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Beta2-microglobulin-deficient mice are resistant to bullous pemphigoid.

Liu Z, Roopenian DC, Zhou X, Christianson GJ, Diaz LA, Sedmak DD, Anderson CL - J. Exp. Med. (1997)

Bottom Line: Recent understanding of the mechanism of immunoglobulin G (IgG) catabolism has yielded new insight into antibody-mediated diseases.Such an hypothesis would predict that beta2m-deficient mice would also be resistant to experimental bullous pemphigoid, a disease with a pathogenesis thought to be much simpler than SLE, being the result of antibody directed toward a pathogenic epitope on the epidermal hemidesmosome that anchors basal keratinocytes to the basement membrane.These data would indicate that autoantibody-mediated inflammation might be prevented or controlled by appropriate modulation of FcRn function.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, Medical College of Wisconsin, Milwaukee, Wisconsin 43226, USA. zhiliu@post.its.mew.edu

ABSTRACT
Recent understanding of the mechanism of immunoglobulin G (IgG) catabolism has yielded new insight into antibody-mediated diseases. We proposed that beta2-microglobulin (beta2m)-deficient mice have been protected from systemic lupus erythematosis (SLE)-like syndromes because they lack the beta2m-associated IgG protection receptor (FcRn) and therefore catabolize IgG, including pathogenic IgG autoantibodies, considerably more rapidly than normal mice. Such an hypothesis would predict that beta2m-deficient mice would also be resistant to experimental bullous pemphigoid, a disease with a pathogenesis thought to be much simpler than SLE, being the result of antibody directed toward a pathogenic epitope on the epidermal hemidesmosome that anchors basal keratinocytes to the basement membrane. To test this hypothesis, we administered pathogenic rabbit antibody directed toward the hemidesmosome to beta2m-deficient mice and to normal control mice, both intraperitoneally and intradermally, and assessed the mice clinically, histologically, and immunologically for manifestations of skin disease. We found that the beta2m-deficient mice were protected when the antibody was given intraperitoneally whereas intradermal administration resulted in blisters only slightly less severe than those seen in normal mice. These data would indicate that autoantibody-mediated inflammation might be prevented or controlled by appropriate modulation of FcRn function.

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Serum anti-mBP180 IgG levels in β2m−/− mice after intradermal injection. Neonatal β2m−/− (bar 1), β2m+/− (bar 2), C57BL/6J (bar  3), and BALB/c (bar 4) mice were injected intradermally with 2.5 mg/g  body weight anti-mBP180 IgG and serum samples were collected 12 h after injection and assayed for rabbit IgG by ELISA. n = 5 for each point.
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Figure 5: Serum anti-mBP180 IgG levels in β2m−/− mice after intradermal injection. Neonatal β2m−/− (bar 1), β2m+/− (bar 2), C57BL/6J (bar 3), and BALB/c (bar 4) mice were injected intradermally with 2.5 mg/g body weight anti-mBP180 IgG and serum samples were collected 12 h after injection and assayed for rabbit IgG by ELISA. n = 5 for each point.

Mentions: Intradermal injection of pathogenic anti-mBP180 IgG induced subepidermal blisters in β2m−/− mice. To demonstrate that anti-mBP180 IgG is pathogenic in β2m−/− mice if it binds to its target antigen sufficiently, neonatal β2m−/− (n = 5), β2m+/− (n = 5), BALB/c (n = 5), and C57BL/6J (n = 5) mice were administered intradermally pathogenic anti-mBP180 IgG (5 mg/g body weight). After 12-h incubation, like normal control mice, β2m−/− mice developed subepidermal blisters, along with in vivo deposition of rabbit IgG and murine C3 at BMZ and neutrophilic infiltration (see Table 1). However, clinical examination showed that disease activity in β2m−/− mice (2+) was less severe than in control mice (3+) (Table 1). Direct IF revealed a less intense staining of BMZ in β2m−/− than in control mice (data not shown). Quantitation of neutrophilic infiltration by the MPO assay also showed a similar trend, with 0.77 ± 0.08 in β2m−/− mice versus 0.89 ± 0.09 in β2m+/− mice (Fig. 4). At 12 h after injection, circulating anti-mBP180 IgG levels in β2m−/− were 77% of those in β2m+/− mice (Fig. 5). Indirect IF of sections of skin from uninjected β2m−/− and normal control mice indicated that the pathogenic rabbit antibody bound the basement membrane zone with equal intensity and pattern (data not shown), indicating that the absence of β2m did not prevent binding of the pathogenic antibody to its target.


Beta2-microglobulin-deficient mice are resistant to bullous pemphigoid.

Liu Z, Roopenian DC, Zhou X, Christianson GJ, Diaz LA, Sedmak DD, Anderson CL - J. Exp. Med. (1997)

Serum anti-mBP180 IgG levels in β2m−/− mice after intradermal injection. Neonatal β2m−/− (bar 1), β2m+/− (bar 2), C57BL/6J (bar  3), and BALB/c (bar 4) mice were injected intradermally with 2.5 mg/g  body weight anti-mBP180 IgG and serum samples were collected 12 h after injection and assayed for rabbit IgG by ELISA. n = 5 for each point.
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Related In: Results  -  Collection

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Figure 5: Serum anti-mBP180 IgG levels in β2m−/− mice after intradermal injection. Neonatal β2m−/− (bar 1), β2m+/− (bar 2), C57BL/6J (bar 3), and BALB/c (bar 4) mice were injected intradermally with 2.5 mg/g body weight anti-mBP180 IgG and serum samples were collected 12 h after injection and assayed for rabbit IgG by ELISA. n = 5 for each point.
Mentions: Intradermal injection of pathogenic anti-mBP180 IgG induced subepidermal blisters in β2m−/− mice. To demonstrate that anti-mBP180 IgG is pathogenic in β2m−/− mice if it binds to its target antigen sufficiently, neonatal β2m−/− (n = 5), β2m+/− (n = 5), BALB/c (n = 5), and C57BL/6J (n = 5) mice were administered intradermally pathogenic anti-mBP180 IgG (5 mg/g body weight). After 12-h incubation, like normal control mice, β2m−/− mice developed subepidermal blisters, along with in vivo deposition of rabbit IgG and murine C3 at BMZ and neutrophilic infiltration (see Table 1). However, clinical examination showed that disease activity in β2m−/− mice (2+) was less severe than in control mice (3+) (Table 1). Direct IF revealed a less intense staining of BMZ in β2m−/− than in control mice (data not shown). Quantitation of neutrophilic infiltration by the MPO assay also showed a similar trend, with 0.77 ± 0.08 in β2m−/− mice versus 0.89 ± 0.09 in β2m+/− mice (Fig. 4). At 12 h after injection, circulating anti-mBP180 IgG levels in β2m−/− were 77% of those in β2m+/− mice (Fig. 5). Indirect IF of sections of skin from uninjected β2m−/− and normal control mice indicated that the pathogenic rabbit antibody bound the basement membrane zone with equal intensity and pattern (data not shown), indicating that the absence of β2m did not prevent binding of the pathogenic antibody to its target.

Bottom Line: Recent understanding of the mechanism of immunoglobulin G (IgG) catabolism has yielded new insight into antibody-mediated diseases.Such an hypothesis would predict that beta2m-deficient mice would also be resistant to experimental bullous pemphigoid, a disease with a pathogenesis thought to be much simpler than SLE, being the result of antibody directed toward a pathogenic epitope on the epidermal hemidesmosome that anchors basal keratinocytes to the basement membrane.These data would indicate that autoantibody-mediated inflammation might be prevented or controlled by appropriate modulation of FcRn function.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, Medical College of Wisconsin, Milwaukee, Wisconsin 43226, USA. zhiliu@post.its.mew.edu

ABSTRACT
Recent understanding of the mechanism of immunoglobulin G (IgG) catabolism has yielded new insight into antibody-mediated diseases. We proposed that beta2-microglobulin (beta2m)-deficient mice have been protected from systemic lupus erythematosis (SLE)-like syndromes because they lack the beta2m-associated IgG protection receptor (FcRn) and therefore catabolize IgG, including pathogenic IgG autoantibodies, considerably more rapidly than normal mice. Such an hypothesis would predict that beta2m-deficient mice would also be resistant to experimental bullous pemphigoid, a disease with a pathogenesis thought to be much simpler than SLE, being the result of antibody directed toward a pathogenic epitope on the epidermal hemidesmosome that anchors basal keratinocytes to the basement membrane. To test this hypothesis, we administered pathogenic rabbit antibody directed toward the hemidesmosome to beta2m-deficient mice and to normal control mice, both intraperitoneally and intradermally, and assessed the mice clinically, histologically, and immunologically for manifestations of skin disease. We found that the beta2m-deficient mice were protected when the antibody was given intraperitoneally whereas intradermal administration resulted in blisters only slightly less severe than those seen in normal mice. These data would indicate that autoantibody-mediated inflammation might be prevented or controlled by appropriate modulation of FcRn function.

Show MeSH
Related in: MedlinePlus