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New insights into innate immune mechanisms underlying allergenicity.

Wills-Karp M, Nathan A, Page K, Karp CL - Mucosal Immunol (2009)

Bottom Line: The molecular basis for the propensity of specific proteins to promote maladaptive, allergic responses has been difficult to define.Recent data suggest that the ability of such proteins to promote allergic responses in susceptible hosts is a function of their ability to interact with diverse pathways of innate immune recognition and activation at mucosal surfaces.A greater understanding of the fundamental origins of allergenicity should help define new preventive and therapeutic targets in allergic disease.

View Article: PubMed Central - PubMed

Affiliation: Division of Immunobiology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA. wildc7@cchmc.org

ABSTRACT
Allergic diseases, which have reached epidemic proportions, are caused by inappropriate immune responses to a relatively small number of environmental proteins. The molecular basis for the propensity of specific proteins to promote maladaptive, allergic responses has been difficult to define. Recent data suggest that the ability of such proteins to promote allergic responses in susceptible hosts is a function of their ability to interact with diverse pathways of innate immune recognition and activation at mucosal surfaces. This review highlights recent insights into innate immune activation by allergens--through proteolytic activity, engagement of pattern recognition receptors, molecular mimicry of TLR signaling complex molecules, lipid-binding activity, and oxidant potential--and the role of such activation in inducing allergic disease. A greater understanding of the fundamental origins of allergenicity should help define new preventive and therapeutic targets in allergic disease.

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Schematic of innate immune mechanisms activated by allergens
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Figure 1: Schematic of innate immune mechanisms activated by allergens

Mentions: Allergen-derived proteases can have direct effects on adaptive immune responses as well, through cleavage of molecules such as CD25, and CD23. Specifically, Der p 1 has been shown to be able to cleave the α chain of the IL-2 receptor (CD25) on human T cells 29 (Figure 1). As a result, T cells exposed directly to Der p 1 display markedly reduced Th1 cytokine production and enhanced Th2 cytokine production, something dependent on the protease activity or Der p 1. Cleavage of CD25 might also, of course, alter regulatory function, as IL-2 stimulation is required for the maintenance of regulatory T cells in the periphery. The overall effect may be to shift the balance of immune responses from a tolerogenic response to one favoring a Th2 pattern of response. Allergenic proteases such as Der p 1 have also been shown to be able to cleave the low affinity receptor for IgE, CD23, from the surface of human B cells, releasing the soluble form of the receptor 30 (Figure 1). As the membrane-bound form of the IgE receptor is thought to act as a negative regulator of IgE synthesis, Der p 1 cleavage of CD23 could potentially disrupt the negative feedback signal and enhance IgE synthesis, thereby amplifying the allergic response. Anti-trypsin can inhibit this effect of Der p 1 on CD23 cleavage, suggesting that disruption of the balance between proteases and protease inhibitors might play a role in allergic sensitization. It should be noted that whether intact proteases such as Der p 1 actually gain functional access to lymphocytes in vivo remains an open question.


New insights into innate immune mechanisms underlying allergenicity.

Wills-Karp M, Nathan A, Page K, Karp CL - Mucosal Immunol (2009)

Schematic of innate immune mechanisms activated by allergens
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2821449&req=5

Figure 1: Schematic of innate immune mechanisms activated by allergens
Mentions: Allergen-derived proteases can have direct effects on adaptive immune responses as well, through cleavage of molecules such as CD25, and CD23. Specifically, Der p 1 has been shown to be able to cleave the α chain of the IL-2 receptor (CD25) on human T cells 29 (Figure 1). As a result, T cells exposed directly to Der p 1 display markedly reduced Th1 cytokine production and enhanced Th2 cytokine production, something dependent on the protease activity or Der p 1. Cleavage of CD25 might also, of course, alter regulatory function, as IL-2 stimulation is required for the maintenance of regulatory T cells in the periphery. The overall effect may be to shift the balance of immune responses from a tolerogenic response to one favoring a Th2 pattern of response. Allergenic proteases such as Der p 1 have also been shown to be able to cleave the low affinity receptor for IgE, CD23, from the surface of human B cells, releasing the soluble form of the receptor 30 (Figure 1). As the membrane-bound form of the IgE receptor is thought to act as a negative regulator of IgE synthesis, Der p 1 cleavage of CD23 could potentially disrupt the negative feedback signal and enhance IgE synthesis, thereby amplifying the allergic response. Anti-trypsin can inhibit this effect of Der p 1 on CD23 cleavage, suggesting that disruption of the balance between proteases and protease inhibitors might play a role in allergic sensitization. It should be noted that whether intact proteases such as Der p 1 actually gain functional access to lymphocytes in vivo remains an open question.

Bottom Line: The molecular basis for the propensity of specific proteins to promote maladaptive, allergic responses has been difficult to define.Recent data suggest that the ability of such proteins to promote allergic responses in susceptible hosts is a function of their ability to interact with diverse pathways of innate immune recognition and activation at mucosal surfaces.A greater understanding of the fundamental origins of allergenicity should help define new preventive and therapeutic targets in allergic disease.

View Article: PubMed Central - PubMed

Affiliation: Division of Immunobiology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA. wildc7@cchmc.org

ABSTRACT
Allergic diseases, which have reached epidemic proportions, are caused by inappropriate immune responses to a relatively small number of environmental proteins. The molecular basis for the propensity of specific proteins to promote maladaptive, allergic responses has been difficult to define. Recent data suggest that the ability of such proteins to promote allergic responses in susceptible hosts is a function of their ability to interact with diverse pathways of innate immune recognition and activation at mucosal surfaces. This review highlights recent insights into innate immune activation by allergens--through proteolytic activity, engagement of pattern recognition receptors, molecular mimicry of TLR signaling complex molecules, lipid-binding activity, and oxidant potential--and the role of such activation in inducing allergic disease. A greater understanding of the fundamental origins of allergenicity should help define new preventive and therapeutic targets in allergic disease.

Show MeSH
Related in: MedlinePlus