Immunoregulation in Cutaneous Allergy
Immunoregulation in Cutaneous Allergy
Purpose of review The cutaneous surface is exposed to a myriad of encounters with chemicals, allergens and microbes. Nevertheless, it withstands these environmental assaults without overt inflammation. We will discuss the role of T regulatory cells in a situation where this tissue homeostasis fails – cutaneous allergy, in particular contact hypersensitivity.
Recent findings Immune regulation is a complex process that is mediated by many cellular players. T regulatory cells have risen to particular prominence as potent immunosuppressors because their absence results in inflammation including skin allergy. Recent findings revealed that T regulatory cells comprise a heterogeneous group of subpopulations with specialized homing capabilities and suppressor functions. The stability of the T regulatory cell subset in proinflammatory microenvironments is controversially discussed. In addition, it has recently been shown that mechanisms by which T regulatory cells exert their immunosuppressive functions can be adopted by pathogenic effector T cells in certain situations.
Summary In cutaneous allergy, immunoregulatory mechanisms are dysfunctional. The cellular players comprise classical T regulatory cells as well as effector T cells with regulatory activities. Understanding their role in skin homeostasis and the mechanisms by which their regulatory functions are abrogated will yield novel therapeutic targets for the treatment of cutaneous allergies.
The role of the immune system is to provide protective defense against invading pathogens. The immune response needs to be tailored to the respective aggressor to guarantee efficient elimination, but it also needs to be well controlled in order to avoid immune-mediated collateral tissue injury. In contact allergies, uncontrolled immune responses ensue because of skin contact with low molecular weight chemicals, the so-called haptens. These molecules are not immunogenic by themselves. Instead, they need to bind to epidermal proteins to generate new antigenic determinants, which can be recognized by the immune system as 'altered self' and thus elicit immune responses. The development of clinical contact dermatitis occurs in two consecutive stages: the primary sensitization (afferent) and secondary elicitation (efferent) phase. During the sensitization phase, the hapten–self-protein complex is taken up by skin resident antigen-presenting cells (APCs), for example Langerhans cells and dermal dendritic cells. The precise events leading to the maturation and activation of APCs, which is a prerequisite for their migration to the draining lymph nodes and for antigen presentation to naïve T cells in the paracortical areas, is still an area of active research. The notion emerges that IL-1β and other IL-1 family members play a crucial role in these processes. The NLRP3 inflammasome, the molecular machinery responsible for IL-1β production, can be activated by haptens.
Hapten-specific naïve T cells, which reside in the skin draining lymph nodes, undergo clonal expansion upon recognition of hapten presenting activated APCs. This involves the coordinated action of cytokines released by APCs, in particular IL-12, and the engagement of costimulatory molecules in a process called priming. The T cells then recirculate through the blood and are recruited to the skin upon re-exposure of the same hapten. IL-17 and IFN-γ produced by CD8 T cells mediate the contact hypersensitivity response. Within 48–72 h, the clinical picture of contact dermatitis emerges including edema, erythema and occasionally blistering. This is reminiscent of delayed-type hypersensitivity (DTH) reactions; the effector cells in contact dermatitis are CD8, whereas the effector T cells involved in DTH are CD4. The crucial impact of the CD8 T-cell compartment is supported by a variety of CD4 versus CD8 depletion studies using monoclonal antibodies or gene-targeting approaches. More recent studies also suggest the involvement of CD4 Th17 cells in the elicitation phase of skin allergies.
Allergic contact dermatitis is a self-limiting disease. Resolution of symptoms has been attributed to clearance of the hapten from the skin. However, more recent studies have demonstrated long-term persistence of immunogenic haptens in the skin despite resolution of symptoms. This suggested active downmodulatory mechanisms responsible for the termination of allergic skin diseases. T regulatory cells (Treg) emerged as the most important cellular mediators of this process. Their role in allergic skin diseases and their mechanisms of action will be discussed in this review. We will in particular focus on the recent findings related to their functional plasticity and homing specialization, which currently dominate the field and are expected to have an impact on future therapeutic strategies in the treatment of allergic skin diseases.
Abstract and Introduction
Abstract
Purpose of review The cutaneous surface is exposed to a myriad of encounters with chemicals, allergens and microbes. Nevertheless, it withstands these environmental assaults without overt inflammation. We will discuss the role of T regulatory cells in a situation where this tissue homeostasis fails – cutaneous allergy, in particular contact hypersensitivity.
Recent findings Immune regulation is a complex process that is mediated by many cellular players. T regulatory cells have risen to particular prominence as potent immunosuppressors because their absence results in inflammation including skin allergy. Recent findings revealed that T regulatory cells comprise a heterogeneous group of subpopulations with specialized homing capabilities and suppressor functions. The stability of the T regulatory cell subset in proinflammatory microenvironments is controversially discussed. In addition, it has recently been shown that mechanisms by which T regulatory cells exert their immunosuppressive functions can be adopted by pathogenic effector T cells in certain situations.
Summary In cutaneous allergy, immunoregulatory mechanisms are dysfunctional. The cellular players comprise classical T regulatory cells as well as effector T cells with regulatory activities. Understanding their role in skin homeostasis and the mechanisms by which their regulatory functions are abrogated will yield novel therapeutic targets for the treatment of cutaneous allergies.
Introduction
The role of the immune system is to provide protective defense against invading pathogens. The immune response needs to be tailored to the respective aggressor to guarantee efficient elimination, but it also needs to be well controlled in order to avoid immune-mediated collateral tissue injury. In contact allergies, uncontrolled immune responses ensue because of skin contact with low molecular weight chemicals, the so-called haptens. These molecules are not immunogenic by themselves. Instead, they need to bind to epidermal proteins to generate new antigenic determinants, which can be recognized by the immune system as 'altered self' and thus elicit immune responses. The development of clinical contact dermatitis occurs in two consecutive stages: the primary sensitization (afferent) and secondary elicitation (efferent) phase. During the sensitization phase, the hapten–self-protein complex is taken up by skin resident antigen-presenting cells (APCs), for example Langerhans cells and dermal dendritic cells. The precise events leading to the maturation and activation of APCs, which is a prerequisite for their migration to the draining lymph nodes and for antigen presentation to naïve T cells in the paracortical areas, is still an area of active research. The notion emerges that IL-1β and other IL-1 family members play a crucial role in these processes. The NLRP3 inflammasome, the molecular machinery responsible for IL-1β production, can be activated by haptens.
Hapten-specific naïve T cells, which reside in the skin draining lymph nodes, undergo clonal expansion upon recognition of hapten presenting activated APCs. This involves the coordinated action of cytokines released by APCs, in particular IL-12, and the engagement of costimulatory molecules in a process called priming. The T cells then recirculate through the blood and are recruited to the skin upon re-exposure of the same hapten. IL-17 and IFN-γ produced by CD8 T cells mediate the contact hypersensitivity response. Within 48–72 h, the clinical picture of contact dermatitis emerges including edema, erythema and occasionally blistering. This is reminiscent of delayed-type hypersensitivity (DTH) reactions; the effector cells in contact dermatitis are CD8, whereas the effector T cells involved in DTH are CD4. The crucial impact of the CD8 T-cell compartment is supported by a variety of CD4 versus CD8 depletion studies using monoclonal antibodies or gene-targeting approaches. More recent studies also suggest the involvement of CD4 Th17 cells in the elicitation phase of skin allergies.
Allergic contact dermatitis is a self-limiting disease. Resolution of symptoms has been attributed to clearance of the hapten from the skin. However, more recent studies have demonstrated long-term persistence of immunogenic haptens in the skin despite resolution of symptoms. This suggested active downmodulatory mechanisms responsible for the termination of allergic skin diseases. T regulatory cells (Treg) emerged as the most important cellular mediators of this process. Their role in allergic skin diseases and their mechanisms of action will be discussed in this review. We will in particular focus on the recent findings related to their functional plasticity and homing specialization, which currently dominate the field and are expected to have an impact on future therapeutic strategies in the treatment of allergic skin diseases.
