Leptin: Linking Malnutrition and Vulnerability to Infection

The correlation between malnutrition and vulnerability to infection has been well established (discussed previously here). While the immune dysfunction could be characterized it was not until the last 10-15 years that an exact mechanism began to resolve.

It all began with the discovery of a new hormone called leptin from an unexpected place, adipose tissue (fat cells). Leptin, a product of the obese (ob) gene, was discovered while looking for factors that regulate body fat. As a consequence of manipulating this gene in an attempt to regulate body fat, it was discovered that mice deficient in leptin had profound immune deficiencies.

The amount of leptin produced by adipose cells (fat cells) is directly proportional to the amount of fat in the cells. (The number of fat cells in adults does not change,  their size just shrinks or swells.) Leptin levels drop as body fat decreases or during fasting. Once leptin levels fall below a threshold, the lack of leptin puts the mammalian body into a starvation response. Areas of leptin activity are signaled by the production of the leptin receptor (OBR gene). Tissues producing the leptin receptor include areas of the hypothalamus that regulate body weight, bone mass, and appetite; ovarian cells, beta-cells of the pancreas, endothelial cells, and bone marrow stem cells, macrophages, and lymphocytes (1). Leptin influences cellular function by directly interacting with peripheral tissues including immune cells in lymph nodes, bone marrow, pancreatic function and bone homeostasis, but also by triggering hormonal changes in the brain, specifically in the hypothalamus. Study of leptin levels has opened previously unsuspected linked between central nervous system control and the development of the immune system.

The Hormonal Trigger of the Starvation Response

Leptin’s control of metabolism and the  immune system. (Ref. 2)

As long as leptin levels stay within normal levels, all of the functions displayed above function normally. As the leptin levels drop, many of these functions are adversely effected. It is a wide-spread trigger for a starvation response.  Why cripple the immune response during starvation? My best guess would be because of the huge energy expenditure required to keep the immune response running normally, especially in cellular proliferation.

When leptin levels drop too low, physiological dysfunction occurs in haematopoiesis (blood cell production), bone metabolism, glucose metabolism and angiogenesis (blood vessel production and maintenance) and immune suppression involving both the innate (non-specific) and adaptive immune system. During malnutrition, the size of the thymus gland shrinks with diminished T cell development. This may be one of the long-term consequences of childhood malnutrition. Children with congenitally low leptin levels have a higher mortality rate due to childhood infections (2).

Leptin modulates immune function (ref. 1)

With all the functions illustrated above, it’s not very surprising that malnutrition is the second most common cause of secondary immune suppression today (2). Alternatively, high leptin levels in obese people have also been linked with increased vulnerability to infection possibly through the development of leptin resistance due to prolonged exposure to excessively high levels of leptin (2). Food for thought considering that obesity was one of the only risk factors for a poor outcome during the recent H1N1 influenza pandemic. We have come to expect malnutrition induced immune suppression, but we may also have to consider over-nutrition induced immune suppression and/or autoimmunity as outcomes of immune dysregulation due to leptin resistance.

References:

[1] La Cava, A., & Matarese, G. (2004). The weight of leptin in immunity Nature Reviews Immunology, 4 (5), 371-379 DOI: 10.1038/nri1350

[2] Procaccini C, Jirillo E, & Matarese G (2012). Leptin as an immunomodulator. Molecular aspects of medicine, 33 (1), 35-45 PMID: 22040697

Health and Healing Sessions at Kalamazoo 2012

Regular readers might remember that last fall I was regularly posting and tweeting a call for papers for a session on health and healing in early medieval Europe for the International Congress on Medieval Studies at Kalamazoo in 2012. The schedule for the Congress is now out so I can tell everyone all about it. As you can see I got a great response to my CFP and the Congress committee let me put together two sessions. So without further ado, here are the sessions co-sponsored by The Heroic Age and Medica: The Society for the Study of Healing in the Middle Ages.

Session 264 (Friday 1:30)
Schneider 1255

Health and Healing in Early Medieval Britain and Ireland
Presider: Deanna Forsman, North Hennepin Community College

• Famine and Pestilence in the Irish Sea Region, 500–800 AD: Michelle Ziegler
• Regional Patterns of Health in Early Medieval Ireland: Distributions of Non-specific Stress Indicators: Mara Tesorieri, Univ. College Cork
• The Experience and Practice of Medicine by the Laity in Anglo-Saxon England: Julia Bolotina, Univ. of Cambridge
• By Rome, or By Spain? Possible Mediterranean Origins of Irish Holy Well Veneration: Silas J. Mallery, North Hennepin Community College

Session 319 (Friday 3:30)
Schneider 1255

Medical Texts of the Early Medieval Mediterranean
Presider: Michelle Ziegler

• Animal-Derived Medicines in Early Medieval Pharmacy: Jayna Brett, Centre for Medieval Studies, Univ. of Toronto
• A Medieval Hippocrates? The construction of the Articella during the eleventh century.: Marco A. Viniegra, Harvard Univ.
• Book-Learning and Medicine in Medieval Byzantium: Theory and Practice in the Alexiad of Anna Comnena: Glen M. Cooper, Brigham Young Univ.

Famine and Epidemics Come Hand in Hand

After many natural disasters, famines and epidemics quickly follow with depressing predictability. It is not just a coincidence related to the damaged infrastructure and loss of stored foodstuffs. It has long been thought that there is a direct link between malnutrition and immune suppression, but the mechanism has been,   and is still,  poorly understood.  It doesn’t take a natural disaster to cause the level of malnutrition necessary to trigger immune suppression. In 2005 malnutrition was considered contributing factor in half (53%) of all infectious disease deaths in children under five in the developing world.[1] There is a growing recognition that the malnutrition-infection relationship is a factor in the quantity and quality of life  in the elderly and chronically ill globally.

Malnutrition and infection can form a vicious cycle that can be hard to break. Malnutrition weakens both the innate (non-specific) and adaptive (specific) immune system making people more vulnerable to infectious diseases. The immune suppression can become so bad that they are as vulnerable as people with full-blown, uncontrolled AIDS. Because of the similarly between the malnourished immune system and AIDS, it is sometimes called “nutritionally acquired immunodeficiency syndrome” [1]. The acute risk of immune suppression is increased vulnerability to infection. Not only do malnourished people contract common diseases at a higher rate, they also contract the rare infections that are typically only found in severely immune compromised people.

Large epidemics (or pandemics) bring society to a stand still. A large number of people are too ill to work or die preventing the most productive members of society from working. Care for ill people and orphans become a drain on community resources.  Historically, few infants who have not been weaned survived the death of their mother.  The lost productivity lowers food production and distribution deepening the malnutrition, setting up a repeat of the cycle until the community is uttered devastated and depopulated.

Malnutrition does not have to begin the cycle. Throughout history there have been laments over ripe fields that were left to rot because there were not enough healthy people to harvest the fields. Further the demands of the infection can cause or deepen malnutrition: diarrheal agents cause dehydration, and  intestinal parasites and chronic infections like tuberculosis and malaria drain nutrients and can cause anemia. A Nigerian study found evidence that acute measles can measurably deepen childhood malnutrition [1].

Today this cycle can be mitigated and eventually broken by international food relief and even limited modern medical treatment. Intravenous hydration, basic antibiotics and vaccines regularly save the lives of thousands in nearly yearly famine related epidemics. International relief is a relatively modern phenomenon.

Indications of Immune Dysfunction

Evidence for the mechanism of immune dysfunction in malnutrition has been slow in coming. Much of the evidence has been observational: the frequency of rare infections like Pneumocystis carinii, and opportunistic infections like Noma [1]. Malnourished populations have a higher incidence of chronic infectious diseases like tuberculosis and malaria.

Ominously, there is evidence that childhood malnutrition can cripple the immune system for life. Malnutrition directly correlates with atrophy of the thymus and consequently reduction in circulating T lymphocytes [1]. Damage to the thymus correlates with increased circulating undifferentiated lymphocytes,  poorly developed peripheral lymph nodes and spleen, and a dysfunctional mucus membrane immune response including poor IgA secretion[1]. Protein synthesis is either insufficient or ineffective throughout the immune system. They lack cytokines and proper cell markers, have abnormal antibody responses and under-produce or lack complement proteins hampering phagocytosis [1]. Some of this can be repaired with restoration of proper nutrition, but not all of it, especially damage to the development of the immune system infrastructure.

All of the abnormalities of the malnourished immune system are too complex to detail in this post. I hope to divide this topic up into multiple posts. The relationship between malnutrition and epidemics will be a returning theme here for the next six months or so. Suggestions on reading material to correlate depth of malnutrition with osteological analysis would be appreciated.

 

[1] Schaible UE, & Kaufmann SH (2007). Malnutrition and infection: complex mechanisms and global impacts. PLoS medicine, 4 (5) PMID: 17472433