Part 12: How the obesity, fat, and sodium contribute to autoimmune diseases

Evolutionary Medicine I: Aging and Disease

The following blog post based of the "Role of "Western Diet" in Inflammatory Autoimmune Diseases" by Manzel et al.

Introduction:

Autoimmune diseases share common hallmarks which include multifactorial etiologies, autoimmune pathomechanisms that involve T cell-mediated, and a chronic clinical course that requires life-long disease management. 

Such autoimmune diseases include:

• multiple sclerosis (MS)
• Rheumatoid arthritis (RA)
• Inflammatory bowel diseases (IBD) such as Crohn's and ulcerative colitis (UC)
• Type 1 diabetes (T1D)
• Psoriasis (Ps)

What contributes to the development of the inflammatory autoimmune disease: 

Monozygotic twin studies of genetic factors contributing to autoimmune diseases have shown that there is a low concordance rate. Additionally, the genetic basis in affected populations has remained constant and does not explain the dramatic increase of autoimmune diseases. 

There is a high prevalence in Western societies and established economies. Prevalence and socio-economic improvement and westernization of countries have a positive correlation to increasing cases of autoimmune disease. 

How does the "Western lifestyle" favor the development of autoimmunity?

1. The hygiene hypothesis states that while hygiene and good health care reduce the burden of infections, they also limit exposure to pathogens that may be beneficial for the proper function of the immune system. 
2. Psychosocial stress caused by high demand productivity
3. Smoking 
4. Alcohol consumption
5. Lack of physical activity in combination with frequency consumption of 'fast food' and excess caloric intake contributes to the high prevalence of obesity.

The lifestyle of developed countries constitutes risk factors for the development of autoimmune disease.

Nutrients in etiology of autoimmune diseases

Diet and risk of developing autoimmune diseases 

So far studies have not verified the functional links between dietary macronutrients and risk for developing autoimmune disease. The inclusive results of epidemiologic studies show the challenge to detect nutrients as influential factors on otherwise heterogeneous populations. Those prone to autoimmune disease have complex individual risk that includes genetic and environmental determinants leading to response to nutrition diverse. 

Obesity as a risk and severity factor in autoimmunity

Obesity is caused by excess calorie intake in relation to calorie expenditure often occurs with changes in dietary composition and physical activity. Since the 1980s, worldwide obesity has doubled. Obesity is often referred to as metabolic syndrome which is characterized as insulin resistance, high triglyceride, low high-density lipoprotein (HDL) levels, hypertension, and systemic inflammation. 

Obesity and metabolic syndrome predispose individuals to many chronic diseases. Case-controlled studies have shown the link between obesity and metabolic synfromw to developing MS, Ps, and RA. 

This shows the importance of to further investigate dietary factors of the "Western diest" that are associated with obesity such as animal-derived fats, refined grains, sugar, and salt. 

Mechanism linking Western diet to autoimmunity

Fat, obesity, and T cell responses

A high-fat diet (promotes obesity) leads to excessive accumulation of white adopose tissue (WAT) and systemic inflammation. WAT is now known as an endocrine organ because it releases pro-inflammatory mediators (adipokines) such as TNF-alpha, IL-6, leptin, resistin, and C-reactive protein. Adipokines cause a chronic low-grade systemic inflammation in obese subjects impacting CD4+ T cell populations, regulatory T cells, promote a TH17-biased immunity, and partly dependancce on IL-6. It was also shown that a high-fat diet can exacerbate IBS, trinitrobenzensuflonic acid (TNBS) induced colitis, collagen-induced arthritis, and experimental autoimmune encephalomyelitis in a rodent model. Published data demonstrates that paracrine interactions occur between lymphocytes and WAT adjacent to lymphatic tissues thus influencing autoimmune responses. 

The most studies adipose-derived hormone is leptin has an important link between calorie intake and autoimmune inflammation. Leptin regulates energy balance and body weight. However, it also co-stimulates T cell proliferation and polarise TH1 responses by direct signaling through T cell-expressed leptin receptors. Both WAT-derived adipokines and its resultant systemic inflammation highly impacts T cell responses and potentially influences autoimmune disease. 

Sodium intake and Th17 cells

Salt consumption varies around the world, where indigenous populations consume >1g/day and >20g/day in the western world and Japan. Processed foods and 'fast food' sodium content in developed countries can be more than 100 times higher than homemade food. 

Osmotic stress can induce the release of proinflammatory cytokines from human mononuclear cells in culture. High NaCl concentrations cause enhanced T cell responses on the cellular level. Transcription factor nuclear factor of activated T cells 5 (NFAT5) and p38/MAPK play an important role of the cellular response to hyperosmotic environment. 

There has been a paradigm shift in the understanding of sodium homeostasis. It was believed that sodium quantitatively eliminate via urinary excretion to achieve isotonicity with constant sodium and water content throughout the plasma tissues. This concept was challenged by observations in laboratory animals and humans. First, high sodium contents were measured in secondary lymphatic organs of mice which were proposed to activate NFAT5 which is required for proper functioning of T cells. Second, high-salt diets can lead to salt accumulation in the skin-interstitum in rodents which activates local macrophages in a NFAT5-dependent way. 

Activiated macrophages --> secretion of vascular endothelial growth factor-C (VEGFC) --> inhibits development of salt senestive hypertension.

Third, daily sodium excretion revealed periodic sodium storage in human while changing salt intake in controlled conditions. Together these findings challenged the classical concept of sodium-water balance by the view that tissue sodium levels are compartmentalized under physiological and pathophysiological conditions. Tissue sodium content is flexible and response to dietary intake which may impact immune function. 

The effects of evelated NaCl were also investigated which resulted in differentiation of human TH17 cells with a highly pro-inflammatory phenotype. This process was dependent on the activation of the osmotic stress pathway.