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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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MPO activity (mean ± SEM) of skin extracts from β2m−/−  and β2m+/− mice injected intraperitoneally with pathogenic rabbit anti-mBP180 IgG. Neonatal β2m−/− (bars 1 and 2), β2m+/− (bars 3 and 4),  C57BL/6J (bars 5 and 6), and BALB/c (bars 7 and 8) mice received 2.5  mg/g body weight anti-mBP180 IgG. Tissue MPO activity in skin at the  back were determined 4 h (open bars) or 24 h (hatched bars) after IgG administration. n = 5 for each group. *P <0.001, Student's t test for paired  samples (bar 1 versus 3).
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Figure 2: MPO activity (mean ± SEM) of skin extracts from β2m−/− and β2m+/− mice injected intraperitoneally with pathogenic rabbit anti-mBP180 IgG. Neonatal β2m−/− (bars 1 and 2), β2m+/− (bars 3 and 4), C57BL/6J (bars 5 and 6), and BALB/c (bars 7 and 8) mice received 2.5 mg/g body weight anti-mBP180 IgG. Tissue MPO activity in skin at the back were determined 4 h (open bars) or 24 h (hatched bars) after IgG administration. n = 5 for each group. *P <0.001, Student's t test for paired samples (bar 1 versus 3).

Mentions: Pathogenic anti-mBP180 antibodies administered intraperitoneally do not induce experimental BP in β2m−/− mice. When neonatal BALB/c (n = 5), C57BL/6J (n = 5), and β2m+/− (n = 5) mice were injected intraperitoneally with pathogenic anti-mBP180 IgG (2.5 mg/g body weight), as expected, these animals developed extensive blisters 24 h after injection (Fig. 1 A; Table 1). The skin of these animals was markedly erythematous and, upon gentle friction, developed persistent epidermal wrinkling due to epidermal detachment from underlying dermis. Direct IF of cryosections of lesional and peri-lesional skin showed in vivo deposition of rabbit IgG and mouse C3 at the dermal– epidermal junction (Fig. 1 B). H/E stained sections from these mice showed dermal–epidermal separation with neutrophilic infiltration (Fig. 1 C). In contrast, β2m−/− mice (n = 5) exhibited no blisters 24 h after injection with an identical dose of pathogenic anti-mBP180 IgG (Fig. 1 D). Direct IF also showed a significant reduction in in situ deposition of rabbit IgG and mouse C3 at the BMZ (Fig. 1 E). H/E staining of the skin sections from injected mice exhibited no epidermal detachment from the dermis and a neutrophilic infiltrate milder (Fig. 1 F) than positive control mice. Quantitation of neutrophilic infiltration with the MPO assay showed significant changes in the extractable enzyme activity at the injected site at 24 h after injection, with 0.06 ± 0.01 in β2m−/− mice versus 0.41 ± 0.04 in BALB/c, 0.38 ± 0.04 in C57BL/6J, and 0.38 ± 0.03 in β2m+/− mice (P <0.001) (Fig. 2). However, there was no difference in tissue MPO activity in both β2m−/− and control mice 4 h after intraperitoneal administration of anti-mBP180 IgG (Fig. 2), suggesting that lack of β2m expression did not interfere with neutrophil migration from circulation into the site of tissue inflammation.


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)

MPO activity (mean ± SEM) of skin extracts from β2m−/−  and β2m+/− mice injected intraperitoneally with pathogenic rabbit anti-mBP180 IgG. Neonatal β2m−/− (bars 1 and 2), β2m+/− (bars 3 and 4),  C57BL/6J (bars 5 and 6), and BALB/c (bars 7 and 8) mice received 2.5  mg/g body weight anti-mBP180 IgG. Tissue MPO activity in skin at the  back were determined 4 h (open bars) or 24 h (hatched bars) after IgG administration. n = 5 for each group. *P <0.001, Student's t test for paired  samples (bar 1 versus 3).
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Figure 2: MPO activity (mean ± SEM) of skin extracts from β2m−/− and β2m+/− mice injected intraperitoneally with pathogenic rabbit anti-mBP180 IgG. Neonatal β2m−/− (bars 1 and 2), β2m+/− (bars 3 and 4), C57BL/6J (bars 5 and 6), and BALB/c (bars 7 and 8) mice received 2.5 mg/g body weight anti-mBP180 IgG. Tissue MPO activity in skin at the back were determined 4 h (open bars) or 24 h (hatched bars) after IgG administration. n = 5 for each group. *P <0.001, Student's t test for paired samples (bar 1 versus 3).
Mentions: Pathogenic anti-mBP180 antibodies administered intraperitoneally do not induce experimental BP in β2m−/− mice. When neonatal BALB/c (n = 5), C57BL/6J (n = 5), and β2m+/− (n = 5) mice were injected intraperitoneally with pathogenic anti-mBP180 IgG (2.5 mg/g body weight), as expected, these animals developed extensive blisters 24 h after injection (Fig. 1 A; Table 1). The skin of these animals was markedly erythematous and, upon gentle friction, developed persistent epidermal wrinkling due to epidermal detachment from underlying dermis. Direct IF of cryosections of lesional and peri-lesional skin showed in vivo deposition of rabbit IgG and mouse C3 at the dermal– epidermal junction (Fig. 1 B). H/E stained sections from these mice showed dermal–epidermal separation with neutrophilic infiltration (Fig. 1 C). In contrast, β2m−/− mice (n = 5) exhibited no blisters 24 h after injection with an identical dose of pathogenic anti-mBP180 IgG (Fig. 1 D). Direct IF also showed a significant reduction in in situ deposition of rabbit IgG and mouse C3 at the BMZ (Fig. 1 E). H/E staining of the skin sections from injected mice exhibited no epidermal detachment from the dermis and a neutrophilic infiltrate milder (Fig. 1 F) than positive control mice. Quantitation of neutrophilic infiltration with the MPO assay showed significant changes in the extractable enzyme activity at the injected site at 24 h after injection, with 0.06 ± 0.01 in β2m−/− mice versus 0.41 ± 0.04 in BALB/c, 0.38 ± 0.04 in C57BL/6J, and 0.38 ± 0.03 in β2m+/− mice (P <0.001) (Fig. 2). However, there was no difference in tissue MPO activity in both β2m−/− and control mice 4 h after intraperitoneal administration of anti-mBP180 IgG (Fig. 2), suggesting that lack of β2m expression did not interfere with neutrophil migration from circulation into the site of tissue inflammation.

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