Are T2D and Obesity-Related IR Autoimmune Diseases?
In line with the above-mentioned adoptive transfer data, genetic deficiencies in B cells, CD8 T cells, and MHC class II expression (which impairs CD4 T-cell development) conferred protection against HFD-feeding–induced inflammation and insulin resistance. In addition, therapy with anti-CD3 mAb, a monoclonal antibody that has shown efficacy in reverting autoimmune type 1 diabetes in mouse models by targeting polyclonal T cells for deletion while expanding Tregs, also shows promise as an immunotherapy that dampens insulin resistance in DIO mice. Similarly, antibody-mediated depletion of CD8 T cells or B cells improves both glucose tolerance and insulin sensitivity in DIO mice. If these B- and T-cell responses are indeed autoimmune in nature, they pose as promising targets for antigen-specific immunotherapy as an alternative or adjunct approach to other anti-inflammatory therapies that are being tested, including the use of salsalate and inhibitory therapy against IL-1β. In place of broad-acting therapies that block entire immunological pathways or effector molecules that are important for our own defense against foreign pathogens or cancer, antigen-specific immunotherapies offer a disease-targeted approach that minimize side effects of compromised systemic immunity.
Taking into consideration the evidence outlined above (Fig. 1), an autoimmune component in the pathology of obesity-linked insulin resistance and type 2 diabetes is entirely possible. In terms of the pathogenesis of obesity-associated insulin resistance, a key missing link is whether any of the identified targeted autoantigens drive the inflammatory response in key sites such as the VAT. Adoptive transfer data attest to the pathogenic nature of subsets of adaptive immune cells, which are further supported by subset-specific deletion or modulation. However, whether these subsets are enriched for autoreactive specificities and how and where such autoreactive responses arise during obesity are as yet intriguing unknowns. Experiments used to clarify the role of autoreactive T cells in type 1 diabetes, such as tissue-specific T-cell and B-cell cloning, antigen discovery, as well as other transgenic approaches, will lend invaluable insights to this issue.
(Enlarge Image)
Figure 1.
Evidence of autoreactivity in T1D and T2D according to modified postulates. Due to the extensive literature describing type 1 diabetes pathogenesis, we reference a number of review articles that can point readers to primary literatures on the different aspects. IR, insulin resistance.
Unlike classical autoimmune diseases such as type 1 diabetes, which follows a chronic, irreversible course of self-tissue destruction, obesity-associated insulin resistance is reversible through weight loss from lifestyle changes or surgical means. This notion implies that whichever stimuli that propagate the adaptive immune responses accompanying obesity may be removed when a lean state is restored. The question then becomes how obesity alters antigen expression, processing, or presentation and modulates adaptive immune cell activation, leading to loss of tolerance against self-tissues. Looking at classical autoimmune diseases, several intrinsic mechanisms are common in promoting loss of tolerance: genetic predisposition to defective antigen presentation on MHC molecules, defective autoantigen expression during central tolerance, defective cytokine pathways leading to Treg dysfunction and effector cell hyperactivation, and defective antigen clearance pathways. Evidence for such genetic predisposition is lacking in obesity-associated insulin resistance and type 2 diabetes, with little overlap found between genetic associations of type 2 diabetes and those of other autoimmune diseases, though some studies show correlation with Toll-like receptor 4 (TLR4) polymorphisms and progression of complications with type 2 diabetes. Nonetheless, in place of the lack of overall genetic predisposition to immune dysregulation, environmental factors, as well as the obese state itself, may provide the needed stimuli.
For all autoimmune diseases, the effects of genetic predisposition are compounded to additional conditioning environmental factors, such as diet, lifestyle, and presence of infectious agents that elicit a nonspecific response through mechanisms such as molecular mimicry. Environmental stimuli may prove all the more important for obesity-related insulin resistance and type 2 diabetes given the lack of known immune predispositions. We propose two overarching pathways highlighted in current literature, which could directly contribute to autoreactive adaptive immune activation through environment stimuli: 1) dietary fat accumulation inducing changes in metabolic tissues, especially in adipose tissue with associated adipocyte cell death, and 2) alteration of the gut microbiota and mucosal immunity (Fig. 2).
(Enlarge Image)
Figure 2.
Proposed pathways, centered in the VAT, to autoimmune responses during obesity. Intrinsic inflammatory changes cooperate with obesity-associated dysbiosis in the gut to initiate self- or microbe-specific adaptive immune responses in the VAT, generating a feed-forward inflammatory loop that worsens insulin signaling. Long-term caloric excess causes hypertrophy and ER stress in white adipocytes, leading to the release of adipokines and chemoattractants that help activate and/or recruit innate cells, such as macrophages, and adaptive immune cells, such as B and T cells, to the VAT. Obesity-associated dysbiosis contributes to increased gut permeability, facilitating leakage of microbial products and oral antigens across the gut epithelium. Together with lipid excess and dying adipocytes, these serve as potential sources of antigens and costimulatory signals for the activation of VAT B and T cells, a process that can potentially take place in the draining lymph nodes or locally in the VAT. Activated B and T cells, in turn, contribute to VAT inflammation through the secretion of inflammatory cytokines and antibodies or through cross talk with other immune cells. DAMPs, danger-associated molecular patterns. PAMPs, pathogen-associated molecular patterns.
Inflammatory Changes in Adipocytes and Lipid Excess Elicit Adaptive Immunity. A large body of evidence supports the concept that the initial trigger for the chronic inflammation in obesity is metabolic in nature. Long-term caloric excess causes white adipocytes to become hypertrophic, accompanied by increased oxidative stress and ER stress as well as activation of the NLRP3 inflammasome, that culminates in the proinflammatory death of adipocytes. The efflux of fatty acids and aberrant production of adipokines and chemoattractants by degenerating adipocytes or from insulin resistance–associated lipolysis, in turn, contribute to the recruitment and activation of both innate and adaptive immune cells. For instance, adipocyte-secreted chemoattractants, such as MCP-1 and RANTES, engage their receptors on macrophages and T cells to effect their recruitment into the VAT, while increased levels of other inflammatory adipokines or cytokines, such as TNF-α, IL-6, and RBP4, can directly activate macrophages to promote VAT inflammation.
HFD-induced adipocyte death itself can trigger VAT inflammation and insulin resistance. Genetic inhibition of a key proapoptotic molecule Bid or adipocyte-specific deletion of proapoptotic Fas protected DIO animals from developing insulin resistance. In dying in a proinflammatory manner, adipocytes may serve as a reservoir of self-antigens for local B and T cells, as well as a source of costimulatory signals that help activate APCs to initiate a self-propagating inflammatory loop. Dietary fats may further enhance these processes by altering membrane organization important for antigen receptor signaling or signaling through TLR2 and TLR4 to induce ER stress and other inflammatory changes. Such stressors to adipocytes may alter folding and processing of cell constituents, resulting in the generation of protein-, lipid-, or carbohydrate-based neo-antigens. Similar changes in response to lipotoxicity may happen over time in other metabolic cells, such as hepatocytes and β-cells of the pancreas. Some stressors have been shown to induce cell senescence in adipocytes and hepatocytes, inducing a senescence-activated secretory phenotype that may produce cytokines to attract T cells. In addition, given that TLR4 is expressed on relevant cell types involved in adaptive immunity, including B cells, adipocytes, and other APCs, such signals may provide the costimulation needed to break tolerance in B and T cells in the inflammatory environment of metabolic tissues. For instance, TLR4 stimulation on B cells causes increased secretion of natural IgM, which forms immune complexes that can facilitate autoantigen presentation to B cells in a manner dependent on apoptosis inhibitor of macrophage.
Activated B and T cells may, in turn, contribute to metabolic tissue inflammation through the secretion of inflammatory cytokines and antibodies or through the recruitment of other immune cells. This sequence of events (Fig. 2) is compatible with the timing of B- and T-cell recruitment to the VAT upon HFD feeding, which coincides with the onset of insulin resistance. In addition to increasing T- and B-cell recruitment and activation, inflammatory disturbances in the VAT can lead to reductions in local Treg numbers and function. Treg cells have been shown to exhibit phenotypic instability in the face of chronic inflammation, and elevated levels of adipokines, such as leptin, or hyperinsulinemia may further impact Treg homeostasis and their function in braking VAT inflammation.
Environmental Status in the Gut Conditions VAT Inflammation. Alterations in the gut microbiota and gut-associated immune responses are shown to accompany obesity in both humans and mice. Disturbances in the gut microbiome inside obese individuals and rodents may contribute to insulin resistance via participating in obesity-linked inflammation through a number of potential pathways. One such pathway involves inflammatory alterations in gut epithelial integrity, leading to increased "leakage" of bacterial products, including endotoxins such as lipopolysaccharides, across the intestinal epithelium. An alternative pathway has also been proposed involving a chylomicron-dependent process that delivers gut-derived lipopolysaccharide into the bloodstream and fat depots. Elevated systemic endotoxin and other gut bacterial components can, in turn, trigger an inflammatory response through binding pattern recognition receptors, such as TLRs and nucleotide-binding oligomerization domain-containing protein (NOD) on innate immune cells and adipocytes alike to mediate insulin resistance. Elevated gut-derived endotoxins can signal through TLR4 and provide the stimulation needed to break tolerance as outlined above. In addition to gut-derived factors with adjuvant effects, gut-derived antigens or dietary factors can also potentiate an obesity-associated inflammatory response. For instance, Western diet composition, such as high salt content, has the potential to skew immune responses toward a Th17 bias and promote autoimmunity. Some organisms found in obese guts, such as the segmented filamentous bacteria, have the capacity to induce organism-specific IL-17 responses that exacerbate obesity-associated liver inflammation and damage. Furthermore, dietary imbalance that results from the lack of dietary fibers can result in the reduction of beneficial metabolites such as butyrate, which has been shown to promote tolerance by inducing Tregs.
Another important but less well-studied aspect is how the gut-microbe interface may allow microbial and oral antigens to gain access to the adaptive immune system through being uptaken by APCs. This process may occur in nearby draining lymph nodes or mesenteric adipose tissue. Alternatively, gut antigens can be accessed by adaptive immune cells in local gut lymphoid structures, which can then leave the bowel and migrate to other tissues. Indeed, IgG antibodies that are immunoreactive against extracts of gut microbes have been detected in obese individuals with diabetes and are indicative of microbial antigen-specific B-cell activation. Nonetheless, it remains to be determined whether such microbe-specific adaptive immune responses have any bearing on the inflammation that is ongoing in obese metabolic tissues, such as the VAT, and whether antigenic mimicry between obesity-associated gut-derived bacteria and self-antigens exists and contributes to breakdown of self-tolerance during obesity.
Mucosal immune responses in the gut may indeed be intimately linked to VAT-associated immune responses and exert a direct impact on insulin resistance. Aside from studies documenting a heightened inflammatory activity in the bowels of obese rodent models and humans, bowel-VAT immune cross talks also have been implicated in inflammatory bowel diseases, where patients with Crohn disease exhibit features of increased visceral adipose tissue expansion, or "creeping fat," and potentially increased inflammation. The nature of this bowel-VAT immune network, how it operates, and how it can be manipulated for therapeutic benefits are areas that warrant future investigations.
Elimination of the Autoimmune Response Dampens Disease Progression
In line with the above-mentioned adoptive transfer data, genetic deficiencies in B cells, CD8 T cells, and MHC class II expression (which impairs CD4 T-cell development) conferred protection against HFD-feeding–induced inflammation and insulin resistance. In addition, therapy with anti-CD3 mAb, a monoclonal antibody that has shown efficacy in reverting autoimmune type 1 diabetes in mouse models by targeting polyclonal T cells for deletion while expanding Tregs, also shows promise as an immunotherapy that dampens insulin resistance in DIO mice. Similarly, antibody-mediated depletion of CD8 T cells or B cells improves both glucose tolerance and insulin sensitivity in DIO mice. If these B- and T-cell responses are indeed autoimmune in nature, they pose as promising targets for antigen-specific immunotherapy as an alternative or adjunct approach to other anti-inflammatory therapies that are being tested, including the use of salsalate and inhibitory therapy against IL-1β. In place of broad-acting therapies that block entire immunological pathways or effector molecules that are important for our own defense against foreign pathogens or cancer, antigen-specific immunotherapies offer a disease-targeted approach that minimize side effects of compromised systemic immunity.
Taking into consideration the evidence outlined above (Fig. 1), an autoimmune component in the pathology of obesity-linked insulin resistance and type 2 diabetes is entirely possible. In terms of the pathogenesis of obesity-associated insulin resistance, a key missing link is whether any of the identified targeted autoantigens drive the inflammatory response in key sites such as the VAT. Adoptive transfer data attest to the pathogenic nature of subsets of adaptive immune cells, which are further supported by subset-specific deletion or modulation. However, whether these subsets are enriched for autoreactive specificities and how and where such autoreactive responses arise during obesity are as yet intriguing unknowns. Experiments used to clarify the role of autoreactive T cells in type 1 diabetes, such as tissue-specific T-cell and B-cell cloning, antigen discovery, as well as other transgenic approaches, will lend invaluable insights to this issue.
(Enlarge Image)
Figure 1.
Evidence of autoreactivity in T1D and T2D according to modified postulates. Due to the extensive literature describing type 1 diabetes pathogenesis, we reference a number of review articles that can point readers to primary literatures on the different aspects. IR, insulin resistance.
Pathways to Autoimmune Responses During Obesity
Unlike classical autoimmune diseases such as type 1 diabetes, which follows a chronic, irreversible course of self-tissue destruction, obesity-associated insulin resistance is reversible through weight loss from lifestyle changes or surgical means. This notion implies that whichever stimuli that propagate the adaptive immune responses accompanying obesity may be removed when a lean state is restored. The question then becomes how obesity alters antigen expression, processing, or presentation and modulates adaptive immune cell activation, leading to loss of tolerance against self-tissues. Looking at classical autoimmune diseases, several intrinsic mechanisms are common in promoting loss of tolerance: genetic predisposition to defective antigen presentation on MHC molecules, defective autoantigen expression during central tolerance, defective cytokine pathways leading to Treg dysfunction and effector cell hyperactivation, and defective antigen clearance pathways. Evidence for such genetic predisposition is lacking in obesity-associated insulin resistance and type 2 diabetes, with little overlap found between genetic associations of type 2 diabetes and those of other autoimmune diseases, though some studies show correlation with Toll-like receptor 4 (TLR4) polymorphisms and progression of complications with type 2 diabetes. Nonetheless, in place of the lack of overall genetic predisposition to immune dysregulation, environmental factors, as well as the obese state itself, may provide the needed stimuli.
For all autoimmune diseases, the effects of genetic predisposition are compounded to additional conditioning environmental factors, such as diet, lifestyle, and presence of infectious agents that elicit a nonspecific response through mechanisms such as molecular mimicry. Environmental stimuli may prove all the more important for obesity-related insulin resistance and type 2 diabetes given the lack of known immune predispositions. We propose two overarching pathways highlighted in current literature, which could directly contribute to autoreactive adaptive immune activation through environment stimuli: 1) dietary fat accumulation inducing changes in metabolic tissues, especially in adipose tissue with associated adipocyte cell death, and 2) alteration of the gut microbiota and mucosal immunity (Fig. 2).
(Enlarge Image)
Figure 2.
Proposed pathways, centered in the VAT, to autoimmune responses during obesity. Intrinsic inflammatory changes cooperate with obesity-associated dysbiosis in the gut to initiate self- or microbe-specific adaptive immune responses in the VAT, generating a feed-forward inflammatory loop that worsens insulin signaling. Long-term caloric excess causes hypertrophy and ER stress in white adipocytes, leading to the release of adipokines and chemoattractants that help activate and/or recruit innate cells, such as macrophages, and adaptive immune cells, such as B and T cells, to the VAT. Obesity-associated dysbiosis contributes to increased gut permeability, facilitating leakage of microbial products and oral antigens across the gut epithelium. Together with lipid excess and dying adipocytes, these serve as potential sources of antigens and costimulatory signals for the activation of VAT B and T cells, a process that can potentially take place in the draining lymph nodes or locally in the VAT. Activated B and T cells, in turn, contribute to VAT inflammation through the secretion of inflammatory cytokines and antibodies or through cross talk with other immune cells. DAMPs, danger-associated molecular patterns. PAMPs, pathogen-associated molecular patterns.
Inflammatory Changes in Adipocytes and Lipid Excess Elicit Adaptive Immunity. A large body of evidence supports the concept that the initial trigger for the chronic inflammation in obesity is metabolic in nature. Long-term caloric excess causes white adipocytes to become hypertrophic, accompanied by increased oxidative stress and ER stress as well as activation of the NLRP3 inflammasome, that culminates in the proinflammatory death of adipocytes. The efflux of fatty acids and aberrant production of adipokines and chemoattractants by degenerating adipocytes or from insulin resistance–associated lipolysis, in turn, contribute to the recruitment and activation of both innate and adaptive immune cells. For instance, adipocyte-secreted chemoattractants, such as MCP-1 and RANTES, engage their receptors on macrophages and T cells to effect their recruitment into the VAT, while increased levels of other inflammatory adipokines or cytokines, such as TNF-α, IL-6, and RBP4, can directly activate macrophages to promote VAT inflammation.
HFD-induced adipocyte death itself can trigger VAT inflammation and insulin resistance. Genetic inhibition of a key proapoptotic molecule Bid or adipocyte-specific deletion of proapoptotic Fas protected DIO animals from developing insulin resistance. In dying in a proinflammatory manner, adipocytes may serve as a reservoir of self-antigens for local B and T cells, as well as a source of costimulatory signals that help activate APCs to initiate a self-propagating inflammatory loop. Dietary fats may further enhance these processes by altering membrane organization important for antigen receptor signaling or signaling through TLR2 and TLR4 to induce ER stress and other inflammatory changes. Such stressors to adipocytes may alter folding and processing of cell constituents, resulting in the generation of protein-, lipid-, or carbohydrate-based neo-antigens. Similar changes in response to lipotoxicity may happen over time in other metabolic cells, such as hepatocytes and β-cells of the pancreas. Some stressors have been shown to induce cell senescence in adipocytes and hepatocytes, inducing a senescence-activated secretory phenotype that may produce cytokines to attract T cells. In addition, given that TLR4 is expressed on relevant cell types involved in adaptive immunity, including B cells, adipocytes, and other APCs, such signals may provide the costimulation needed to break tolerance in B and T cells in the inflammatory environment of metabolic tissues. For instance, TLR4 stimulation on B cells causes increased secretion of natural IgM, which forms immune complexes that can facilitate autoantigen presentation to B cells in a manner dependent on apoptosis inhibitor of macrophage.
Activated B and T cells may, in turn, contribute to metabolic tissue inflammation through the secretion of inflammatory cytokines and antibodies or through the recruitment of other immune cells. This sequence of events (Fig. 2) is compatible with the timing of B- and T-cell recruitment to the VAT upon HFD feeding, which coincides with the onset of insulin resistance. In addition to increasing T- and B-cell recruitment and activation, inflammatory disturbances in the VAT can lead to reductions in local Treg numbers and function. Treg cells have been shown to exhibit phenotypic instability in the face of chronic inflammation, and elevated levels of adipokines, such as leptin, or hyperinsulinemia may further impact Treg homeostasis and their function in braking VAT inflammation.
Environmental Status in the Gut Conditions VAT Inflammation. Alterations in the gut microbiota and gut-associated immune responses are shown to accompany obesity in both humans and mice. Disturbances in the gut microbiome inside obese individuals and rodents may contribute to insulin resistance via participating in obesity-linked inflammation through a number of potential pathways. One such pathway involves inflammatory alterations in gut epithelial integrity, leading to increased "leakage" of bacterial products, including endotoxins such as lipopolysaccharides, across the intestinal epithelium. An alternative pathway has also been proposed involving a chylomicron-dependent process that delivers gut-derived lipopolysaccharide into the bloodstream and fat depots. Elevated systemic endotoxin and other gut bacterial components can, in turn, trigger an inflammatory response through binding pattern recognition receptors, such as TLRs and nucleotide-binding oligomerization domain-containing protein (NOD) on innate immune cells and adipocytes alike to mediate insulin resistance. Elevated gut-derived endotoxins can signal through TLR4 and provide the stimulation needed to break tolerance as outlined above. In addition to gut-derived factors with adjuvant effects, gut-derived antigens or dietary factors can also potentiate an obesity-associated inflammatory response. For instance, Western diet composition, such as high salt content, has the potential to skew immune responses toward a Th17 bias and promote autoimmunity. Some organisms found in obese guts, such as the segmented filamentous bacteria, have the capacity to induce organism-specific IL-17 responses that exacerbate obesity-associated liver inflammation and damage. Furthermore, dietary imbalance that results from the lack of dietary fibers can result in the reduction of beneficial metabolites such as butyrate, which has been shown to promote tolerance by inducing Tregs.
Another important but less well-studied aspect is how the gut-microbe interface may allow microbial and oral antigens to gain access to the adaptive immune system through being uptaken by APCs. This process may occur in nearby draining lymph nodes or mesenteric adipose tissue. Alternatively, gut antigens can be accessed by adaptive immune cells in local gut lymphoid structures, which can then leave the bowel and migrate to other tissues. Indeed, IgG antibodies that are immunoreactive against extracts of gut microbes have been detected in obese individuals with diabetes and are indicative of microbial antigen-specific B-cell activation. Nonetheless, it remains to be determined whether such microbe-specific adaptive immune responses have any bearing on the inflammation that is ongoing in obese metabolic tissues, such as the VAT, and whether antigenic mimicry between obesity-associated gut-derived bacteria and self-antigens exists and contributes to breakdown of self-tolerance during obesity.
Mucosal immune responses in the gut may indeed be intimately linked to VAT-associated immune responses and exert a direct impact on insulin resistance. Aside from studies documenting a heightened inflammatory activity in the bowels of obese rodent models and humans, bowel-VAT immune cross talks also have been implicated in inflammatory bowel diseases, where patients with Crohn disease exhibit features of increased visceral adipose tissue expansion, or "creeping fat," and potentially increased inflammation. The nature of this bowel-VAT immune network, how it operates, and how it can be manipulated for therapeutic benefits are areas that warrant future investigations.
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