Tag Archives: Somatic Mutation

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MedWire News: Researchers have identified the primary target of the autoantibodies found in the serum of patients with the blistering skin disorder pemphigus vulgaris (PV).

PV patients develop antibodies against the proteins desmoglein (DSG)1 and 3, which help epidermal cells stick together and maintain the integrity of the skin, causing painful blistering on the skin and mucus membranes.

Giovanna Zambruno (Istituto Dermopatico dell’Immacolata, Rome, Italy) and colleagues found that the cis-adhesive interface of the DSG3 extracellular domain (EC)1 is the main target of the PV autoantibody (A)224 generated in the serum of patients with PV.

Existing therapies for the condition target the whole immune system, but this can cause problems with side effects and can result in patients being vulnerable to infections.

To pinpoint the trigger of the autoantibody production in PV more specifically, Zambruno and team isolated 15 immunoglobulin (Ig)G antibodies specific for DSG3 from two patients with the disorder.

Of these, three disrupted layers of skin cells in the laboratory and two were pathogenic when expressed in a murine passive transfer model.

The epitopes recognized by the pathogenic PV antibodies were isolated to the DSG3 EC1 and EC2 subdomains and a specific serologic assay was used to pinpoint the target of the PVA224 as being the cis-adhesive interface on EC1.

The researchers suggest that the autoreactivity seen in PV is due to somatic mutations that are generated by an antigen other than DSG3, as binding to DSG3 disappeared when the somatic mutations reverted to the germline sequence.

“The identification of an immunodominant region targeted by pathogenic antibodies has implications for diagnosis of PV and opens new perspectives toward the establishment of therapeutic approaches for treatment of PV patients,” write Zambruno and team in the Journal of Clinical Investigation.

“Finally, the germlined version of the PV autoantibodies may lead to the identification of the antigens that eventually lead to development of this life-threatening disease.”

medwireNews (www.medwire-news.md) is an independent clinical news service provided by Springer Healthcare Limited. © Springer Healthcare Ltd; 2012

Read at: http://www.medwire-news.md/66/101414/Dermatology/Therapeutic_targets_for_pemphigus_vulgaris_discovered.html

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Pemphigus vulgaris (PV) is an autoimmune blistering disease of skin and mucous membranes caused by autoantibodies to the desmoglein (DSG) family proteins DSG3 and DSG1, leading to loss of keratinocyte cell adhesion. To learn more about pathogenic PV autoantibodies, we isolated 15 IgG antibodies specific for DSG3 from 2 PV patients. Three antibodies disrupted keratinocyte monolayers in vitro, and 2 were pathogenic in a passive transfer model in neonatal mice. The epitopes recognized by the pathogenic antibodies were mapped to the DSG3 extracellular 1 (EC1) and EC2 subdomains, regions involved in cis-adhesive interactions. Using a site-specific serological assay, we found that the cis-adhesive interface on EC1 recognized by the pathogenic antibody PVA224 is the primary target of the autoantibodies present in the serum of PV patients. The autoantibodies isolated used different heavy- and light-chain variable region genes and carried high levels of somatic mutations in complementary-determining regions, consistent with antigenic selection. Remarkably, binding to DSG3 was lost when somatic mutations were reverted to the germline sequence. These findings identify the cis-adhesive interface of DSG3 as the immunodominant region targeted by pathogenic antibodies in PV and indicate that autoreactivity relies on somatic mutations generated in the response to an antigen unrelated to DSG3.

Pemphigus vulgaris (PV) is a life-threatening autoimmune blistering disease of skin and mucous membranes caused by autoantibodies that bind to the cadherin-type cell-cell adhesion molecules desmoglein 3 (DSG3) and DSG1, the main constituents of desmosomes, and cause the loss of keratinocyte cell adhesion. The critical role of autoantibodies in PV pathogenesis is supported by the observations that the disease activity correlates with anti-DSG3 antibody titers , that newborns of mothers with active PV exhibit blisters caused by the placental transfer of maternal antibodies, and that pemphigus-like lesions are induced in neonatal mice by passive transfer of anti-DSG3 IgG from PV patients.

In the skin, DSG3 is mainly expressed in the basal and suprabasal layers, while DSG1 is predominantly expressed in the upper epidermal layers. In contrast, in noncornified stratified epithelia, such as the oral mucosa, DSG3 is highly expressed throughout the epithelium, while DSG1 is expressed at a much lower level. The differential expression pattern of DSG1 and DSG3 is responsible for clinical variants of pemphigus: antibodies to DSG3 are present in the mucosal form, while antibodies to both DSG3 and DSG1 are associated with mucocutaneous lesions.

DSG3 is a calcium-binding membrane glycoprotein with an extracellular domain comprising 5 distinct subdomains (EC1–EC5), and it is synthesized as proprotein, which is processed in the Golgi apparatus by removal of a propeptide before transporting to the cell surface. The cleavage of the propeptide occurs upstream of a conserved tryptophan residue in the EC1 subdomain, unmasking residues critical for the formation of homophilic interactions with DSG3 on opposing cells. Several studies have shown that polyclonal antibodies in PV serum react primarily with the aminoterminus of DSG3 in the EC1 and EC2 subdomains (amino acids 1–161).

The isolation of pathogenic mAbs is instrumental for addressing questions as to the mechanism that induces the autoreactive response and drives blister formation in PV patients. Amagai and coworkers isolated from an active mouse model of PV a pathogenic antibody, AK23, which causes loss of cell adhesion by binding to the EC1 subdomain of DSG3 that is involved in the formation of the trans-adhesive interface. A number of human anti-DSG pathogenic and nonpathogenic mAbs were isolated as single-chain variable-region fragments (scFvs) from a PV patient . Similarly to the AK23 mAb, the pathogenic activity of these human antibodies was mapped to the aminoterminal region of EC1, which is masked by the propeptide . Taken together, the human and mouse data suggest that pathogenic antibodies bind primarily to EC1 and disrupt the keratinocyte adhesion by interfering with the trans-adhesive interface of DSG3.

In this study, we isolated from 2 PV patients several IgG autoantibodies that bind DSG3. These antibodies carried high levels of somatic mutations that were required for binding to DSG3. The epitopes recognized by 3 pathogenic antibodies were mapped to the EC1 and EC2 subdomains in regions that are expected to be involved in cis-adhesive interactions. This region was found to be the primary target of serum autoantibodies in PV patients. These results identify the cis-adhesive interface as the immunodominant region targeted by pathogenic antibodies in PV and suggest that autoreactivity relies on somatic mutations triggered by an unrelated antigen.

Full article Available at: http://www.jci.org/articles/view/64413