Beautiful blistering
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《血液学杂志》
Leukocyte integrins are required for neutrophil emigration in a number of disease models. Studies of a neonatal mouse model of immune complex-mediated bullous pemphigoid have revealed independent roles for the primary leukocyte integrins LFA-1 versus Mac-1 in this autoimmune disease.
Bullous pemphigoid (BP) is a chronic autoimmune syndrome of elderly patients that manifests as skin blistering.1 These patients develop autoAbs against 2 hemidesmosomal plaque proteins (BP180 and BP230) that function to anchor epithelial cells to the underlying basement membrane. Binding of autoAbs to these proteins leads to complement fixation and active inflammation, resulting in the separation of the epidermis from underlying dermal tissues. Liu and colleagues developed a neonatal mouse model of BP by injecting rabbit polyclonal Abs raised against the extracellular domain of murine BP180 into the dermis of newborn mice. Within 24 hours, the mice develop blisters at the injection site whose histopathology closely resembles the human disease. With this model in hand, Zhi Liu and colleagues have done a beautiful job of dissecting the cellular and molecular pathophysiology of this blistering disease.2 Complement activation is critical in initiating the disease since C5-deficient mice are resistant to experimental BP. Like several other immune complex diseases,3 mice lacking mast cells are resistant to anti-BP180 Ab injection. In the absence of complement, skin mast-cell degranulation is blocked, suggesting that the products of complement fixation (such as C5a) directly lead to mast-cell degranulation. Depletion of macrophages or neutrophils protects animals from experimental BP. Mast-cell degranulation precedes neutrophil infiltration into the skin, suggesting that chemokines released by mast cells are responsible for neutrophil recruitment. Once in the skin, neutrophils release proteolytic enzymes such as neutrophil elastase and gelatinase B (MMP9) that induce tissue injury. Mice deficient in these proteins are resistant to experimental BP. It is believed that the neutrophil elastase directly cleaves the extracellular region of BP180, causing separation of the epidermis from the dermis (see figure).
In this issue of Blood, Liu and colleagues have examined the roles of LFA-1 (CD11a/CD18) and Mac-1 (CD11b/CD18) in experimental BP using knock-out mice and blocking mAbs. Mac-1-deficient mice failed to develop blisters after injection of anti-BP180, despite basement membrane deposition of Ig/complement and normal mast-cell degranulation. mAb blockade of LFA-1 also protected animals from experimental BP. Neutrophil infiltration into the skin was reduced by approximately one half in Mac-1 KO or the anti-LFA-1-treated animals. Blister formation could be restored in the Mac-1 KO mice by injection of either wild-type or Mac-1-deficient cells into the skin. Kinetic analysis of neutrophil infiltration in anti-LFA-1-treated versus Mac-1 KO mice suggests that these leukocyte integrins serve differential functions in this immune complex disease. LFA-1 is required for establishing the early phase of inflammation, while Mac-1 amplifies the response to the point that significant levels of neutrophil proteinases accumulate, leading to blister formation.
A number of studies have suggested that LFA-1 functions primarily in leukocyte recruitment, while Mac-1 is more involved in cellular activation. Indeed, Mac-1 is a major phagocytic receptor on neutrophils and is involved in apoptotic signaling.4 However, in most immune complex diseases so far studied, Mac-1 appears dispensable for the inflammatory response. In contrast, Mac-1 may play a more significant role in host defense to infectious challenge, consistent with its function in phagocyte activation.5 Thus, the finding that these integrins have overlapping function in the BP model for leukocyte recruitment is somewhat unique. Undoubtedly, the differential requirement for integrin function will depend on the tissue site and inflammatory stimulus involved—inflammation in the skin is not the same as inflammation in the joints or the lung. In previous studies that have compared LFA-1 and Mac-1 function in inflammatory disease, investigators have directly compared these knock-out animals. This is a limitation of the current Liu et al study, which compared Mac-1 KO and anti-LFA-1 mAb-treated animals. Nevertheless, this intriguing result from Liu and colleagues will certainly lead to follow-up studies. Is there a differential requirement for LFA-1 versus Mac-1 on macrophages versus neutrophils in BP? Are Fc receptors on infiltrating cells versus tissue resident mast cells involved in this disease? What are the relative contributions of C5a versus mast cell-derived chemoattractants in leukocyte recruitment in BP? An obvious implication of the Liu et al study is that specific inhibition of integrin function may be of benefit in defined inflammatory disease states. Clearly, the relative contribution of LFA-1 versus Mac-1 to different inflammatory diseases remains an active area of research.
Model of the pathogenesis of bullous pemphigoid. Deposition of anti-BP180 Abs along the basement membrane zone led to complement fixation and release of C5a. The C5a activates resident mast cells, which in turn release proinflammatory mediators, such as TNF and IL-8, leading to neutrophil recruitment. Activated neutrophils release proteinases such as neutrophil elastase (NE) and MMP9, which digest the BP180, causing blister formation.
References
Yeh SW, Ahmed B, Sami N, Razzaque Ahmed A. Blistering disorders: diagnosis and treatment. Dermatol Ther. 2003;16: 214-223.
Liu Z. Bullous pemphigoid: using animal models to study the immunopathology. J Investig Dermatol Symp Proc. 2004;9: 41-46.
Benoist C, Mathis D. Mast cells in autoimmune disease. Nature. 2002;420: 875-878.
Mayadas TN, Cullere X. Neutrophil 2 integrins: moderators of life or death decisions. Trends Immunol. 2005;26: 388-395.
Prince JE, Brayton CF, Fossett MC, et al. The differential roles of LFA-1 and Mac-1 in host defense against systemic infection with Streptococcus pneumoniae. J Immunol. 2001;166: 7362-7369.(Clifford A. Lowell)
Bullous pemphigoid (BP) is a chronic autoimmune syndrome of elderly patients that manifests as skin blistering.1 These patients develop autoAbs against 2 hemidesmosomal plaque proteins (BP180 and BP230) that function to anchor epithelial cells to the underlying basement membrane. Binding of autoAbs to these proteins leads to complement fixation and active inflammation, resulting in the separation of the epidermis from underlying dermal tissues. Liu and colleagues developed a neonatal mouse model of BP by injecting rabbit polyclonal Abs raised against the extracellular domain of murine BP180 into the dermis of newborn mice. Within 24 hours, the mice develop blisters at the injection site whose histopathology closely resembles the human disease. With this model in hand, Zhi Liu and colleagues have done a beautiful job of dissecting the cellular and molecular pathophysiology of this blistering disease.2 Complement activation is critical in initiating the disease since C5-deficient mice are resistant to experimental BP. Like several other immune complex diseases,3 mice lacking mast cells are resistant to anti-BP180 Ab injection. In the absence of complement, skin mast-cell degranulation is blocked, suggesting that the products of complement fixation (such as C5a) directly lead to mast-cell degranulation. Depletion of macrophages or neutrophils protects animals from experimental BP. Mast-cell degranulation precedes neutrophil infiltration into the skin, suggesting that chemokines released by mast cells are responsible for neutrophil recruitment. Once in the skin, neutrophils release proteolytic enzymes such as neutrophil elastase and gelatinase B (MMP9) that induce tissue injury. Mice deficient in these proteins are resistant to experimental BP. It is believed that the neutrophil elastase directly cleaves the extracellular region of BP180, causing separation of the epidermis from the dermis (see figure).
In this issue of Blood, Liu and colleagues have examined the roles of LFA-1 (CD11a/CD18) and Mac-1 (CD11b/CD18) in experimental BP using knock-out mice and blocking mAbs. Mac-1-deficient mice failed to develop blisters after injection of anti-BP180, despite basement membrane deposition of Ig/complement and normal mast-cell degranulation. mAb blockade of LFA-1 also protected animals from experimental BP. Neutrophil infiltration into the skin was reduced by approximately one half in Mac-1 KO or the anti-LFA-1-treated animals. Blister formation could be restored in the Mac-1 KO mice by injection of either wild-type or Mac-1-deficient cells into the skin. Kinetic analysis of neutrophil infiltration in anti-LFA-1-treated versus Mac-1 KO mice suggests that these leukocyte integrins serve differential functions in this immune complex disease. LFA-1 is required for establishing the early phase of inflammation, while Mac-1 amplifies the response to the point that significant levels of neutrophil proteinases accumulate, leading to blister formation.
A number of studies have suggested that LFA-1 functions primarily in leukocyte recruitment, while Mac-1 is more involved in cellular activation. Indeed, Mac-1 is a major phagocytic receptor on neutrophils and is involved in apoptotic signaling.4 However, in most immune complex diseases so far studied, Mac-1 appears dispensable for the inflammatory response. In contrast, Mac-1 may play a more significant role in host defense to infectious challenge, consistent with its function in phagocyte activation.5 Thus, the finding that these integrins have overlapping function in the BP model for leukocyte recruitment is somewhat unique. Undoubtedly, the differential requirement for integrin function will depend on the tissue site and inflammatory stimulus involved—inflammation in the skin is not the same as inflammation in the joints or the lung. In previous studies that have compared LFA-1 and Mac-1 function in inflammatory disease, investigators have directly compared these knock-out animals. This is a limitation of the current Liu et al study, which compared Mac-1 KO and anti-LFA-1 mAb-treated animals. Nevertheless, this intriguing result from Liu and colleagues will certainly lead to follow-up studies. Is there a differential requirement for LFA-1 versus Mac-1 on macrophages versus neutrophils in BP? Are Fc receptors on infiltrating cells versus tissue resident mast cells involved in this disease? What are the relative contributions of C5a versus mast cell-derived chemoattractants in leukocyte recruitment in BP? An obvious implication of the Liu et al study is that specific inhibition of integrin function may be of benefit in defined inflammatory disease states. Clearly, the relative contribution of LFA-1 versus Mac-1 to different inflammatory diseases remains an active area of research.
Model of the pathogenesis of bullous pemphigoid. Deposition of anti-BP180 Abs along the basement membrane zone led to complement fixation and release of C5a. The C5a activates resident mast cells, which in turn release proinflammatory mediators, such as TNF and IL-8, leading to neutrophil recruitment. Activated neutrophils release proteinases such as neutrophil elastase (NE) and MMP9, which digest the BP180, causing blister formation.
References
Yeh SW, Ahmed B, Sami N, Razzaque Ahmed A. Blistering disorders: diagnosis and treatment. Dermatol Ther. 2003;16: 214-223.
Liu Z. Bullous pemphigoid: using animal models to study the immunopathology. J Investig Dermatol Symp Proc. 2004;9: 41-46.
Benoist C, Mathis D. Mast cells in autoimmune disease. Nature. 2002;420: 875-878.
Mayadas TN, Cullere X. Neutrophil 2 integrins: moderators of life or death decisions. Trends Immunol. 2005;26: 388-395.
Prince JE, Brayton CF, Fossett MC, et al. The differential roles of LFA-1 and Mac-1 in host defense against systemic infection with Streptococcus pneumoniae. J Immunol. 2001;166: 7362-7369.(Clifford A. Lowell)