J
JoJo
Guest
for some reason i am finding it quite hard to comprehend this article, can you please read it and tell me what it is about. (lamins terms please)
Type 1 diabetes is characterized by T-cell-mediated destruction of insulin-producing [beta]-cells. Progression of [beta]-cell autoimmunity is simplistically viewed as a functional imbalance favoring the development of [beta]-cell-specific pathogenic type 1 versus immunoregulatory T-cells (Tregs) (1,2). The latter consist of a number of distinct subsets with varying functions that can prevent differentiation or function of type 1 T-cells (3). It is unclear how this functional balance between pathogenic T-cells and Tregs goes awry, leading to massive [beta]-cell destruction, or is maintained in at-risk individuals who remain diabetes free. In this issue of Diabetes, Peakman and colleagues (4) investigate dendritic cells in diabetic patients and provide suggestive evidence for a new player in regulating [beta]-cell-specific T-cell reactivity.
Dendritic cells are a heterogeneous group of innate effectors that serve two general functions in controlling T-cell immunity. The first is to process and present antigens to T-cells, which is essential for T-cell activation and expansion. Second, dendritic cells secrete cytokines that condition the extracellular milieu and determine the nature of the T-cell response. Although much attention has been focused on the capacity of dendritic cells to initiate proinflammatory responses to microbial pathogens, it is clear that dendritic cells serve an important role in establishing and maintaining tolerance to self-antigens (5). These opposing functions are governed by the maturation status and types of cytokines secreted by dendritic cells (6). For instance, infectious microbes in contact with immature dendritic cells promote maturation, which is characterized by the following: 1) an increased capacity to present antigens and stimulate T-cells and 2) secretion of proinflammatory cytokines, which promote differentiation of type 1 T-cells that efficiently clear the infectious agent (6). Depending on the type of dendritic cell, different cytokines are secreted to establish a proinflammatory milieu. Mature myeloid dendritic cells (mDCs) secrete interleukin (IL)-12, which directly induces differentiation of type 1 T-cells (6). Plasmacytoid dendritic cells (pDCs), the focus of the Peakman group's study, secrete interferon (IFN)-[alpha], which is well known for its potent antiviral properties (7).
Self-tolerance is mediated by the dendritic cell via passive and active processes. Under noninflammatory or homeostatic conditions, the majority of dendritic cells are found in an immature state. Immature dendritic cells presenting self-antigens fail to both stimulate T-cells and secrete cytokines (8). Under certain conditions, immature dendritic cells presenting self-antigens can be tolergenic by inducing either a state of unresponsiveness or apoptosis in the autoreactive T-cells (9). In addition, immature dendritic cells stimulated by apoptotic bodies or cytokines such as transforming growth factor-[beta] and IL-10 develop a tolergenic phenotype upon subsequent maturation, characterized by the secretion of anti-inflammatory cytokines or a capacity to preferentially expand Treg (9).
In view of their pivotal role regulating T-cell immunity, dendritic cells would be expected to impact the functional balance between pathogenic T-cells and Tregs in type 1 diabetes. Indeed, studies in the nonobese diabetic (NOD) mouse, a spontaneous model of type 1 diabetes, have shown that mDCs exhibit a hyperinflammatory phenotype. Namely, NOD dendritic cells have an elevated capacity to stimulate T-cells and secrete proinflammatory cytokines such as IL-12 (10,11). This dendritic cell phenotype would be expected to directly drive differentiation of pathogenic type 1 T-cells and promote [beta]-cell destruction. Studies in diabetic patients, however, suggest a different scenario. Monocyte-derived dendritic cells from peripheral blood of diabetic patients exhibit a limited T-cell stimulatory capacity relative to at-risk or healthy individuals (12,13). Accordingly, it has been proposed that these "immature-like" dendritic cells are less effective at stimulating Tregs, which in turn would be predicted to indirectly favor differentiation and expansion of pathogenic type 1 T-cells (12,13).
Whereas most studies to date have investigated mDCs in diabetic individuals, the report by Peakman and colleagues focuses on pDCs. pDCs are of particular interest in view of studies linking this dendritic cell subset with other types of autoimmunity, most notably systemic lupus erythematosus (SLE). Patients with SLE exhibit elevated levels of serum IFN-[alpha], which activates several pathways that promote inflammation (e.g., autoimmunity) (14). Interestingly, pDC activation and IFN-[alpha] secretion are attributed to binding of immune complexes consisting of autoantibo
Type 1 diabetes is characterized by T-cell-mediated destruction of insulin-producing [beta]-cells. Progression of [beta]-cell autoimmunity is simplistically viewed as a functional imbalance favoring the development of [beta]-cell-specific pathogenic type 1 versus immunoregulatory T-cells (Tregs) (1,2). The latter consist of a number of distinct subsets with varying functions that can prevent differentiation or function of type 1 T-cells (3). It is unclear how this functional balance between pathogenic T-cells and Tregs goes awry, leading to massive [beta]-cell destruction, or is maintained in at-risk individuals who remain diabetes free. In this issue of Diabetes, Peakman and colleagues (4) investigate dendritic cells in diabetic patients and provide suggestive evidence for a new player in regulating [beta]-cell-specific T-cell reactivity.
Dendritic cells are a heterogeneous group of innate effectors that serve two general functions in controlling T-cell immunity. The first is to process and present antigens to T-cells, which is essential for T-cell activation and expansion. Second, dendritic cells secrete cytokines that condition the extracellular milieu and determine the nature of the T-cell response. Although much attention has been focused on the capacity of dendritic cells to initiate proinflammatory responses to microbial pathogens, it is clear that dendritic cells serve an important role in establishing and maintaining tolerance to self-antigens (5). These opposing functions are governed by the maturation status and types of cytokines secreted by dendritic cells (6). For instance, infectious microbes in contact with immature dendritic cells promote maturation, which is characterized by the following: 1) an increased capacity to present antigens and stimulate T-cells and 2) secretion of proinflammatory cytokines, which promote differentiation of type 1 T-cells that efficiently clear the infectious agent (6). Depending on the type of dendritic cell, different cytokines are secreted to establish a proinflammatory milieu. Mature myeloid dendritic cells (mDCs) secrete interleukin (IL)-12, which directly induces differentiation of type 1 T-cells (6). Plasmacytoid dendritic cells (pDCs), the focus of the Peakman group's study, secrete interferon (IFN)-[alpha], which is well known for its potent antiviral properties (7).
Self-tolerance is mediated by the dendritic cell via passive and active processes. Under noninflammatory or homeostatic conditions, the majority of dendritic cells are found in an immature state. Immature dendritic cells presenting self-antigens fail to both stimulate T-cells and secrete cytokines (8). Under certain conditions, immature dendritic cells presenting self-antigens can be tolergenic by inducing either a state of unresponsiveness or apoptosis in the autoreactive T-cells (9). In addition, immature dendritic cells stimulated by apoptotic bodies or cytokines such as transforming growth factor-[beta] and IL-10 develop a tolergenic phenotype upon subsequent maturation, characterized by the secretion of anti-inflammatory cytokines or a capacity to preferentially expand Treg (9).
In view of their pivotal role regulating T-cell immunity, dendritic cells would be expected to impact the functional balance between pathogenic T-cells and Tregs in type 1 diabetes. Indeed, studies in the nonobese diabetic (NOD) mouse, a spontaneous model of type 1 diabetes, have shown that mDCs exhibit a hyperinflammatory phenotype. Namely, NOD dendritic cells have an elevated capacity to stimulate T-cells and secrete proinflammatory cytokines such as IL-12 (10,11). This dendritic cell phenotype would be expected to directly drive differentiation of pathogenic type 1 T-cells and promote [beta]-cell destruction. Studies in diabetic patients, however, suggest a different scenario. Monocyte-derived dendritic cells from peripheral blood of diabetic patients exhibit a limited T-cell stimulatory capacity relative to at-risk or healthy individuals (12,13). Accordingly, it has been proposed that these "immature-like" dendritic cells are less effective at stimulating Tregs, which in turn would be predicted to indirectly favor differentiation and expansion of pathogenic type 1 T-cells (12,13).
Whereas most studies to date have investigated mDCs in diabetic individuals, the report by Peakman and colleagues focuses on pDCs. pDCs are of particular interest in view of studies linking this dendritic cell subset with other types of autoimmunity, most notably systemic lupus erythematosus (SLE). Patients with SLE exhibit elevated levels of serum IFN-[alpha], which activates several pathways that promote inflammation (e.g., autoimmunity) (14). Interestingly, pDC activation and IFN-[alpha] secretion are attributed to binding of immune complexes consisting of autoantibo