Daniel A. Winer

B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies

Chronic inflammation characterized by T cell and macrophage infiltration of visceral adipose tissue (VAT) is a hallmark of obesity-associated insulin resistance and glucose intolerance. Here we show a fundamental pathogenic role for B cells in the development of these metabolic abnormalities. B cells accumulate in VAT in diet-induced obese (DIO) mice, and DIO mice lacking B cells are protected from disease despite weight gain. B cell effects on glucose metabolism are mechanistically linked to the activation of proinflammatory macrophages and T cells and to the production of pathogenic IgG antibodies. Treatment with a B cell–depleting CD20 antibody attenuates disease, whereas transfer of IgG from DIO mice rapidly induces insulin resistance and glucose intolerance. Moreover, insulin resistance in obese humans is associated with a unique profile of IgG autoantibodies. These results establish the importance of B cells and adaptive immunity in insulin resistance and suggest new diagnostic and therapeutic modalities for managing the disease.

Regulation of obesity-related insulin resistance with gut anti-inflammatory agents.

Obesity has reached epidemic proportions, but little is known about its influence on the intestinal immune system. Here we show that the gut immune system is altered during high-fat diet (HFD) feeding and is a functional regulator of obesity-related insulin resistance (IR) that can be exploited therapeutically. Obesity induces a chronic phenotypic pro-inflammatory shift in bowel lamina propria immune cell populations. Reduction of the gut immune system, using beta7 integrin-deficient mice (Beta7(null)), decreases HFD-induced IR. Treatment of wild-type HFD C57BL/6 mice with the local gut anti-inflammatory, 5-aminosalicyclic acid (5-ASA), reverses bowel inflammation and improves metabolic parameters. These beneficial effects are dependent on adaptive and gut immunity and are associated with reduced gut permeability and endotoxemia, decreased visceral adipose tissue inflammation, and improved antigen-specific tolerance to luminal antigens. Thus, the mucosal immune system affects multiple pathways associated with systemic IR and represents a novel therapeutic target in this disease.

The adaptive immune system as a fundamental regulator of adipose tissue inflammation and insulin resistance

Over the past decade, chronic inflammation in visceral adipose tissue (VAT) has gained acceptance as a lead promoter of insulin resistance in obesity. A great deal of evidence has pointed to the role of adipokines and innate immune cells, in particular, adipose tissue macrophages, in the regulation of fat inflammation and glucose homeostasis. However, more recently, cells of the adaptive immune system, specifically B and T lymphocytes, have emerged as unexpected promoters and controllers of insulin resistance. These adaptive immune cells infiltrate obesity expanded VAT and through cytokine secretion and macrophage modulation dictate the extent of the local inflammatory response, thereby directly impacting insulin resistance. The remarkable ability of our adaptive immune system to regulate insulin sensitivity and metabolism has unmasked a novel physiological function of this system, and promises new diagnostic and therapeutic strategies to manage the disease. This review highlights critical roles of adipose tissue lymphocytes in governing glucose homeostasis.

The Intestinal Immune System in Obesity and Insulin Resistance

Obesity and insulin resistance are associated with chronic inflammation in metabolic tissues such as adipose tissue and the liver. Recently, growing evidence has implicated the intestinal immune system as an important contributor to metabolic disease. Obesity predisposes to altered intestinal immunity and is associated with changes to the gut microbiota, intestinal barrier function, gut-residing innate and adaptive immune cells, and oral tolerance to luminal antigens. Accordingly, the gut immune system may represent a novel therapeutic target for systemic inflammation in insulin resistance. This review discusses the emerging field of intestinal immunity in obesity-related insulin resistance and how it affects metabolic disease.

B Lymphocytes in obesity-related adipose tissue inflammation and insulin resistance.

Obesity-related insulin resistance is a chronic inflammatory condition that often gives rise to type 2 diabetes (T2D). Much evidence supports a role for pro-inflammatory T cells and macrophages in promoting local inflammation in tissues such as visceral adipose tissue (VAT) leading to insulin resistance. More recently, B cells have emerged as an additional critical player in orchestrating these processes. B cells infiltrate VAT and display functional and phenotypic changes in response to diet-induced obesity. B cells contribute to insulin resistance by presenting antigens to T cells, secreting inflammatory cytokines, and producing pathogenic antibodies. B cell manipulation represents a novel approach to the treatment of obesity-related insulin resistance and potentially to the prevention of T2D. This review summarizes the roles of B cells in governing VAT inflammation and the mechanisms by which these cells contribute to altered glucose homeostasis in insulin resistance.

Primary Sjögren's syndrome and deficiency of ICA69

BACKGROUND Sjögrens syndrome is a common (about 1% of the population) autoimmune disease of salivary and lacrimal glands. Its cause and pathogenesis are poorly understood, and treatments are mostly for symptoms of the disease. ICA69 is a self-antigen expressed in brain, pancreas, salivary, and lacrimal glands. NOD-strain mice are an animal model of spontaneous Sjögrens syndrome. We aimed to assess the role of ICA69 in autoimmunity against Sjögrens syndrome. METHODS We inactivated the genomic ICA69 locus, generated NOD congenic mice that were deficient in ICA69, and assessed development of Sjögrens syndrome. ICA69 autoimmunity was investigated in controls and in patients with primary Sjögrens syndrome or systemic lupus erythematosus, and in various NOD mice, some of which were given an ICA69-directed prototype peptide vaccine. FINDINGS Disruption of the ICA69 locus prevented lacrimal gland disease and greatly reduced salivary gland disease in NOD mice. In healthy NOD mice, ICA69-specific T cells accumulated in lymph nodes that drain salivary tissue. T-cell and B-cell autoreactivity against ICA69 was much the same in patients with primary Sjögrens syndrome, but not in those with systemic lupus erythematosus or in healthy controls. Immunotherapy with a high-affinity mimicry peptide targeting ICA69-specific T-cells reduced established Sjögrens syndrome in wild-type NOD mice in the long term. INTERPRETATION ICA69 is a new autoantigen in primary Sjögrens syndrome that has an important role in progression of disease and could be of diagnostic value. Immunotherapy of primary Sjögrens syndrome is promising, since autoimmunity in NOD mice with Sjögrens syndrome seems to be uniquely susceptible to such treatment even late in disease.

Development of an Orthotopic Model of Invasive Pancreatic Cancer in an Immunocompetent Murine Host

Purpose: The most common preclinical models of pancreatic adenocarcinoma utilize human cells or tissues that are xenografted into immunodeficient hosts. Several immunocompetent, genetically engineered mouse models of pancreatic cancer exist; however, tumor latency and disease progression in these models are highly variable. We sought to develop an immunocompetent, orthotopic mouse model of pancreatic cancer with rapid and predictable growth kinetics. Experimental Design: Cell lines with epithelial morphology were derived from liver metastases obtained from KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre mice. Tumor cells were implanted in the pancreas of immunocompetent, histocompatible B6/129 mice, and the mice were monitored for disease progression. Relevant tissues were harvested for histologic, genomic, and immunophenotypic analysis. Results: All mice developed pancreatic tumors by two weeks. Invasive disease and liver metastases were noted by six to eight weeks. Histologic examination of tumors showed cytokeratin-19–positive adenocarcinoma with regions of desmoplasia. Genomic analysis revealed broad chromosomal changes along with focal gains and losses. Pancreatic tumors were infiltrated with dendritic cells, myeloid-derived suppressor cells, macrophages, and T lymphocytes. Survival was decreased in RAG−/− mice, which are deficient in T cells, suggesting that an adaptive immune response alters the course of disease in wild-type mice. Conclusions: We have developed a rapid, predictable orthotopic model of pancreatic adenocarcinoma in immunocompetent mice that mimics human pancreatic cancer with regard to genetic mutations, histologic appearance, and pattern of disease progression. This model highlights both the complexity and relevance of the immune response to invasive pancreatic cancer and may be useful for the preclinical evaluation of new therapeutic agents. Clin Cancer Res; 16(14); 3684–95. ©2010 AACR.

T H 1, T H 2, and T H 17 cells instruct monocytes to differentiate into specialized dendritic cell subsets

Monocytes and T helper (T(H)) cells rapidly infiltrate inflamed tissues where monocytes differentiate into inflammatory dendritic cells (DCs) through undefined mechanisms. Our studies indicate that T(H) cells frequently interact with monocytes in inflamed skin and elicit the differentiation of specialized DC subsets characteristic of these lesions. In psoriasis lesions, T(H)1 and T(H)17 cells interact with monocytes and instruct these cells to differentiate into T(H)1- and T(H)17-promoting DCs, respectively. Correspondingly, in acute atopic dermatitis, T(H)2 cells interact with monocytes and elicit the formation of T(H)2-promoting DCs. DC formation requires GM-CSF and cell contact, whereas T(H) subset specific cytokines dictate DC function and the expression of DC subset specific surface molecules. Moreover, the phenotypes of T cell-induced DC subsets are maintained after subsequent stimulation with a panel of TLR agonists, suggesting that T(H)-derived signals outweigh downstream TLR signals in their influence on DC function. These findings indicate that T(H) cells govern the formation and function of specialized DC subsets.

Interleukin-17 in post-stroke neurodegeneration

Stroke is a leading cause of physical disability with neurodegenerative sequelae such as dementia and depression causing significant excess morbidity. Stroke severity can be exacerbated by apoptotic cell death in ischemic tissue, of which inflammatory activity is a key determinant. Studies have identified harmful and beneficial sets of T lymphocytes that infiltrate the brain post-stroke and their activation signals, suggesting that they might be targeted for therapeutic benefit. Animal models and human studies implicate interleukin(IL)-17 and its congeners (e.g. IL-23, IL-21) as mediators of tissue damage in the delayed phase of the inflammatory cascade and the involvement of T lymphocytes in propagating IL-17 release. In this review, we highlight the current understanding of IL-17 secreting cells, including sets of CD4(+) αβ and CD4(-) γδ T lymphocytes, as potentially important mediators of brain pathology post-stroke. Interactions between the IL-17 axis and innate pathways, positive feedback mechanisms that prolong or amplify IL-17, and IL-17 regulatory pathways may offer intervention targets to enhance recovery, prevent long-term decline, and improve quality of life.

DJ-1 links muscle ROS production with metabolic reprogramming and systemic energy homeostasis in mice

Reactive oxygen species (ROS) have been linked to a wide variety of pathologies, including obesity and diabetes, but ROS also act as endogenous signalling molecules, regulating numerous biological processes. DJ-1 is one of the most evolutionarily conserved proteins across species, and mutations in DJ-1 have been linked to some cases of Parkinsons disease. Here we show that DJ-1 maintains cellular metabolic homeostasis via modulating ROS levels in murine skeletal muscles, revealing a role of DJ-1 in maintaining efficient fuel utilization. We demonstrate that, in the absence of DJ-1, ROS uncouple mitochondrial respiration and activate AMP-activated protein kinase, which triggers Warburg-like metabolic reprogramming in muscle cells. Accordingly, DJ-1 knockout mice exhibit higher energy expenditure and are protected from obesity, insulin resistance and diabetes in the setting of fuel surplus. Our data suggest that promoting mitochondrial uncoupling may be a potential strategy for the treatment of obesity-associated metabolic disorders.