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D R Garrod

Publications and source records attributed to D R Garrod.

At least 37 records · Page 2Linked to original sources
PubMed1998

Desmoglein in multiple self-healing squamous epithelioma of Ferguson-Smith--comparison of staining patterns with actinic keratoacanthoma and squamous cell carcinoma of the skin.

BACKGROUND: Multiple self-healing squamous cell epithelioma of the skin (MSSE) is the most common variant of multiple keratoacanthoma. Although the morphology of the lesions in MSSE is similar to classical actinic keratoacanthoma (KA), several distinctive features in clinical presentation and histology have been emphasized. Desmosomes have been shown to be downregulated in certain types of carcinoma. Desmogleins (Dsg) are transmembrane desmosomal glycoproteins that exist as three isoforms. Dsg markers have been found to be reduced or absent in squamous cell carcinoma (SCC) but preserved in KA. OBJECTIVE: This study was designed to determine the pattern of Dsg staining in MSSE. METHODS: Eight tumors from two female patients with MSSE were stained with the antidesmoglein monoclonal antibody 32-2B, which recognizes Dsgl and Dsg3. RESULTS: All eight tumors showed uniform pericellular Dsg staining throughout the nonkeratinized layers of the neoplastic epithelium. This pattern is entirely similar to that observed in actinic KA, normal epidermis or follicular epithelium. CONCLUSION: Despite the differences, uniform preservation of Dsg seems to be the invariable feature of both MSSE and KA. Further studies are necessary to evaluate this antibody in routine dermatopathology of MSSE and SCC.

Aged↗
PubMed1998

Immunohistochemical staining for desmogleins 1 and 2 in keratinocytic neoplasms with squamous phenotype: actinic keratosis, keratoacanthoma and squamous cell carcinoma of the skin.

Desmosomes are intercellular junctions that have been shown to be down-regulated in certain types of carcinoma and that may play a role in suppression of invasion and metastasis. This paper describes an immunohistochemical study of three types of epidermal neoplasms with monoclonal antibody to desmoglein in order to determine how desmosomal staining correlates with the clinical, biological and histopathological features of these neoplasms. Actinic keratosis (AK) is the most common keratinocytic premalignant neoplasm that was reported to have a 10-20% rate of malignant transformation into squamous cell carcinoma (SCC). Keratoacanthoma (KA) is a benign neoplasm that involutes spontaneously after a few months of rapid growth. SCC is a malignant tumour capable of metastasis. Electron microscope studies of KA and SCC showed significantly reduced staining for desmosomes in SCC but not in KA. We have examined staining for desmoglein using the monoclonal antibody 33-3D, a mouse IgM monoclonal antibody, that recognizes the cytoplasmic domains of desmoglein (Dsg)1 and Dsg2 on frozen sections. Immunohistochemical staining of normal skin with this antibody revealed strong pericellular localization of the antigen, outlining the cell membranes of the keratinocytes. A series of 30 AKs, 12 KAs and 24 SCCs was stained immunohistochemically with 33-3D monoclonal antibody. All examined KAs showed extensive pericellular staining for Dsg. By contrast, juxtanuclear staining for Dsg was noted in 12 SCCs, and completely negative staining in seven SCCs. The five remaining SCCs showed focal pericellular staining for the Dsg marker. The most common finding in AK was focal pericellular staining for Dsg, with complete absence of staining in dysplastic areas (25 cases). In five cases negative pericellular staining in dysplastic areas was associated with juxtanuclear accumulation of the Dsg marker. A strong negative correlation between Dsg staining and degree of dysplasia was obtained. The Dsg pattern in KA is similar to normal epidermis and shows a clear difference between KA and SCC. AK has a limited loss of Dsg expression in a SCC-like pattern that is congruent with its premalignant nature. As the stain works on frozen tissue, it may be helpful for rapid differentiation in selected cases in cutaneous oncology and Mohs micrographic surgery. This antibody may also have great potential for the detection of the effects of chemopreventive agents in skin cancer.

Animals↗
PubMed1998

Class specific inhibition of house dust mite proteinases which cleave cell adhesion, induce cell death and which increase the permeability of lung epithelium.

1. House dust mite (HDM) allergens with cysteine and serine proteinase activity are risk factors for allergic sensitization and asthma. A simple method to fractionate proteinase activity from HDM faecal pellets into cysteine and serine class activity is described. 2. Both proteinase fractions increased the permeability of epithelial cell monolayers. The effects of the serine proteinase fraction were inhibited by 4-(2-aminoethyl)-benzenesulphonyl fluoride hydrochloride (AEBSF) and soybean trypsin inhibitor (SBTI). The effects of the cysteine proteinase fraction could be inhibited by E-64. No reciprocity of action was found. 3. Treatment of epithelial monolayers with either proteinase fraction caused breakdown of tight junctions (TJs). AEBSF inhibited TJ breakdown caused by the serine proteinase fraction, whereas E-64 inhibited the cysteine proteinase fraction. 4. Agarose gel electrophoresis revealed that the proteinases induced DNA cleavage which was inhibited by the matrix metalloproteinase inhibitor BB-250. Compound E-64 inhibited DNA fragmentation caused by the cysteine proteinase fraction, but was without effect on the serine proteinase fraction. Staining of proteinase-treated cells with annexin V (AV) and propidium iodide (PI) revealed a diversity of cellular responses. Some cells stained only with AV indicating early apoptosis, whilst others were dead and stained with both AV and PI. 5. HDM proteinases exert profound effects on epithelial cells which will promote allergic sensitization; namely disruption of intercellular adhesion, increased paracellular permeability and initiation of cell death. Attenuation of these actions by proteinase inhibitors leads to the conclusion that compounds designed to be selective for the HDM enzymes may represent a novel therapy for asthma.

Animals↗
PubMed1998

All-trans retinoic acid compromises desmosome expression in human epidermis.

An undesirable side-effect of retinoid treatment is skin fragility. As desmosomes are important in maintaining the cohesion of epidermal keratinocytes, we investigated whether all-trans-retinoic acid (RA) compromises desmosome expression in human epidermis, thereby predisposing skin to fragility. Solutions containing 0.025% RA, 5% sodium dodecyl sulphate (SDS) as an irritant control, or vehicle alone were applied to three sites on the buttocks of normal volunteers (n = 9). Treated sites were occluded for 4 days, and biopsies taken under local anaesthesia. Cryostat sections were stained with a panel of antibodies to desmosomal proteins and visualized by immunofluorescence microscopy. Stained sections were randomized and assessed for intensity of staining. The epidermal thickness of each treated site was quantified by image analysis. Western blots of epidermal desmocollins were quantified by densitometry. RA and SDS treatments significantly, but equivalently, increased epidermal thickness compared with vehicle. Immunohistochemically, both RA and SDS were shown to reduce epidermal staining for desmoplakin, desmoglein 1, plakophilin 1 and desmocollin 3 equally compared with vehicle-treated skin (P < 0.001). RA produced a greater reduction in desmocollin 1 staining compared with SDS (P < 0.001). Similar reductions in desmocollins were found by Western blot analysis. Reduced desmocollin expression may indicate compromised desmosomal adhesion, leading to the skin fragility that results from retinoid treatment.

Adult↗
PubMed1998

Cell lines of pulmonary and non-pulmonary origin as tools to study the effects of house dust mite proteinases on the regulation of epithelial permeability.

BACKGROUND: Allergenic and non-allergenic proteinases from house dust mites (HDM) cause loss of adhesion between airway epithelial cells that may result in a loss of functional cohesion between the cells and thus assist in allergen presentation. Improved cellular assay systems are needed to ascertain the mechanisms involved. OBJECTIVES: To survey a series of epithelial cell lines (Calu-3, 16HBE14o-, NCI-H292 and A549 from human airways, and MDCK from dog kidney) and establish their utility for studies of the effects of HDM proteinases from D. pteronyssinus on epithelial permeability. To develop an improved method for measuring changes in epithelial permeability induced by HDM proteinases and other provocants. METHODS: The permeability of epithelial monolayer cultures to mannitol was calculated from measurements of clearance using a technique that permits mathematical estimation and reduction of non-cellular diffusional constraints. Permeability was studied under control conditions and after perturbation of monolayers with HDM proteinases (separated into serine- and cysteine-proteinase classes) or chelation of extracellular Ca2+. Fluorescent antibody staining was used to investigate whether the cells expressed tight junctions (staining of ZO-1), desmosomes (staining of desmoplakin) and zonulae adherentes (staining of E-cadherin). RESULTS: The Calu-3 line was identified as an airway cell line that expressed functional tight junctions, desmosomes and zonulae adherentes. Calu-3 monolayers exhibited a low clearance and permeability to mannitol, similar to that seen in the extensively characterized MDCK cell line. Clearance and permeability were significantly increased by treatment with either HDM proteinase fraction or by calcium chelation. 16HBE14o- cells also had a low permeability to mannitol under control conditions and expressed a similar repertoire of functional proteins from major intercellular junctions. In contrast, NCI-H292 and A549 cell lines were functionally deficient in tight junctions, although they did express desmosomes and zonulae adherentes to a greater extent. Epithelial permeability was found to be a more appropriate and sensitive index of epithelial perturbation than was tracer clearance. CONCLUSION: These results suggest that the Calu-3 and 16HBE14o- cell lines are useful tools in studying the mechanism of HDM proteinases on airway epithelial cell function. HDM proteinases of both cysteine and serine mechanistic classes were found to perturb epithelial adhesion and function.

Adult↗
PubMed1997

Changing pattern of desmocollin 3 expression accompanies epidermal organisation during skin development.

The adhesive core of the desmosome is composed of cadherin-like glycoproteins of 2 families, desmocollins and desmogleins. The desmosomal cadherins show distinct patterns of expression in adult epidermis, and we have suggested that the desmocollins have a functional role in regulating the differentiation and/or morphogenesis of that epithelium (North et al. [1996] Proc. Natl. Acad. Sci. USA 93:7701-7705.). To examine this hypothesis, we cloned murine desmocollins and examined the induction patterns of desmocollins 1 and 3 during skin and skin appendage development. Desmocollins 3 and 1 were first expressed in epidermis in highly regional patterns at embryonic days 13.0 and 13.5, respectively, and both were up-regulated in general body epidermis at day 14.5. At this stage, epidermis is undifferentiated and the desmocollins showed an unexpected expression pattern. However, by day 18.5 when skin had undergone terminal differentiation, desmocollin 1 and 3 expression resembled that found in the adult. Thus, the establishment of the adult pattern of desmocollin expression corresponds to the adult pattern of epidermal stratification. We suggest that it is the ratio of desmocollin 1 to desmocollin 3 expression at different levels in the epidermis that is fundamental in establishing this pattern of differentiation.

Amino Acid Sequence↗
PubMed1997

Molecular aspects of the epithelial phenotype.

Epithelia can be defined morphologically as tissues that line surfaces, and ultrastructurally with reference to their cells' apico-basal polarity and possession of specific cell-cell junctions. Defining the epithelial phenotype at a molecular level is more problematic--while it is easy to name proteins (e.g. keratins) expressed by a 'typical' epithelium, no known molecules are expressed by every epithelium but by no other tissues. Cells can differentiate to and from the epithelial state as part of normal development, as a response to disease or when manipulated in culture. Many factors (matrix components, adhesion molecules, growth factors, transcription factors) have been identified that can trigger these transitions of phenotype in specific cases, but to date no general master regulators of the epithelial state have been found. The epithelial state may therefore be controlled by multiple regulatory genes so that there is no single molecule responsible for all of the diverse types of epithelium that exist in higher animals.

Animals↗
PubMed1997

Mutations in the plakophilin 1 gene result in ectodermal dysplasia/skin fragility syndrome.

Members of the armadillo protein gene family, which includes plakoglobin and beta-catenin, have important functions in cytoskeleton/cell membrane interactions. These proteins may act as linker molecules at adherens junctions and desmosomes at the plasma membrane; in addition, they may have pivotal roles in signal transduction pathways and significant effects on cell behaviour during development. Here, we describe the first human mutations in one of these dual function proteins, plakophilin 1 (band-6 protein; refs 8-10). The affected individual has a complete absence of immunostaining for plakophilin 1 in the skin and is a compound heterozygote for autosomal-recessively inherited premature termination codons of translation on both alleles of the plakophilin 1 gene (PKP1). Clinically, there are features of both cutaneous fragility and congenital ectodermal dysplasia affecting skin, hair and nails. There is no evidence of significant abnormalities in other epithelia or tissues. Desmosomes in the skin are small and poorly formed with widening of keratinocyte intercellular spaces and perturbed desmosome/keratin intermediate filament interactions. The molecular findings and clinical observations in this patient attest to the dual importance of plakophilin 1 in both cutaneous cell-call adhesion and epidermal morphogenesis.

Base Sequence↗
PubMed1997

Human desmocollin 1 (Dsc1) is an autoantigen for the subcorneal pustular dermatosis type of IgA pemphigus.

IgA pemphigus showing IgA anti-keratinocyte cell surface autoantibodies is divided into subcorneal pustular dermatosis (SPD) and intraepidermal neutrophilic IgA dermatosis (IEN) types. We previously showed by immunoblotting that IgA from some IgA pemphigus patients reacted with bovine desmocollins (Dsc), but not human Dsc. To determine the antigen for IgA pemphigus, we focused on conformation-dependent epitopes of Dsc, because sera of patients with classical pemphigus recognize conformation-sensitive epitopes of desmogleins. We constructed mammalian expression vectors containing the entire coding sequences of human Dsc1, Dsc2, and Dsc3 and transiently transfected them into COS7 cells by lipofection. Immunofluorescence of COS7 cells transfected with single human Dscs showed that IgA antibodies of all six SPD-type IgA pemphigus cases reacted with the surface of cells expressing Dsc1, but not with cells expressing Dsc2 or Dsc3. In contrast, none of seven IEN-type IgA pemphigus cases reacted with cells transfected with any Dscs. These results convincingly indicate that human Dsc1 is an autoantigen for SPD-type IgA pemphigus, suggesting the possibility of an important role for Dsc1 in the pathogenesis of this disease. This study shows that a Dsc can be an autoimmune target in human skin disease.

Animals↗
PubMed1997

Protein phosphatases maintain the organization and structural interactions of hepatic keratin intermediate filaments.

The importance of protein phosphatases in the maintenance of cytoskeletal structure is supported by the serious liver injury caused by microcystin-LR, a hepatotoxic inhibitor of type-1 and type-2A serine/threonine protein phosphatases. We used the microcystin-LR-induced cell injury as a model to study the roles of protein dephosphorylation in maintaining cytoskeletal structure and cellular interactions in primary rat hepatocyte cultures. Confocal microscopy revealed that the first visible effect of microcystin-LR is disruption of desmoplakin organization at the cell surface, indicating dissociation of desmosomes. This effect is followed by a dramatic reorganization of both the intermediate filament (keratins 8 and 18) and microfilament networks, resulting in a merged structure in which the intermediate filaments are organized around a condensed actin core. Keratin 8, keratin 18 and desmoplakin I/II are the major cytoskeleton-associated targets for microcystin-LR-induced phosphorylation. Hyperphosphorylation of keratin 8 and 18 is accompanied by an increased keratin solubility, which correlates with the observed morphological effects. Phosphopeptide mapping shows that four specific tryptic phosphopeptides are highly phosphorylated predominantly in the soluble pool of keratin 18, whereas keratin 8 shows no indications of such assembly state-specific sites. Phosphopeptide maps of keratins phosphorylated in vivo and in vitro indicate that Ca2+/calmodulin-dependent kinase may be involved in regulating the serine-specific phosphorylation of both keratin 8 and keratin 18, while cAMP-dependent protein kinase does not seem to play a major role in this context. Taken together, our results show that the interactions between keratin intermediate filaments and desmosomes as well as the assembly states of their main constituent proteins, are directly regulated by serine/threonine kinase/phosphatase equilibria.

Actin Cytoskeleton↗
PubMed1997

The use of antidesmoglein stains in Mohs micrographic surgery. A potential aid for the differentiation of basal cell carcinoma from horizontal sections of the hair follicle and folliculocentric basaloid proliferation.

BACKGROUND: Histopathologic differentiation between benign and malignant tissue is of utmost importance for the Mohs surgeon. Folliculocentric basaloid proliferation (FBP) shares many histologic features with basal cell carcinoma (BCC). It is most commonly associated with tumors of areas with abundant hair follicles such as nasal and perinasal skin. Residual BCC incorrectly identified as a horizontally sectioned hair follicle undoubtedly increases the risk of tumor recurrence. Excision of additional layers of normal tissue to remove "funny looking follicles" may have profound impacts on tissue conservation, preservation of function, and cosmesis. Electron microscope studies of BCC revealed a significant reduction of desmosomes compared with normal basal cells and hair follicle keratinocytes. OBJECTIVE: This study has assessed the potential of rapid staining with monoclonal antidesmoglein antibody (33-3D) to discriminate between BCC, horizontally sectioned hair follicles, and FBP. METHODS: A rapid immunoperoxidase technique with 33-3D antidesmoglein antibody was performed on Mohs frozen sections. We selected 18 patients with BCC of nasal and perinasal locations where histologic discrimination between residual tumor and tumor-free margins with FBP or horizontally sectioned hair follicle was equivocal. RESULTS: Fourteen sections disclosed the preservation of desmoglein marker delineating the cell membranes ("perimembranous" pattern) consistent with normal hair follicles. The sections were identified as tumor-free and no additional stages were performed. The remaining four sections revealed absent perimembranous pattern but presence of diffuse cytoplasmic staining. These were diagnosed as positive for residual BCC requiring the excision of another layer of tissue to obtain tumor-free margins. A follow-up period ranging from 6 to 24 months revealed no instance of recurrent disease. CONCLUSION: Rapid detection of desmoglein with 33-3D antibody is a promising tool for discrimination between residual BCC and FBP or horizontally sectioned hair follicles. It may enhance the sensitivity of Mohs surgery by disclosing the hidden foci of BCC, thus preventing tumor recurrence and unnecessary excision of normal tissue.

Aged↗
PubMed1996

Distinct desmocollin isoforms occur in the same desmosomes and show reciprocally graded distributions in bovine nasal epidermis.

The adhesive core of the desmosome is composed of cadherin-like glycoproteins of two families, desmocollins and desmogleins. Three isoforms of each are expressed in a tissue-specific and developmentally regulated pattern. In bovine nasal epidermis, the three desmocollin (Dsc) isoforms are expressed in overlapping domains; Dsc3 expression is strongest in the basal layer, while Dsc2 and Dsc1 are strongly expressed in the suprabasal layers. Herein we have investigated whether different isoforms are assembled into the same or distinct desmosomes by performing double immunogold labeling using isoform-specific antibodies directed against Dsc1 and Dsc3. The results show that individual desmosomes harbor both isoforms in regions where their expression territories overlap. Quantification showed that the ratio of the proteins in each desmosome altered gradually from basal to immediately suprabasal and upper suprabasal layers, labeling for Dsc1 increasing and Dsc3 decreasing. Thus desmosomes are constantly modified as cells move up the epidermis, with continuing turnover of the desmosomal glycoproteins. Statistical analysis of the quantitative data showed a possible relationship between the distributions of the two isoforms. This gradual change in desmosomal composition may constitute a vertical adhesive gradient within the epidermis, having important consequences for cell positioning and differentiation.

Animals↗
PubMed1996

Immunohistochemical staining of desmosomal components in oral squamous cell carcinomas and its association with tumour behaviour.

Desmosomes are intercellular junctions that have been shown to be down-regulated in certain types of carcinomas and that may play a role in suppression of invasion and metastasis. We have shown previously that immunohistochemical staining for the major desmosomal glycoprotein, desmoglein (Dsg), is reduced in some cases of squamous cell carcinoma (SCC) of the head and neck, and that reduced staining correlates with lymph node involvement. Desmosomes are multicomponent organelles. We therefore sought to determine whether another major desmosomal molecule, desmoplakin (Dp), showed similar reduced expression to that shown by desmoglein. We have stained 65 specimens of primary SCC of the oral cavity (37 non-metastatic and 28 metatastic) with monoclonal antibodies to both desmoglein and desmoplakin. We show that reduction of Dp staining correlates with loss of differentiation of the primary tumour, degree of invasion and presence of lymph node metastases. Similar correlations were found with Dsg staining. There was also correlation between reduction in Dp staining and reduction in Dsg staining. It is concluded that down-regulation of desmosomal expression occurs in some cases of SCC of the oral cavity and is associated with invasion and metastasis. Desmosomes may have an invasion and metastasis suppressor function.

Carcinoma, Squamous Cell↗
PubMed1996

Expression of full-length desmosomol glycoproteins (desmocollins) is not sufficient to confer strong adhesion on transfected L929 cells.

Desmocollins are cadherin-like glycoproteins that are localized in desmosomes. They are thought to play a role in cell adhesion but direct evidence for this is currently unavailable. For this reason we have expressed cDNAs encoding full-length bovine desomocollin type 1a and type 1b in mouse fibroblast (L929) cells. This system has previously been used to demonstrate the adhesive properties of E-cadherin. E-cadherin-mediated cell-cell adhesion is thought to require interaction of the cytoplasmic domain with the catenins that are expressed in L-cells. Because L929 cells do not express cytoplasmic desmosomal components that may be required for desmocollin-mediated adhesion, we constructed a chimeric cDNA encoding the bovine type 1 extracellular domain linked to the mouse E-cadherin transmembrane and cytoplasmic domains. cDNAs were transfected into cells and clones that expressed heterologous protein at the cell surface were isolated. The full-length desmocollins apparently did not interact with any other molecules, but the chimeric protein did bind to endogenous mouse alpha- and beta-catenin. Surprisingly none of the desmocollin-transfected cell lines showed significant adhesive properties under conditions where cells transfected with E-cadherin exhibited strong adhesiveness. We conclude that desmcollin expression alone is not sufficient to confer adhesion on transfected cells and more than one desmosomal component may be required.

Animals↗
PubMed1996

Differential expression of desmosomal glycoproteins in keratoacanthoma and squamous cell carcinoma of the skin: an immunohistochemical aid to diagnosis.

The distinction between keratoacanthoma and squamous cell carcinoma is a common dermatopathological dilemma. Although the mainstay of the diagnosis is still clinico-pathological correlation, many dermatopathologists now include keratoacanthomas in the spectrum of squamous cell carcinomas. Recent reports, however, have pointed out that keratoacanthoma is "deficient squamous cell carcinoma" since it loses the expression of bcl-2 antigen, consistent with initiation of apoptosis, i.e. its involution. Electron microscope studies performed in keratoacanthomas and squamous cell carcinomas also revealed significantly reduced desmosomes in squamous cell carcinoma, but not in keratoacanthoma. A series of 38 keratoacanthomas and 62 squamous cell carcinomas of the skin (28 well-differentiated, 21 moderately differentiated and 13 poorly differentiated) were stained immunohistochemically with the monoclonal antibody 32-2B to desmosomal glycoproteins desmoglein 1 and desmoglein 3. Thirty-five keratoacanthomas showed extensive pericellular desmoglein expression. Three keratoacanthomas and 20 squamous cell carcinomas (19 well-differentiated, 1 moderately differentiated) showed focal staining, and in 11 squamous cell carcinomas (2 moderately differentiated, 9 poorly differentiated) the staining was negative. The remaining 31 squamous cell carcinomas (9 well differentiated, 18 moderately differentiated, 4 poorly differentiated) showed juxtanuclear staining. None of the squamous cell carcinomas exhibited the extensive pericellular pattern found in keratoacanthomas. Assessment of staining intensity, by 3 independent examiners, revealed a strong negative correlation between desmoglein expression and degree of dysplasia in the squamous cell carcinomas (p < 0.01). This antibody therefore clearly distinguishes these tumours and may be of value in the differential diagnosis of keratoacanthoma and squamous cell carcinomas in routine histopathology.

Autoantigens↗
PubMed1996

IgA antikeratinocyte surface autoantibodies from two types of intercellular IgA vesiculopustular dermatosis recognize distinct isoforms of desmocollin.

We previously proposed the term intercellular IgA vesiculopustular dermatosis (IAVPD) for cases showing IgA antikeratinocyte surface autoantibodies. This condition is divided into two subtypes: intraepidermal neutrophilic IgA dermatosis (IEN), showing pustule formation in the entire epidermis, and subcorneal pustular dermatosis (SPD) showing pustule formation in the uppermost epidermis. We have previously reported that serum from certain IAVPD patients reacts with bovine desmocollin (Dsc), a desmosomal cadherin. In this study we showed that two Dsc isoforms with a slightly different molecular weight were recognized by the serum from these patients. Further analysis revealed that serum from patients with the SPD type, which stained the cell surface in the uppermost epidermis with immunofluorescence, seem to react with Dsc1. By contrast, serum from patients with the IEN type, which stained the cell surface at all levels of the epidermis with immunofluorescence, seemed to react with Dsc3. This difference of distribution between the two distinct Dsc molecules may contribute to the different clinicopathological features between the IEN and SPD type of IAVPD.

Autoantibodies↗