum levels of CRP are not only often increased in BP patients [3] but there was a significant correlation with the serum IL-6 levels in this study. In a previous report, we observed increased sEselectin (an endothelial activation marker) levels in the sera of BP patients [18]. TNF-alpha induces the expression of E-selectin, which may therefore represent a marker of TNF-alpha activity and, as expected, a statistically significant correlation between these two molecules was found, suggesting that the former might mediate the endothelial activation in BP. Also IL-10 showed increased serum levels in BP patients and has been reported to induce E-selectin molecules on the endothelial cells [19]. IL-10 exerts stimulatory functions on mast cell growth [7,8], another cell known to play a role in the development of BP lesions [20], and inhibits CD4 + T-cell
5. Discussion Elevated concentrations of IL-4, IL-6 and IL-10 at the local level (blister fluid) have already been described in patients with BP [11]; in agreement with these data, high levels of these cytokines and other anti- and pro-inflammatory modulators in BP blister fluids were reported [12–15], pointing to a local production of these molecules. In the present study, increased levels of IL-6, TNF-alpha and IL10 are also described for the first time in the sera of BP patients.
Fig. 2. Correlation between the serum levels of TNF-alpha (pg/ml) and the number of skin lesions of 15 BP patients.
14
L. D’Auria et al. / J. Eur. Acad. Dermatol. Venereol. 12 (1999) 11–15
functions mediated by the cytokines released by monocyte/macrophage cells [21]. Together with IL4, IL-10 is considered the most representative biological modulator of a Th2 response, characterizing pregnancy, chronic infections and inflammatory or allergic diseases [22]. The data presented in this report stress the relationship between the serum increases of those cytokines already shown to be elevated in blister fluids [11,12] and indicates that local production conditions the serum concentrations. The correlations between the serum levels of IL-6 and TNF-alpha with the number of the skin lesions (blisters and/or erosions) of each patient, a par-ameter of disease activity, further emphasizes the role of these molecules as mediators of the pathogenetic steps leading to the development of blisters in BP.
[7]
[8]
[9]
[10] [11]
[12]
Acknowledgements This work was partially supported by the ‘Pemphigus’ Project of the Italian Ministry of Health.
[13]
[14]
References [15] [1] Stanley JR. Bullous pemphigoid, cicatritial pemphigoid and chronic bullous diseases of childhood. In: Fitzpatrick TB, Eiden AZ, Wolff K, Freedberg IM, Austen KF, editors. Dermatology in general medicine, fourth ed., Chp. 53. New York: McGraw-Hill, 1993, pp. 615–625. [2] Kikutami H, Tetsuya T, Akira S, et al. Effect of B cell differentiation factor (BCDF) on biosynthesis and secretion of immunoglobulin molecules in human B cell lines. J Immunol 1985;134:990–995. [3] Baumann H, Jahreis GP, Sauder DN, Koj A. Human keratinocytes and monocytes release factors which regulate the synthesis of major acute phase plasma proteins in hepatic cells from man, rat and mouse. J Biol Chem 1984;259: 7331–7342. [4] Hirano T. Interleukin-6 and its relation to inflammation and disease. Clin Immunol Immunopathol 1992;62:S60– 65. [5] Aggarwal BB, Natarajan K. Tumor necrosis factors: developments during the last decade. Eur Cyt Netw 1996;7:93– 124. [6] de Waal Malefyt R, Haanen J, Spits H, et al. Interleukin-10 (IL-10) and viral IL-10 strongly reduce antigen -specific human T cell proliferation by diminishing the antigen-pre-
[16]
[17]
[18]
[19]
[20]
senting capacity of monocytes via downregulation of class II major histocompatibility complex expression. J Exp Med 1991;174:915–924. Rennik D, Hunte B, Dang W, Thompson-Snipes W, Hudak S. Interleukin-10 promotes the growth of megakaryocyte, mastcells, and multilineage colonies: analysis with committed progenitors and Thy10Sca1 + stem cells. Exp Hematol 1994;22: 136–141. Thompson-Snipes L, Dhar V, Bond MW, Mosmann TR, Moore KW, Rennik DM. Interleukin-10: a novel stimulatory factor for mast cells and their progenitors. J Exp Med 1991;173:507–510. Sironi M, Mun˜oz C, Pollicino T, et al. Divergents effects of interleukin-10 on cytokine production by mononuclear phagocytes and endothelial cells. Eur J Immunol 1993;23:2692– 2695. Snedcor GW, Cochran WG. Statistical methods, sixth ed. Ames, IA: IOWA State University Press, 1967. Schmidt E, Bastian B, Dummer R, Tony HP, Bro¨cker EB, Zillikens D. Detection of elevated levels of IL-4, IL-6, and IL-10 in blister fluid of bullous pemphigoid. Arch Dermatol Res 1996;288:353–357. Ameglio F, D’Auria L, Bonifati C, et al. Blister fluids and serum concentrations of different cytokines in patients with bullous pemphigoid. Int J Immunopath Pharm 1997;10:97– 98. Ameglio F, D’Auria L, Bonifati C, Ferraro C, Mastroianni A, Giacalone B. Cytokine pattern in blister fluids and serum of patients with bullous pemphigoid; relationships with disease intensity. Br J Dermatol 1998;138:611–614. Caproni M, Bianchi B, Amato LE, Fabbri P. Th2-like and fibrogenic cytokines expression in cicatritial pemphigoid. Int J Immunopath Pharm 1997;10:99–102. D’Auria L, Pietravalle M, Mastroianni A, et al. IL-5 levels in the serum and blister fluid of patients with bullous pemphigoid: correlations with eosinophilic cationic protein, RANTES, IgE and disease severity. Arch Dermatol Res 1998;290:25–27. Nestor MS, Cochran AJ, Ahmed AR. Mononuclear cell infiltrate in bullous disease. J Invest Dermatol 1987;88:172– 175. Terr AI. Inflammation. In: Stites DP, Terr AI, Parslow TG, editors. Basic and clinical immunology, eight ed., Chp. 11. Appleton and Lange, Norwalk, CT, USA, 1994, p. 139. D’Auria L, Cordiali-Fei P, Pietravalle M, et al. The serum levels of sE-selectin are increased in patients with bullous pemphigoid or pemphigus vulgaris. Correlation with the number of skin lesions and recovery after corticosteroid therapy. Br J Dermatol 1997;137:59–64. Palmetshofer A, Schwarz A, Mahnke K, Bhardwaj R, Luger TA, Schwarz T. Interleukin-10 affects the expression of adhesion molecules on human dermal microvascular endothelial cells. Abstracts of the Sixth Immunodermatology Symposium of European Immunodermatology Society, Mu¨nster, Germany, 24–26 June, 1994. Wintroub BU, Mihm MC, Goetzl EJ, Soter NA, Austen KF. Morphologic and functional evidence for release of mast-cell
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