B cell projects

Obesity is a rapidly growing global health problem that has plagued almost every developed nation on earth. Due to many lifestyle factors including exercise habits and dietary preferences, USA has the highest percentage of obese people on earth. According to CDC, prevalence of obesity increased from 30.5% to 42.4% in the last twenty years and its age of onset has recently decreased to pre-teenager years creating a public health burden to people at all age groups. Owing to the complex nature of the disease, obesity affects all systems in the organism ranging from musculoskeletal and cardiovascular effects to changes in psychological state. Immune system is not immune from obesity related changes either. Due to release of TNF and other immune modulatory molecules from adipose tissue, obesity introduces a proinflammatory environment which has the potential to modulate functioning of immune cells not only within the adipose tissue but also systemically. Current SARS-CoV2 and recent H1N1 influenza pandemics both clearly revealed the predisposition of obese patients to poor disease outcomes. Despite these very concerning observations, the research in how obesity influences immune responses are limited. This is particularly so in the field of humoral immune responses orchestrated by B cells. B cells are not only a cornerstone of adaptive immune responses, and therefore immune memory, but also the target of almost all successful vaccines that act through inducing high titers of protective antibodies. A common working principle for effective vaccines is inducing B cell differentiation into long lived plasma cells. Only if we fully decipher the diet and obesity induced alterations in humoral immunity to the resolution of a single cell, we can design revolutionary vaccines with the highest coverage and efficiency.

Our previous work has documented how microenvironmental signals decide the proliferation, differentiation and death of B cells via regulating their metabolic fitness and ionic homeostasis. We hypothesize that obesity related changes in the metabolic and cytokine milieu of organism might interfere with the fate decision of B cells and create a vulnerability in hosts defense against infections. Thus far, our preliminary observations in animal models showed that diet induced obesity influences the distribution and abundance of B cell subsets, their metabolic states and expression levels of homing and costimulatory markers. We have discovered an increased likelihood of spontaneous germinal center (GC) formation and IgG isotype switching in obese mice in the absence of an overt infection or immune challenge while GC response to a viral pathogen was markedly reduced. This points out to an obesity induced dysregulation in B cell responses that might result in defective responses to infections and tendency to autoreactivity.  These observations are particularly important as the world is being ravaged by a viral pandemic, so we will decipher how B cell responses are dysregulated by the most common comorbidity in the US.

Project 1 aims to reveal how the most common comorbidity of the US people affect the B cells’ ability to fight infections and respond to vaccines. This project focuses on comparing high fat diet (HFD) fed obese and normal fat diet (NFD) fed lean animals in steady state to delineate what might go wrong with B cell development and function in obesity. We investigate i) developing B cells in the bone marrow, ii) mature B cells in the secondary lymphoid organs using conventional immunological and metabolic assays as well as an unbiased analysis of single cell transcriptome to decipher the state of basal B cell activity, metabolism and homing at the highest possible resolution and reveal obesity-driven compartmentalization of B cell subpopulations. These will be complemented with a repertoire sequencing to unearth the B cell clones that form spontaneous, most likely self-reactive, GC in obese mice. Additionally, blood samples obtained from an established cohort of otherwise healthy obese individuals will be analyzed to document, for the first time, the signature of obesity in human B cells. This project also proposes to delineate the effects of obesity on B cell fitness and responses during well-established models of virus and parasite infections as well as immunization with adjuvanted foreign antigens. Our lab has already produced robust preliminary evidence for a reduced GC formation and isotype switching in obese mice infected with a viral pathogen. We will build on this observation to decipher the signature of obesity in B cell function and correlate it with the disease outcomes.

Project 2 explores the contribution of diet in B cell responses to answer whether it is the state of obesity or the continuous long-term exposure to high fat diet that affects B cell responses. We investigate this by comparing the effects of the obesity induced by normal fat high calorie dietary regimens. This project employs a novel experimental strategy to trace B cells from obese vs. lean animals in a third animal fed with NFD or HFD to investigate whether altered B cell responses due to obesity can be reversed by changing the diet. This will be complemented with an investigation of the long-term effects of obesity on B cell responses with comprehensive analysis of human and mouse samples obtained from obese subjects that have lost weight. Altogether, this project aims to reveal whether B cell responses can be manipulated by changing the diet and/or losing weight.

In conclusion, using human samples and mouse models, we propose to delineate the effects of obesity and diet on humoral immunity and pave the way for developing more effective vaccines and immunotherapies that also meet the needs of obese individuals.