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IgG4 autoantibodies induce dermal-epidermal separation.

Mihai S, Chiriac MT, Herrero-González JE, Goodall M, Jefferis R, Savage CO, Zillikens D, Sitaru C - J. Cell. Mol. Med. (2007 Sep-Oct)

Bottom Line: In these diseases, IgG1 and IgG3 isotypes, but not the IgG4 subclass, are thought to trigger inflammatory pathways resulting in tissue damage.Purified IgG4 did not fix complement, but, interestingly, like IgG1, activated leucocytes and induced dermal-epidermal separation.The potential of IgG4 autoantibodies to induce Fc-dependent dermal-epidermal separation was significantly lower compared to IgG1.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, University of Lübeck, Lübeck, Germany.

ABSTRACT
Bullous pemphigoid (BP) is a sub-epidermal autoimmune blistering disease associated with autoantibodies to the dermal-epidermal junction (DEJ). Patients' autoantibodies induce dermal-epidermal separation when co-incubated with cryosections of human skin and leucocytes from healthy volunteers. IgG autoantibodies trigger complement and/or leucocyte activation resulting in specific pathology in several autoimmune conditions. In these diseases, IgG1 and IgG3 isotypes, but not the IgG4 subclass, are thought to trigger inflammatory pathways resulting in tissue damage. The capacity of IgG4 autoantibodies to mediate tissue damage has not yet been demonstrated. In this study, we isolated IgG1 and IgG4 autoantibodies from bullous pemhigoid patients'serum and analysed their blister-inducing potential in our cryosection assay. As expected, complement-fixing IgG1 autoantibodies induced sub-epidermal splits in this experimental model. Purified IgG4 did not fix complement, but, interestingly, like IgG1, activated leucocytes and induced dermal-epidermal separation. The potential of IgG4 autoantibodies to induce Fc-dependent dermal-epidermal separation was significantly lower compared to IgG1. Our results demonstrate that IgG4 autoantibodies are able to activate leucocytes and point to a hitherto less recognized function of IgG4. Moreover, for the first time, we clearly demonstrate that BP IgG4 autoantibodies have the capacity to induce leucocyte-dependent tissue damage.

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Related in: MedlinePlus

IgG4 autoantibodies, in contrast to IgG1, do not fix complement to the dermal–epidermal junction. In a representative experiment, cryosections of normal human skin were incubated with serum and purified antibody preparations from patient 2 and, subsequently, treated with fresh human serum as a source of complement. Both serum (A) and purified IgG1 autoantibodies (B) fixed complement C3 at the dermal–epidermal junction in a linear fashion. In contrast, incubation of cryosections with IgG4 specific for the dermal–epidermal junction (C) or serum from a healthy control (D) does not result in C3 deposition (all magnifications, ×200).
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fig02: IgG4 autoantibodies, in contrast to IgG1, do not fix complement to the dermal–epidermal junction. In a representative experiment, cryosections of normal human skin were incubated with serum and purified antibody preparations from patient 2 and, subsequently, treated with fresh human serum as a source of complement. Both serum (A) and purified IgG1 autoantibodies (B) fixed complement C3 at the dermal–epidermal junction in a linear fashion. In contrast, incubation of cryosections with IgG4 specific for the dermal–epidermal junction (C) or serum from a healthy control (D) does not result in C3 deposition (all magnifications, ×200).

Mentions: Serum samples from BP patients and their purified IgG1 (n = 3) and IgG4 (n = 5) fractions, as well as serum samples from healthy controls, were incubated with cryosections of human skin, in the presence of normal human serum as a source of complement. As expected, like the original sera (Fig. 2A), IgG1 autoantibodies (Fig. 2B) fixed complement to the basement membrane zone. In contrast, in sections treated with IgG4 autoantibodies (Fig. 2C) or serum from a healthy control (Fig. 2D), deposition of complement at the DEJ was not detected.


IgG4 autoantibodies induce dermal-epidermal separation.

Mihai S, Chiriac MT, Herrero-González JE, Goodall M, Jefferis R, Savage CO, Zillikens D, Sitaru C - J. Cell. Mol. Med. (2007 Sep-Oct)

IgG4 autoantibodies, in contrast to IgG1, do not fix complement to the dermal–epidermal junction. In a representative experiment, cryosections of normal human skin were incubated with serum and purified antibody preparations from patient 2 and, subsequently, treated with fresh human serum as a source of complement. Both serum (A) and purified IgG1 autoantibodies (B) fixed complement C3 at the dermal–epidermal junction in a linear fashion. In contrast, incubation of cryosections with IgG4 specific for the dermal–epidermal junction (C) or serum from a healthy control (D) does not result in C3 deposition (all magnifications, ×200).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4401274&req=5

fig02: IgG4 autoantibodies, in contrast to IgG1, do not fix complement to the dermal–epidermal junction. In a representative experiment, cryosections of normal human skin were incubated with serum and purified antibody preparations from patient 2 and, subsequently, treated with fresh human serum as a source of complement. Both serum (A) and purified IgG1 autoantibodies (B) fixed complement C3 at the dermal–epidermal junction in a linear fashion. In contrast, incubation of cryosections with IgG4 specific for the dermal–epidermal junction (C) or serum from a healthy control (D) does not result in C3 deposition (all magnifications, ×200).
Mentions: Serum samples from BP patients and their purified IgG1 (n = 3) and IgG4 (n = 5) fractions, as well as serum samples from healthy controls, were incubated with cryosections of human skin, in the presence of normal human serum as a source of complement. As expected, like the original sera (Fig. 2A), IgG1 autoantibodies (Fig. 2B) fixed complement to the basement membrane zone. In contrast, in sections treated with IgG4 autoantibodies (Fig. 2C) or serum from a healthy control (Fig. 2D), deposition of complement at the DEJ was not detected.

Bottom Line: In these diseases, IgG1 and IgG3 isotypes, but not the IgG4 subclass, are thought to trigger inflammatory pathways resulting in tissue damage.Purified IgG4 did not fix complement, but, interestingly, like IgG1, activated leucocytes and induced dermal-epidermal separation.The potential of IgG4 autoantibodies to induce Fc-dependent dermal-epidermal separation was significantly lower compared to IgG1.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, University of Lübeck, Lübeck, Germany.

ABSTRACT
Bullous pemphigoid (BP) is a sub-epidermal autoimmune blistering disease associated with autoantibodies to the dermal-epidermal junction (DEJ). Patients' autoantibodies induce dermal-epidermal separation when co-incubated with cryosections of human skin and leucocytes from healthy volunteers. IgG autoantibodies trigger complement and/or leucocyte activation resulting in specific pathology in several autoimmune conditions. In these diseases, IgG1 and IgG3 isotypes, but not the IgG4 subclass, are thought to trigger inflammatory pathways resulting in tissue damage. The capacity of IgG4 autoantibodies to mediate tissue damage has not yet been demonstrated. In this study, we isolated IgG1 and IgG4 autoantibodies from bullous pemhigoid patients'serum and analysed their blister-inducing potential in our cryosection assay. As expected, complement-fixing IgG1 autoantibodies induced sub-epidermal splits in this experimental model. Purified IgG4 did not fix complement, but, interestingly, like IgG1, activated leucocytes and induced dermal-epidermal separation. The potential of IgG4 autoantibodies to induce Fc-dependent dermal-epidermal separation was significantly lower compared to IgG1. Our results demonstrate that IgG4 autoantibodies are able to activate leucocytes and point to a hitherto less recognized function of IgG4. Moreover, for the first time, we clearly demonstrate that BP IgG4 autoantibodies have the capacity to induce leucocyte-dependent tissue damage.

Show MeSH
Related in: MedlinePlus