Pemphigus vulgaris (PV) is a potentially life-threatening disease, characterized immunohistologically by IgG deposits and complement activation on the surface of keratinocytes. Complement activation has been implicated in the pathogenesis with C3 deposits in about 90% of patients.
Objective:
In order to further elucidate the role of complement in PV and to define which cytokines play a role in C3 mRNA expression, we performed an in vitro study in human keratinocytes.
Methods:
Normal human epidermal keratinocytes (NHuK) were incubated with PV serum and C3 mRNA was measured. We previously had shown that IL-1α and TNF-α are expressed in PV in vivo and in vitro. Since cytokines are able to modulate complement activation, mRNA expression was evaluated in a similar experiment after pretreatment using antibodies against IL-1α and TNF-α.
Results:
Incubation of NHuK with PV sera caused their detachment from the plates after 20–30 minutes with a complete acantholysis within 12 hours. An early C3 mRNA expression was seen after 30 minutes with a peak level after 1 hour. Blocking studies, using antibodies against human IL-1α and TNF-α in NHuK together with PV-IgG, showed reduction of in vitro induced acantholysis and inhibition of C3 mRNA expression.
Conclusions:
This study supports the hypothesis that complement C3 is important in PV acantholysis and that complement activation is increased by IL-1α and TNF-α.
Get full access to this article
View all access options for this article.
References
1.
HunzikerTVassalliJD. Plasmin induces acantholysis in skin organ cultures. Arch Dermatol Res1987; 279:341–346.
2.
BurgeSMMarshallJMCederholm-WilliamsS. Plasminogen binding sites in normal skin. Br J Dermatol1992; 126:35–41.
3.
FabbriPLottiTBonanP. Pathogenesis of pemphigus. The role of epidermal plasminogen activators in acantholysis. Int J Dermatol1985; 24:422–425.
4.
ReinartzJBartlaRBoukampP. Binding and activation of plasminogen at the surface of human keratinocytes. Exp Cell Res1993; 208:197–208.
5.
SeishimaMSatohSNojiriM. Pemphigus IgG induces expression of urokinase plasminogen activator receptor on the cell surface of cultured keratinocytes. J Invest Dermatol1997; 109:650–655.
6.
DobrevHPopovaLVlashevD. Proteinase inhibitors and pemphigus vulgaris. An in vitro and in vivo study. Arch Dermatol1996; 288:648–655.
7.
HashimotoKWunTCBairdJ. Characterization of keratinocyte plasminogen activator inhibitors and demonstration of the prevention of pemphigus IgG-induced acantholysis by a purified plasminogen activator inhibitor. J Invest Dermatol1989; 92:310–315.
8.
ZillikensDAmbachAZenterA. Evidence for cell-mediated immune mechanisms in the pathology of pemphigus. Br J Dermatol1993, 128:636–643.
9.
HertlMAmagaiMSundaramH. Recognition of desmoglein-3 by autoreactive T cells in pemphigus vulgaris patients and normals. J Invest Dermatol1998; 110:62–66.
10.
LinMSSwartzSJLopezA. Development and characterization of desmoglein-3-specific T cells from patients with pemphigus vulgaris. J Clin Invest1997; 99:31–40.
RamadoriGVan DammeJRiederH. Interleukin-6, the third mediator of acute-phase reaction, modulates hepatic protein synthesis in human and mouse: Comparison with interleukin-1α and tumor necrosis factor-α. Eur J Immunol1988; 18:1259–1264.
15.
KatzYStrunkRC. IL-1 and tumor necrosis factor: Similarities and differences in stimulation of expression of alternative pathway of complement and IFN-β2/IL-6 genes in human fibroblasts. J Immunol1989; 142:3862–3867.
16.
TeruiTIshiiKOzawaM. C3 production of cultured human epidermal keratinocytes is enhanced by IFN-γ and TNF-α through different pathways. J Invest Dermatol1997; 108:62–67.
17.
LeeSJLiZShermanBFosterCS. Serum levels of tumor necrosis factor-α and interleukin-6 in ocular cicatricial pemphigoid. Invest Ophthalmol Vis Sci1993; 34:3522–3525.
18.
GrandoSAGlukhenkyBTDrannikGN. Mediators of inflammation in blister fluids from patients with pemphigus vulgaris and bullous pemphigoid. Arch Dermatol1989; 125: 925–930.
19.
GrandoSAGlukhenkyBTDrannikGN. Pemphigus and pemphigoid epidermocytes interfere with interleukin cascade reactions. J Clin Lab Immunol1990; 32:137–141.
20.
BrooksWSLeeYYAbellEDengJS. Comparison of IgG subclasses and complement binding activity of autoantibodies from patients with bullous pemphigoid and pemphigus. J Clin Lab Anal1989; 3:307–311.
21.
ShirakataYShiraishiSSayamaKMikiY. Subclass characteristics of IgG autoantibodies in bullous pemphigoid and pemphigus. J Dermatol1990; 17:661–666.
22.
FelicianiCPourS MohammadProiettoG. Interleukin 1α and TNF-α expression on keratinocytes in pemphigus [Abstr]. J Invest Dermatol1995; 104:474.
23.
FelicianiCTotoPPourS Mohammad: IL-1alpha and TNF-alpha are the main mediators of acantholysis in pemphigus. [Abstr]. J Invest Dermatol1997; 109:406.
24.
JordonREXiaPGeogheganWD. Bullous pemphigoid autoantibodies reactive with intracellular basal keratinocyte antigens: Studies of subclass distribution and complement activation. J Clin Immunol1992; 12:163–169.
25.
PatelHPDiazLAnhaltGJ. Demonstration of pemphigus antibodies on the cell surface of murine epidermal cell monolayers and their internalization. J Invest Dermatol1984; 83: 409–415.
26.
SedgleyCMSamaranayakeLPDarvellBW. The adherence of oral isolates of Enterobacteriacae to Hela cells. An in vitro method using image analysis. APMIS1996; 104:39–46.
BradleyKNorthJSaundersD. Synthesis of classical pathway complement components by chondrocytes. Immunology1996; 88:648–656.
29.
SchiltzJRMichelB. Production of epidermal acantholysis in normal human skin in vitro by the IgG fraction from pemphigus serum. J Invest Dermatol1976; 67:254–260.
30.
BarlowYWrayD. Ultrastructural alterations associated with in vivo and in vitro bound pemphigus antibodies in cultured oral epithelial cells. J Oral Pathol Med1991; 20:241–244.
31.
HashimotoKJensenPJLazarusGS. In vitro studies of acantholysis of keratinocytes induced by pemphigus antibodies. Immunol Serol1989; 46:277–290.
32.
HashimotoTSugiuraMKuriharaS. In vitro complement activation by intercellular antibodies. J Invest Dermatol1982; 78:316–318.
NishikawaTKuriharaSHaradaT. Capability of complement fixation of pemphigus antibodies in vitro. Arch Dermatol Res1977; 260:1–6.
35.
KawanaSGeogheganWDJordonRE. Deposition of the membrane attack complex of complement in pemphigus vulgaris and pemphigus foliaceus skin. J Invest Dermatol1989; 92:588–592.
36.
MascaroJMJrEspanaALiuZ. Mechanisms of acantholysis in pemphigus vulgaris: Role of IgG valence. Clin Immunol Immunopathol1997; 85:90–96.
37.
EspanaADiazLAMascaroJMJr. Mechanisms of acantholysis in pemphigus foliaceus. Clin Immunol Immunopathol1997; 85:83–89.
