Pemphigus autoantibodies generated through somatic mutations target the desmoglein-3 cis-interface

Abstract

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.

MuSK IgG4 autoantibodies cause myasthenia gravis by inhibiting binding between MuSK and Lrp4

“…There is growing evidence, however, that IgG4 antibodies can be pathogenic: IgG4 antibodies against desmoglein cause a skin-blistering disease, termed pemphigus (50), and IgG4 antibodies to the phospholipase A2 receptor are thought to contribute to membranous nephropathy (51). Moreover, IgG4 autoantibodies to Leucine-rich glioma inactivated 1 (Lgi1), a regulator of the voltage-gated potassium channel, are thought to be responsible for limbic encephalitis (52).…”

Characterization of pathogenic human monoclonal autoantibodies against GM-CSF

“…A paper that was published recently characterized pathogenic mAbs that cause pemphigus vulgaris (40). They reverted the somatic mutations from four mAbs against desmoglein-3 (DSG3) and found that the unmutated antibodies did not bind to DSG3.…”

Desmosomal Cadherins and Signaling: Lessons from Autoimmune Disease

“…Direct steric inhibition apparently mimics the so-called tryptophan-swap between interacting Dsg3 molecules which hampers cis-and trans-interaction (Di Zenzo et al, 2012;Spindler et al, 2013;Yamagami et al, 2010). As inhibition of Dsg3 binding contributes to loss of cell cohesion in vivo and in vitro (Heupel et al, 2009b(Heupel et al, , 2008Spindler et al, 2013), it is possible that this mechanism alone is suffi cient to cause blister formation in some cases, especially when blistering is mechanically induced (Mao et al, 2013;Saito et al, 2012).…”