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Structural Characteristics of HLA-DQ that May Impact DM Editing and Susceptibility to Type-1 Diabetes.

Zhou Z, Jensen PE - Front Immunol (2013)

Bottom Line: Autoreactive CD4+ T cells initiate the chronic autoimmune disease Type-1 diabetes (T1D), in which multiple environmental and genetic factors are involved.The association of HLA, especially the DR-DQ loci, with risk for T1D is well documented.However, the molecular mechanisms are poorly understood.

View Article: PubMed Central - PubMed

Affiliation: ARUP Laboratories, Department of Pathology, University of Utah , Salt Lake City, UT , USA.

ABSTRACT
Autoreactive CD4+ T cells initiate the chronic autoimmune disease Type-1 diabetes (T1D), in which multiple environmental and genetic factors are involved. The association of HLA, especially the DR-DQ loci, with risk for T1D is well documented. However, the molecular mechanisms are poorly understood. In this review, we explore the structural characteristics of HLA-DQ and the role of HLA-DM function as they may contribute to an understanding of autoreactive T cell development in T1D.

No MeSH data available.


Related in: MedlinePlus

Model of autoreactive CD4+ T cell development in T1D. In the thymus, Aire regulates tissue-specific autoantigen expression. Autoantigen peptides are processed in the late endosomal compartment and loaded in the peptide-binding groove of MHCII by DM editing. In case of inefficient DM editing, the pre-bound CLIP peptide may escape peptide exchange, resulting high levels of CLIP presentation (1). Secondly, the inefficient DM editing may lead to presentation of both low affinity and high affinity peptides on the cell surface (2). The stable MHCII-peptide complex will deliver strong signal through the T cell receptor (TCR) and induce the deletion of CD4+ T cells by negative selection, while the unstable MHCII-peptide complex will deliver weak signal and this signal may induce the positive selection of CD4+ T cells. Alternatively, the unstable complexes presented on the cell surface may be more susceptible to DM-independent peptide exchange (3). Those escaped CD4+ T cells will migrate into the periphery and initiate the β cell destruction in pancreas under certain conditions.
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Figure 2: Model of autoreactive CD4+ T cell development in T1D. In the thymus, Aire regulates tissue-specific autoantigen expression. Autoantigen peptides are processed in the late endosomal compartment and loaded in the peptide-binding groove of MHCII by DM editing. In case of inefficient DM editing, the pre-bound CLIP peptide may escape peptide exchange, resulting high levels of CLIP presentation (1). Secondly, the inefficient DM editing may lead to presentation of both low affinity and high affinity peptides on the cell surface (2). The stable MHCII-peptide complex will deliver strong signal through the T cell receptor (TCR) and induce the deletion of CD4+ T cells by negative selection, while the unstable MHCII-peptide complex will deliver weak signal and this signal may induce the positive selection of CD4+ T cells. Alternatively, the unstable complexes presented on the cell surface may be more susceptible to DM-independent peptide exchange (3). Those escaped CD4+ T cells will migrate into the periphery and initiate the β cell destruction in pancreas under certain conditions.

Mentions: Based on current findings, we postulate that the T1D-associated DQ molecules (DQ2, DQ8, and the DQ2/8 trans-dimers) share a common feature, a relative resistance to DM-mediated peptide exchange, and editing. This impacts antigen presentation in two ways (Figure 2). A substantially increased fraction of MHCII molecules escape even one round of peptide exchange, resulting in high levels of CLIP presentation in the periphery and presumably also in the thymus. Secondly, a reduction in the efficiency of further peptide editing may lead to presentation of an array of relatively unstable peptide complexes. High levels of CLIP in the thymus might result in positive selection of T cells that cross-reactive with autoantigens in the periphery, or a reduction in the negative selection of self-reactive T cells, as is seen in the extreme case in mice with targeted deletion of DM (51). Increased presentation of unstable self-peptide complexes might also lead to inefficient negative selection and survival of T cells with a capacity to be activated in the periphery under conditions where the concentration of pancreatic β cell antigens is high. Alternatively, unstable complexes may be more susceptible to DM-independent peptide exchange in the periphery, promoting the activation of “type B” T cells that recognize β cell peptides bound to MHCII through an alternative register or conformation generated through alternative presentation pathways (34). These potential mechanisms may contribute to the pathogenesis of T1D but further elements are needed to explain the specificity for β cells as opposed to other tissues. This is presumably related to the capacity of the T1D-associated DQ molecules to bind and present key β cell self-peptides.


Structural Characteristics of HLA-DQ that May Impact DM Editing and Susceptibility to Type-1 Diabetes.

Zhou Z, Jensen PE - Front Immunol (2013)

Model of autoreactive CD4+ T cell development in T1D. In the thymus, Aire regulates tissue-specific autoantigen expression. Autoantigen peptides are processed in the late endosomal compartment and loaded in the peptide-binding groove of MHCII by DM editing. In case of inefficient DM editing, the pre-bound CLIP peptide may escape peptide exchange, resulting high levels of CLIP presentation (1). Secondly, the inefficient DM editing may lead to presentation of both low affinity and high affinity peptides on the cell surface (2). The stable MHCII-peptide complex will deliver strong signal through the T cell receptor (TCR) and induce the deletion of CD4+ T cells by negative selection, while the unstable MHCII-peptide complex will deliver weak signal and this signal may induce the positive selection of CD4+ T cells. Alternatively, the unstable complexes presented on the cell surface may be more susceptible to DM-independent peptide exchange (3). Those escaped CD4+ T cells will migrate into the periphery and initiate the β cell destruction in pancreas under certain conditions.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3756536&req=5

Figure 2: Model of autoreactive CD4+ T cell development in T1D. In the thymus, Aire regulates tissue-specific autoantigen expression. Autoantigen peptides are processed in the late endosomal compartment and loaded in the peptide-binding groove of MHCII by DM editing. In case of inefficient DM editing, the pre-bound CLIP peptide may escape peptide exchange, resulting high levels of CLIP presentation (1). Secondly, the inefficient DM editing may lead to presentation of both low affinity and high affinity peptides on the cell surface (2). The stable MHCII-peptide complex will deliver strong signal through the T cell receptor (TCR) and induce the deletion of CD4+ T cells by negative selection, while the unstable MHCII-peptide complex will deliver weak signal and this signal may induce the positive selection of CD4+ T cells. Alternatively, the unstable complexes presented on the cell surface may be more susceptible to DM-independent peptide exchange (3). Those escaped CD4+ T cells will migrate into the periphery and initiate the β cell destruction in pancreas under certain conditions.
Mentions: Based on current findings, we postulate that the T1D-associated DQ molecules (DQ2, DQ8, and the DQ2/8 trans-dimers) share a common feature, a relative resistance to DM-mediated peptide exchange, and editing. This impacts antigen presentation in two ways (Figure 2). A substantially increased fraction of MHCII molecules escape even one round of peptide exchange, resulting in high levels of CLIP presentation in the periphery and presumably also in the thymus. Secondly, a reduction in the efficiency of further peptide editing may lead to presentation of an array of relatively unstable peptide complexes. High levels of CLIP in the thymus might result in positive selection of T cells that cross-reactive with autoantigens in the periphery, or a reduction in the negative selection of self-reactive T cells, as is seen in the extreme case in mice with targeted deletion of DM (51). Increased presentation of unstable self-peptide complexes might also lead to inefficient negative selection and survival of T cells with a capacity to be activated in the periphery under conditions where the concentration of pancreatic β cell antigens is high. Alternatively, unstable complexes may be more susceptible to DM-independent peptide exchange in the periphery, promoting the activation of “type B” T cells that recognize β cell peptides bound to MHCII through an alternative register or conformation generated through alternative presentation pathways (34). These potential mechanisms may contribute to the pathogenesis of T1D but further elements are needed to explain the specificity for β cells as opposed to other tissues. This is presumably related to the capacity of the T1D-associated DQ molecules to bind and present key β cell self-peptides.

Bottom Line: Autoreactive CD4+ T cells initiate the chronic autoimmune disease Type-1 diabetes (T1D), in which multiple environmental and genetic factors are involved.The association of HLA, especially the DR-DQ loci, with risk for T1D is well documented.However, the molecular mechanisms are poorly understood.

View Article: PubMed Central - PubMed

Affiliation: ARUP Laboratories, Department of Pathology, University of Utah , Salt Lake City, UT , USA.

ABSTRACT
Autoreactive CD4+ T cells initiate the chronic autoimmune disease Type-1 diabetes (T1D), in which multiple environmental and genetic factors are involved. The association of HLA, especially the DR-DQ loci, with risk for T1D is well documented. However, the molecular mechanisms are poorly understood. In this review, we explore the structural characteristics of HLA-DQ and the role of HLA-DM function as they may contribute to an understanding of autoreactive T cell development in T1D.

No MeSH data available.


Related in: MedlinePlus