Sep 7 2012
By Helen Albert, Senior medwireNews Reporter
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."
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