Delineation of diversified desmoglein distribution in stratified squamous epithelia: implications in diseases

Mahoney, Mỹ G.; Hu, Ying; Brennan, Donna; Bazzi, Hisham; Christiano, Angela M.; Wahl, James K.

doi:10.1111/j.1600-0625.2006.00391.x

Cited by 70 publications

(85 citation statements)

References 40 publications

(43 reference statements)

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“…Because incubation with PF-IgG (containing Dsg 1-specific autoantibodies only) led to keratinocyte dissociation and epidermal splitting, these results demonstrate that Dsg 3 in these models does not compensate for the functional loss of Dsg 1. Our results on the distribution patterns of Dsg 1 and Dsg 3 in human epidermis are supported by a recent study by Mahoney et al, 19 who also found that Dsg 1 and Dsg 3 broadly overlap in the epidermis and that restriction of Dsg 1 to the superficial epidermis and of Dsg 3 to the basal layer is only observed in mouse but not human epidermis. All these data suggest that the clinical phenotype of PV and PF in humans may not be explained by the distribution patterns of Dsg 1 and Dsg 3 alone.…”

Section: Dsg 3 Does Not Compensate For Dsg 1 In Human Epidermissupporting

confidence: 79%

“…4,16 However, recent studies indicate that the expression patterns of Dsg 1 and Dsg 3 in mice profoundly differ from those in humans. 19 iv) To visualize the desmoglein localization pattern in human epidermis, autoantibodies from patients with PV and PF have been applied. 15,20 In these studies, either whole sera of PV and PF patients were used without characterization of the autoantibody profile 20 or IgG fractions were used after immunosabsorption with recombinant Dsg extracellular domains fused to the Fc portion of human IgG.…”

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confidence: 99%

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Pemphigus IgG Causes Skin Splitting in the Presence of Both Desmoglein 1 and Desmoglein 3

Spindler

Drenckhahn

Zillikens

et al. 2007

The American Journal of Pathology

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According to the desmoglein (Dsg) compensation concept, different epidermal cleavage planes observed in pemphigus vulgaris and pemphigus foliaceus have been proposed to be caused by different autoantibody profiles against the desmosomal proteins Dsg 1 and Dsg 3. According to this model, Dsg 1 autoantibodies would only lead to epidermal splitting in those epidermal layers in which no Dsg 3 is present to compensate for the functional loss of Dsg 1. We provide evidence that both pemphigus foliaceus-IgG containing Dsg 1-but not Dsg 3-specific antibodies and pemphigus vulgaris-IgG with antibodies to Dsg 1 and Dsg 3 were equally effective in causing epidermal splitting in human skin and keratinocyte dissociation in vitro. These effects were present where keratinocytes expressed both Dsg 1 and Dsg 3, demonstrating that Dsg 3 does not compensate for Dsg 1 inactivation. Rather, the cleavage plane in intact human skin caused by pemphigus autoantibodies was similar to the plane of keratinocyte dissociation in response to toxin B-mediated inactivation of Rho GTPases. Because we recently demonstrated that pemphigus-IgG causes epidermal splitting by inhibition of Rho A, we propose that Rho GTPase inactivation contributes to the mechanisms accounting for the cleavage plane in pemphigus skin splitting. Pemphigus is an autoimmune blistering skin disease caused by autoantibodies directed to the cadherin-type adhesion molecules desmoglein (Dsg) 1 and 3.1-4 Antibodies against other antigens, including cholinergic receptors, have also been implicated in the pathogenesis.5-9 Several theories have been proposed to explain the mechanisms underlying blister formation by Dsg autoantibodies. However, the different clinical phenotypes of pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are still not fully understood. 10 -12 It is well established that PV is characterized by deep (suprabasal) epidermal blistering, whereas PF exhibits superficial blistering (involving granular or spinous cell layers). In PF, mucous membranes are not involved; whereas in PV, mucosal disease is a regular finding, and skin involvement may occur in addition. 4 Interestingly, these phenotypes usually correlate with different autoantibody profiles. PV patients with only mucosal lesions show autoantibodies to Dsg 3 but not to Dsg 1. PF patients (skin involvement only) reveal autoantibodies to Dsg 1 but not to Dsg 3. In PV patients with both mucous membrane and skin involvement, autoantibodies to Dsg 3 and Dsg 1 may be detected. 4,13,14 These observations, together with studies reporting that Dsg 1 is predominantly expressed in superficial epidermal layers but absent in the suprabasal layer, whereas Dsg 3 is restricted to deep epidermal layers, and that Dsg 1 is less abundantly expressed in mucosal epithelia, have led to the desmoglein compensation hypothesis as an explanation for the different epidermal cleavage planes in PV and PF. 3,4,[15][16][17] According to this model, in the deep epidermis, Dsg 3 compensates for the functional loss of Dsg 1 induced by Ds...

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Section: Dsg 3 Does Not Compensate For Dsg 1 In Human Epidermissupporting

confidence: 79%

mentioning

confidence: 99%

Pemphigus IgG Causes Skin Splitting in the Presence of Both Desmoglein 1 and Desmoglein 3

Spindler

Drenckhahn

Zillikens

et al. 2007

The American Journal of Pathology

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“…For immunofluorescence, OCT-fixed tissue sections (5 pm) were prepared as previously described (Mahoney et al, 2006) with DAPI (100 ng/ml) for DNA counterstaining. OCT-fixed tissues were used with the following antibodies: Flag, MP6, CK6, CK10, 23F4, 1 1E4, and (3-catenin.…”

Section: Immunoblotting and Immunohistochemistrymentioning

confidence: 99%

“…Four distinct desmogleins (Dsgl-4) have been reported with differential expression profiles dependent on the tissue type and differentiation state (Cheng and Koch, 2004;Garrod et al, 2002;Mahoney et al, 2006). Unlike Dsgl and Dsg3 whose expression is restricted to complex stratified epithelia, Dsg2 and Dsg4 are expressed in a wide range of other cell types.…”

Section: Introductionmentioning

confidence: 99%

“…These adhesion structures are essential to maintaining tissue architecture during embryonic development and in the adult organism (Garrod et al, 2002). Desmosomes establish cell-cell contact through three families of proteins including the desmosomal cadherins, armadillo, and plakin proteins (Yin and Green, 2004;Kottke et al, 2006 (Cowin, 1994;Cowin and Burke, 1996;Green and Jones, 1996).Four distinct desmogleins (Dsgl-4) have been reported with differential expression profiles dependent on the tissue type and differentiation state (Cheng and Koch, 2004;Garrod et al, 2002;Mahoney et al, 2006). Unlike Dsgl and Dsg3 whose expression is restricted to complex stratified epithelia, Dsg2 and Dsg4 are expressed in a wide range of other cell types.…”

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confidence: 99%

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Molecular Characterization of Squamous Cell Carcinomas From Recessive Dystrophic Epidermolysis Bullosa

Mahoney¹,

Rodeck²,

Uitto³

2006

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE (DD-MM-YYYY)2. REPORT TYPE 3. DATES COVERED (From -To) PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBERThomas Jefferson University Philadelphia, Pennsylvania 19107 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES ABSTRACTPatients with recessive dystrophic epidermolysis bullosa (RDEB) frequently present with squamous cell carcinomas (SCCs) probably as a result of chronic blistering and extensive scarring. These tumors are clinically aggressive as they metastasize readily. The metastasis-associated protein (MTA)-I, a transcription suppressor, is overexpressed in several epithelial neoplasms including SCCs. Our preliminary results demonstrate that MTAI expression is induced by activation of the epidermal growth factor receptor (EGFR). As deregulation of EGFR signaling is frequently observed in aggressive epithelial neoplasms we propose to study the role of EGFR signaling and MTA1 expression in SCCs derived in RDEB patients. Our Specific Aims are to establish cell lines derived from SCCs in non-RDEB and RDEB patients, characterize the malignant phenotype of these cells as it relates to EGFR expression and signaling and to expression of MTA1, examine the contribution of EGFR/MTA1 to proliferation, invasiveness, and cell survival and identify EGFRdependent signaling pathways contributing to MTA1 expression in these cells. The results from this research will provide invaluable tools for future analysis of the pathobiology of carcinoma cells and will ascertain whether EGFR/MTA1 signaling pathways contributes significantly to the metastasis and invasiveness of SCC derived from RDEB patients. Mahoney, M.G. SUBJECT TERMS INTRODUCTIONA malignant cancer is characterized by its metastatic and invasive properties. Thus, identifying and characterizing the genes that are involved in metastasis will provide the mean...

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Specialized Intercellular Junctions in Epithelial Cells: The Tight Junction and Desmosome

2011

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Delineation of diversified desmoglein distribution in stratified squamous epithelia: implications in diseases

Cited by 70 publications

References 40 publications

Pemphigus IgG Causes Skin Splitting in the Presence of Both Desmoglein 1 and Desmoglein 3

Pemphigus IgG Causes Skin Splitting in the Presence of Both Desmoglein 1 and Desmoglein 3

Molecular Characterization of Squamous Cell Carcinomas From Recessive Dystrophic Epidermolysis Bullosa

Specialized Intercellular Junctions in Epithelial Cells: The Tight Junction and Desmosome

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