Decreases in the immune response with aging, including B lymphocytes and their progeny, antibody- secreting (ASC), are a major contributor to mortality and morbidity in the elderly population. This can be seen by increased infections and lower response to vaccination as well as an increase in various diseases such as cancer and autoimmunity. The age-related decrease in B cell function is associated with chronic low-grade inflammation and associated with an increase in fat, visceral adipose tissue (VAT). Despite its public health importance, the root causes of this decrease in B cell function are not well understood. We have recently shown that aged/old mice have increased VAT associated with lower in vivo antibody response, and adipocyte-derived molecules may not only recruit immune cells but also contribute to the inflammatory process. Our preliminary data in mice show infiltrating immune cells in the VAT, higher percentages of pro- inflammatory B cells (Age-associated B Cells, ABC) and T cells (??, gamma-delta), and higher amounts of the IgG2c subclass, associated with autoimmune antibodies. We hypothesize that the VAT is an important generator of inflammatory B (and T) cells which contributes to the dysfunction of the aged immune system. Our preliminary data show that adipocytes secrete chemokines which could attract B cells to the VAT and for which the corresponding receptors are expressed by VAT B cells. In this proposal, Aim 1 will determine if the adipose tissue is contributing to the phenotypic and functional changes in B cell subsets observed in older/obese mice. Included in these studies will be testing for the promotion of pro-inflammatory B cell subsets by co-culture of adipocytes from the VAT with splenic B cells from the same mice. Our preliminary data for this show an increase in the relative percentage of the inflammatory ABC, similar to what we have observed in the VAT. We will also confirm if adipocytes produce several pro-inflammatory chemokines and if there are autoantibodies in the VAT for self-antigens.
In Aim 2 we will determine which changes in metabolic pathways are responsible for the reduced antibody responses in mice undergoing DIO (diet-induced obesity) by doing mechanistic studies on mitochondrial function in DIO and controls and associating with an in vitro B cell response. An in vivo response to NP-OVA will also be measured in DIO mice.
In Aim 3 we will determine if ABC are making autoimmune antibodies and less protective antibodies (than FO, follicular B cells) in response to in vivo antigen stimulation and do interventions to determine how that might be improved. These studies will help to determine mechanisms for obesity-related changes in inflammation, how these decrease the function of the immune system and if we can restore B cell function in the aged and obese mice. At the conclusion of our studies we will have expanded our knowledge of mechanisms for inflammation generating B cell deficiencies in aging/obesity and identified candidate strategies for their improvement.
Aged mice and humans have suboptimal immune responses, e.g. ability to make good vaccine responses, and chronic inflammation and obesity contribute to this. This project investigates the root causes of this inflammation and of defects in antibody producing cells in aging and obesity and provides models for intervention/treatment.
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