IMMUNE SYSTEM

I. Immune System Organization

male and female human body showing immune system organization

The human immune system operates with two distinct arms: i) the innate (or non-specific) immune-type, the first line of defense against invading organisms; and ii) the adaptive (or specific) immune-type, which acts as a second line of defense to provide protection against re-exposure to the same pathogen. The interplay between these two arms of immune system establishes an effective host defense by different functional mechanisms and pathways. The adaptive immune system requires some reaction time to process an invading organism, whereas the innate immune system includes defenses that are constitutively present and readily mobilize upon infection. Also, the adaptive immune system is antigen specific and reacts only with the organism that induced the response. In contrast, the innate system is not antigen specific and reacts universally to a variety of invaders. Finally, the adaptive immune system demonstrates immunological memory, that it “remembers and recognizes” a previously encountered organism and reacts more rapidly on subsequent exposure. In contrast, the innate immune system has no immunological memory.

Everyone is born with innate immunity, a type of general protection with anatomical, humoral and cellular barriers. These protective barriers are equipped with chemical and biological agents.

A) Anatomical barriers

  • Mechanical factors: The epithelial surfaces form a physical barrier that is highly impermeable to most infectious agents. Thus, skin provides an imposing barrier to invading microbes. It is generally penetrable only through cuts or tiny abrasions. The digestive and respiratory tracts—both portals of entry for a number of microbes—also have their own levels of protection. Microbes entering the nose often cause the nasal surfaces to secrete more protective mucus, and attempts to enter the nose or lungs can trigger a sneeze or cough reflex to force microbial invaders out of the respiratory passageways. The stomach contains a strong acid that destroys many pathogens that are swallowed with food.
  • Chemical factors: Fatty acids in sweat inhibit microbial growth. Lysozyme and phospholipase found in tears, saliva and nasal secretions can breakdown the cell wall of bacteria and kill organisms. The low pH of sweat and gastric secretions can prevent bacterial proliferation. Defensins (low molecular weight proteins) found in the lung and gastrointestinal tract have antimicrobial activity. Surfactants in the lung act as opsonins (substances that promote phagocytosis of particles by phagocytic cells).
  • Biological factors: The normal flora of the skin and probiotic lactic acid bacteria in the gastrointestinal tract can prevent the colonization of pathogenic bacteria by secreting toxic substances (bacteriocins) or by competing with pathogenic bacteria for nutrients or attachment to cell surfaces

B) Humoral barriers

  • Anatomical barriers are very effective in preventing microbial colonization. However, when there is damage to tissues the anatomical barriers are breached and microbial infection may occur. When pathogens invade the tissues, inflammation, another innate defense mechanism is activated. Humoral factors play an important role in inflammation characterized by edema and initiation of phagocytosis. These humoral factors are found in plasma or released at the site of infection.
  • Complement system is the major humoral defense mechanism that can lead to increased vascular permeability, recruitment of phagocytic cells that breakdown and engulf pathogens.
  • Coagulation system: According to the severity of tissue injury, certain components of the coagulation system can increase vascular permeability and act as chemotactic agents in promoting phagocytosis. Furthermore, some of the coagulation products such as beta-lysin, a protein produced by platelets can lyse many Gram positive bacteria by acting as a cationic detergent.
  • Cytokine system:
    • Interferons (IFNs) are proteins released by host cells in response to an infection. IFNs are named after their ability to "interfere" with viral replication within host cells. IFNs have other functions: they activate immune cells, such as natural killer cells and macrophages; they increase recognition of infection or tumor cells by up-regulating antigen presentation to T-lymphocytes; and they increase the ability of uninfected host cells to resist new infection by virus. Certain host symptoms, such as aching muscles and fever, are related to the production of IFNs during infection.
    • Interleukins (ILs) are proteins, a group of signaling molecules expressed by a wide variety of body cells (predominantly by leukocytes) and act on leukocytes. Several immune functions are dependent on ILs. They participate in the regulation of immune responses, inflammatory reactions, and hematopoiesis. ILs can induce fever and production of acute phase proteins, some of which are antimicrobial with opsonic effects on susceptible organisms.

C) Cellular barriers

Inflammatory response includes the recruitment of neutrophils and macrophages to sites of infection. These cells are the main line of defense in the non-specific immune system.

  • Neutrophils are recruited to the site of infection where they engulf and kill the invading organisms. In addition, neutrophils contribute to collateral tissue damage that occurs during inflammation.
  • Macrophages are newly recruited monocytes that differentiate into phagocytic cells that perform intra-cellular killing of microorganisms. In addition, macrophages are capable of extra-cellular killing of infected or altered self target cells. Furthermore, macrophages contribute to tissue repair and act as antigen-presenting cells, which are required for the induction of specific immune responses.
  • Natural killer (NK) and lymphokine activated killer (LAK) cells can non-specifically kill virus infected and tumor cells. These cells are not part of the inflammatory response but are important in non-specific immunity to viral infections and tumor surveillance.
  • Eosinophils are white blood cells responsible for combating multi-cellular parasites and certain infections. Along with mast cells, they also control mechanisms associated with allergy and asthma.

Adaptive immunity develops throughout our active lifespan. This actively acquired immunity involves the lymphocytes and develops as people are exposed to diseases or immunized against diseases through vaccination. It is highly specific, since each lymphocyte carries surface receptors for a single antigen. The acquired immune response becomes effective over several days after the initial activation, but it also persists for some time after the removal of the initiating antigen. This persistence gives rise to immunological memory, which is the basis for a stronger, more effective immune response upon re-exposure to an antigen (re-infection with the same pathogen). Adaptive immunity is classified in two categories: A) Humoral Immunity, and B) Cell Mediated Immunity.

A) Humoral Immune Response

The term humoral immunity relates to the involvement of substances found in the humours, or body fluids. B-lymphocytes (B-cells) with co-stimulation transform into plasma cells that secrete antibodies. Humoral immune response is mediated by secreted antibodies produced by B-cells, which are specific for an individual antigen. This immunity involving antibodies deals with extracellular pathogens.

B) Cell Mediated Immune Response

However, some pathogens, particularly viruses, but also some bacteria, infect individuals by entering cells. These pathogens will escape humoral immunity and are instead dealt with by cell mediated immunity, which is conferred by T-lymphocytes (T-cells). T-cells express antigen-specific T-cell receptors on their surface. However, unlike B-celss, they are only able to recognize antigens that are presented to them on a cell surface; this is the distinguishing feature between humoral and cell mediated immunity. Therefore, infection of a cell by an intra-cellular pathogen is signaled to T-cells by cell surface expression of peptide fragments derived from the pathogen. These fragments are transported to the surface of the infected cell and expressed there in conjunction with proteins called the major histocompatibility complex (MHC); in humans, MHC is referred to as the human leukocyte antigen. It is the combination of the pathogen-derived peptide fragment bound to MHC that is recognized by T-cells. Intracellular pathogens stimulate cytotoxic T-cells to destroy the infected cell, while extracellular pathogens stimulate a helper T-cell–mediated response.

Passive immunity is the transfer of ready-made antibodies from one individual to another. Such antibodies which are transferred have a lifespan of only about 3–6 months, therefore, this short acting immunization is typically used in cases of high risk of infection and insufficient time for the body to develop its own immune response, or to reduce the symptoms of ongoing or immunosuppressive diseases. This temporary immunity provides immediate protection, but the body does not develop memory, therefore the patient is at risk of being infected by the same pathogen later. Passive immunity can be administered in natural or artificial form.

A) Natural passive immunity is when maternal antibodies are transferred to the fetus via the placenta or transmitted through the colostrum (breast secretions that serve as newborn’s first meal). Passive immunity is also provided through the transfer of lactoferrin and IgA antibodies found in breast milk. This allows some protection for the infant while its own immune system is under development.

B) Artificial passive immunity is a short-term immunization achieved through administration of antibodies specific for a pathogen or toxin in several forms to non-immune individuals; as human or animal blood plasma or serum, and as monoclonal antibodies (MAb). Antiserum from other mammals, notably horses, has been used in humans with generally good and often life-saving results, but there is some risk of anaphylactic shock and even death from this procedure because the human body sometimes recognizes antibodies from other animals as foreign (non-self) proteins.

Compromised immunity or immune-deficiency results in an inability to combat certain diseases and may be of two types: A) Primary or B) Secondary.

A) Primary immuno-deficiency is caused by genetic or developmental defects in the immune system. These defects are present at birth but may show up later on in life.

B) Secondary or acquired immune-deficiency is the loss of immune function as a result of aging, immune suppresive drugs, exposure to disease agents, malignant diseases, or environmental factors.  

  • Age-associated immuno-deficiencies manifest due to a progressive decrease in thymic cortex, hypo-cellularity of and reduction in the size of thymus, a decrease in suppressor cell function and hence an increase in auto-reactivity, a decrease in CD4 cells functions.
  • Drug-induced immuno-deficiencies are common with chemotherapy, disease-modifying anti-rheumatic drugs, and anti-inflammatory agents (corticosteroids). These drug treatments can damage lymphocytes. Individuals with auto-immune disorders or who have undergone organ transplants may need to take immune-suppressant medications, which also can reduce the immune system's ability to fight infections and can cause secondary immunodeficiency.
  • Infection- associated immuno-deficiencies: Bacterial, viral, protozoan, helminthic and fungal infections may lead to B cell, T cell, neutrophils, and macrophage deficiencies. Immune suppression is the hallmark of acquired immunodeficiency syndrome (AIDS), caused by the human immunodeficiency virus (HIV). HIV directly infects a small number of T helper cells, and also impairs other immune system responses indirectly.
  • Disease and malignancy-associated immuno-deficiencies include many types of cancer, particularly those of the bone marrow and blood cells (leukemia, lymphoma, multiple myeloma), and certain chronic infections. Other conditions in which secondary immune-deficiencies occur are sickle cell anemia, diabetes mellitus, protein calorie malnutrition, burns, alcoholic cirrhosis, rheumatoid arthritis, renal malfunction, etc.

An allergy is a hypersensitivity disorder of the immune system. An allergic reaction is an inflammatory process triggered by a foreign substance known as an allergen. These reactions are acquired, predictable, rapid and typically develop after repeated exposure to an allergen. Allergic reactions are distinctive because of excessive activation of certain white blood cells called mast cells and basophils by IgE antibody. This reaction results in an inflammatory response which can range from uncomfortable to dangerous. Symptoms of allergic reactions include skin lesions known as hives, tongue or facial swelling, sneezing, itchy eyes, nausea, vomiting, and a variety of rashes. Allergic reactions may range from mild, self-limited sniffles to life-threatening conditions such as anaphylaxis, in which the mouth and tongue may swell to a point that makes it difficult to breathe.

There are many types of allergies. Some of the more common allergens include certain foods, medications, latex, aspirin, shellfish, dust, pollen, mold, animal dander, and poison ivy. Bee stings, fire ant stings, penicillin, sulfa antibiotics, and peanuts are known for causing dramatic reactions in some people that can be serious and involve the whole body. Minor injuries, hot or cold temperatures, exercise, or even emotions may be triggers. Seasonal allergies appear periodically at the same time of the year with exposure to pollens from trees, grasses, or weeds. Hay fever is the most common seasonal allergy. Allergies that occur for more than 9 months out of the year are called perennial allergies. Often, the specific allergen cannot be identified unless an individual had a similar reaction in the past.

BOOKS
 
  • Abbas AK, Lichtman AH (2010) Basic Immunology: Functions and Disorders of the Immune System, 3rd Edition. Philadelphia: Saunders
  • Kindt TJ, Osborne BA, Goldsby RA (2006) Kuby Immunology, 6th Edition. San Fransisco: WH Freeman & Company
  • Male D, Brostoff J, Roth D, Roitt I (2006) Immunology, 7th Edition. London:Mosby.
  • Walport M, Janeway C, Travers P, Murphy KP (2008) Immunobiology, 7th Edition, New York: Garland Publishing
REVIEWS AND ARTICLES 
 
  • Aw D, Silva AB, Palmer DB (2007) Immunosenescence: Emerging challenges for an ageing population. Immunology 120:435-446.
  • Finlay BB, McFadden G (2006) Anti-immunology: Evasion of the host immune system by bacterial and viral pathogens. Cell 124:767-782.
  • Hayakawa Y, Smyth MJ (2006) Innate immune recognition and suppression of tumors. Advances in Cancer Research 95:293-322.
  • Kawai T, Akira S (2006) Innate immune recognition of viral infection. Nature Immunology 7:131-137.
  • Kay AB (2000) Allergy and allergic diseases: with a view to the future. British Medical Bulletin 56: 843-864.
  • Pancer Z, Cooper MD (2006) The evolution of adaptive immunity. Annual Review of Immunology 24:497-518.
  • Rosen FS, Cooper MD, Wedgwood RJ (1995) The primary immunodeficiencies. New England Journal Medicine 333:431-440.
 

II. Immune System Nutrients

There is growing evidence that lifestyle factors and dietary behavior are important co-factors in the immune response. Inadequate nutritional intake is the prevailing cause of immuno-compromised host status worldwide. Vitamins, minerals, amino acids, fats and calories are necessary for a balanced immune function. Deficiency of certain nutrients could lead to immune suppression, a condition of inability to produce enough immune cells to protect an individual against infections and allergies. Malnutrition is associated with a significant impairment of cell-mediated immunity, phagocyte function, complement system, antibody levels, and cytokine production. Deficiency of single nutrients also results in altered immune responses: this is observed even when the deficiency state is relatively mild. However, overnutrition and obesity can also influence immune mechanisms. Obesity can promote the development of diabetes, which can alter the immune state. Finally, immunity becomes less effective with ageing and this process is enhanced by associated malnutrition. [Keith & Jeejeebhoy 1997, Chandra 2002, Marcos et al 2003].

Mineral deficiency leads to compromised host condition, resulting from suppressed innate T-cell-mediated immune response and adaptive antibody response. Minerals, in particular, zinc, magnesium, copper, and selenium could significantly impact immune health. [Wintergerst et al 2007]

Zinc (Zn2+) affects multiple aspects of the immune system, from the barrier of the skin to gene regulation within lymphocytes. The relationship between zinc and the immune system is complex, since there are four different types of influence associated with zinc. (i) The dietary intake and the resorption of zinc depend on the composition of the diet and also on age and disease status. (ii) Zinc is a co-factor in more than 300 enzymes influencing various organ functions having a secondary effect on the immune system. (iii) Zinc affects production, maturation of lymphocytes and antibody production, particularly immunoglobulin G. Zinc is also critical for normal development and function of cells mediating non-specific immunity such as neutrophils and natural killer cells. (iv) Zinc influences the function of immune-stimulants. Zinc has diverse effects on immune functions. During zinc deficiency different immune functions are decreased. All these impaired functions are completely restored by zinc supplementation. A review of ten randomized studies on zinc supplementation in children reported a reduction of pneumonia and diarrhea by 41 and 25 percent, respectively. In healthy individuals, Zinc supplementation may reduce the length of common cold. One study reported that individuals taking a zinc lozenge (containing 13.3 mg of Zn2+) every two hours were sick on average 3.2 less days than subjects who did not take zinc. Another study reported that zinc supplementation reduced the duration of cold symptoms by 42 percent compared the placebo group [Fischer-Walker & Black 2010].

Magnesium (Mg2+) is involved in both innate and acquired immune responses. Magnesium acts as a co-factor for immunoglobulin synthesis, immune cell adherence, antibody-dependant cytolysis, lymphocyte binding, macrophage function, T helper-B-cell adherence, etc. [Tam et al 2003]

Copper (Cu2+) could influence T-cell proliferation and interleukin-2 production. Copper also affects neutrophil-mediated superoxide anion generation, the innate microbicidal activity in human peripheral blood. Accordingly, neutrophils accumulate copper during cellular differentiation. [Percival 1998]

Selenium (Se2+) is incorporated into proteins to make selenoproteins, the antioxidant enzymes, which help regulate thyroid function and play a role in the immune system. Thus, selenium supplementation has measurable immune-stimulant effects including making more T-cells and natural killer (NK) cells. These cells are essential in good quantities for an optimum immune function. [McKenzie et al 1998].

 

Adequate intake of vitamins is required for the immune system to function efficiently. Vitamin-deficiency suppresses immunity by affecting antibody responses, leading to imbalances in the immune system. This situation increases susceptibility to infections, which increases morbidity and mortality risk.

Vitamin C (ascorbic acid) has non-specific effects on various pathways of immune system. Vitamin C is an efficient water-soluble antioxidant that protects host tissue against damaging free radicals released by phagocytes. Phagocytes also have a specific transport system to absorb oxidized form of vitamin C (dehydroascorbic acid) and regenerate into its functional form [Leibovitz & Siegal 1981]. Several studies demonstrated an immune-modulatory role for vitamin C in random migration and chemotaxis of phagocytes, transformation of influenza virus-infected lymphocytes, interferon production, up-regulation of complement and immunoglobulin levels [Jariwalla & Harakeh 1996, Webb & Villamor 2007]. A review of 20 double-blind studies concluded that vitamin C has only a small effect in preventing colds, however, when taken at the onset of a cold, it does significantly reduce the duration of a cold. In controlled studies on individuals performing heavy exercise, cold frequency was reduced an average of 50% with vitamin C supplements ranging from 600 to 1,000 mg per day. [Hemilä 1992, 1996]

Vitamin D interaction with the immune system is one of the most well-established non-classical effects. Recent reports have supported a role for vitamin D in mediating normal function of both the innate and adaptive immune systems. These effects appear to be mediated via localized autocrine or paracrine synthesis of vitamin D [1,25(OH)2D3] from precursor 25-hydroxyvitamin D3, the main circulating metabolite of vitamin D [Hewison 2010]. Recent studies have shown that vitamin D can enhance the induction of the antimicrobial peptides cathelicidin and β-defensin which are found on mucosal and epithelial surfaces and act as the body's first line of defense against microbial pathogens [Watkins et al 2011].

Vitamin B12 (cobalamin) deficiency has been associated with decreased immune function. In a controlled trial, individuals with B12-deficiency anemia were also found to have markedly decreased levels of white blood cells associated with immune function. Restoration of B12 stores (by injections) improved levels of these immune cells. B12 acted as an immune-modulator for cellular immunity, especially on T-lymphocyte function and natural killer (NK) cell activity [Tamura et al 1999].

Vitamin A (beta-carotene) deficiency impairs innate immunity by impeding normal regeneration of mucosal barriers damaged by infection, and by diminishing the function of neutrophils, macrophages, and natural killer cells. Vitamin A is also required for adaptive immunity and plays a role in the development of T-helper and B-cells. In particular, vitamin A deficiency diminishes antibody-mediated responses directed by T-helper cells. [Stephensen 2001].

Amino acids play a major role on immune function. Muscle proteins in our body provide amino acids for synthesizing new cells, proteins, and peptides for the immune response. These amino acids also serve as fuel by the immune system either directly, or following their conversion to other amino acids. Catabolic states such as surgery, wound repair are associated with increased susceptibility to infections. This condition is associated with suboptimal supply of substrates to the immune system, especially the amino acids. Clinical studies have shown that enhanced supply of key amino acids in certain clinical conditions improve immune status of individuals. However, this immuno-block application has centered largely upon glutamine, arginine and citrulline. [Calder et al 2002, Newsholme 2001, Evoy et al 1998, Popovic et al 2007]

Glutamine has an important role in cell-mediated immuni¬ty and the integrity of the intestinal mucosa [Cetinbas et al 2010]. During severe metabolic stress (i.e., trauma, sepsis, major surgery, bone marrow transplant, chemotherapy and radiotherapy), gluta¬mine stores are depleted. Glutamine supplementation during illness increases gut barrier and lymphocyte func¬tion and preserves lean body mass [Andrews & Griffiths 2002]. Glutamine protects against septic shock by preventing the depletion of glutathi¬one and thus reducing cell death, which occurs during shock. In surgical or cancer patients, glutamine supple-mentation decreases the production of some pro-inflammatory cytokines.

Arginine: T-lymphocytes depend on arginine for multiple key immune-biological processes. Arginine along with certain micronutrients has been widely used to create immune-enhancing diets (IED) [Ochoa et al 2004]. To date about 40 trials using IED have been performed in a wide variety of patient populations [Grimble 2005]. Based on these studies, the European Society of Parenteral and Enteral Nutrition recently published its guidelines that recommends routine use of arginine-containing diets in surgical patients [Schutz et al 2006]. Citrulline, an arginine precursor, is a functional alternative, because it is well tolerated and may be beneficial even under conditions with high arginase 1 activity [Bansal et al 2004].

The immune system can be influenced by protein-energy malnutrition. Rapid protein synthesis is required to initiate and maintain an immune response, therefore, proteins, peptides and amino acids are critical to immune function. Inadequate protein intake impairs immunity, with a particularly detrimental impact on the T-cell system, resulting in an increased incidence of opportunistic infections.

Whey proteins (WP) are the soluble class of dairy proteins that make up approximately 20% of the total bovine milk proteins, predominantly alpha-lactalbumin and beta-lactoglobulin. WP fractions are linked to a range of bioactive functions such as prebiotic effects, promotion of tissue repair, maintenance of intestinal integrity, destruction of pathogens and elimination of toxins [Ha & Zemel, 2003]. WP appears to modulate immune function by boosting glutathione (GSH) production in various tissues and preserving the muscle glutamine reservoir [Micke et al 2000]. Cysteine is the rate limiting amino acid in GSH formation and WP is a rich source of this amino acid. GSH is the centerpiece of the body’s antioxidant defense system that regulates many aspects of immune function [Townsend et al 2003]. Muscle glutamine is the essential fuel of the immune system. Therefore, WP supplementation may help promote strong immunity and protect the health of active people of all ages as well as those with a compromised immune system [Cross & Gill 1999]. WP is shown to significantly improve primary and secondary intestinal tract antibody responses [Low et al 2003]. Alpha-lactalbumin-enriched WP could stimulate white blood cell (CD4+ and CD8+), lymphocyte counts and higher cytokine production by spleen cells. WP supplementation could enhance the ability of neutrophils to neutralize free radical production and minimize oxidative stress. Addition of lactoferrin to WP results in synergic enhancement of T cell-meditated NK cell function and increased protection against cytomegalovirus [Wong et al 1998].

Colostrum, the first lacteal secretion produced by the mammary gland of a mother prior to the production of milk, is a provide of natural passive immunity. Colostrum is rich in proteins, vitamin A, and sodium chloride, but contains low amounts of carbohydrates, lipids, and potassium than normal milk. The most pertinent bioactive components in colostrum are growth factors and antimicrobial factors. The antibodies in colostrum provide passive immunity, while growth factors stimulate the development of the gut. They are passed to the neonate and provide the first protection against pathogens [Pakkanen & Aalto 1997, Playford et al 2000].

Proline-rich Polypeptides (PRP) also known as colostrinin or transfer factor, are small immune signaling peptides found in colostrum and blood plasma. Initially, PRPs were considered in the transfer of immunity from one system to another; however, later studies suggested a limited role for PRP in the cell-mediated immunity [Zimecki 2008]. PRP-rich preparations from bovine colostrum have shown some activity against a broad-spectrum of pathogens including viruses, bacteria and fungi. As an immune modulator, PRP is also effective in disease states characterized by an overactive immune system, such as allergies, asthma, and auto-immune diseases [Keech 2008].

Several studies have demonstrated immune stimulating effects of various dietary polysaccharides: (i) beta-glucans from Saccharomyces cerevisiae (yeast) Agaricus subrufescens (A. blazei Murill mushroom), and Lentinula edodes (shiitake mushroom); (ii) laminarin from Laminaria digitata; (iii) SSG from Sclerotinia sclerotiorum; (iv) furanose extract from P. quiquefolium; (v) pectins from Buplerum falcatum and Malus (apple) spp.; and (vi) galactomannan (guar gum) from Cyamopsis tetragonolobus.Such Arabinogalactans, galactomannans, alpha-glucan (laminarin), glucomannan, and mixed polysaccharide products are partially hydrolyzed by human colonic bacteria. The immune-modulatory mechanism, could possibly due to the hydrolyzed polysaccharide fragments binding to gut epithelia and exerting localized and/or systemic immune response.

Dietary polysaccharides, particularly the glucan types, elicit a wide range of immune-modulatory effects. A number of clinical studies in healthy human adults demonstrated immune stimulating effects of oral polysaccharides [Ramberg et al 2010]. Glucan extracts from the Trametes versicolor (mushroom) improved survival and immune function in cancer patients; glucans, arabinogalactans and fucoidans elicited immune-modulatory effects in healthy adults and patients with canker sores and seasonal allergies. Arabinogalactans from Larix occidentalis (Western larch) were shown to increase lymphocyte proliferation and IgG subtype response. A furanose extract from Panax quiquefolium (North American ginseng) was shown to decrease the incidence of acute respiratory illness and symptom duration. Also, healthy adults consuming Undaria pinnatifida (wakame) fucoidans found both immune stimulating and suppressing effects, including increased stromal-derived factor-1, interferon-gamma and decreased blood leukocytes and lymphocytes.

Flavonoids and polyphenolic compounds that exert many anti-inflammatory and anti-microbial effects, also exhibit an anti-allergic action. Some of these agents are natural allergy remedies that strengthen the immune system. They soothe mucus membranes and help resist irritation from allergens.

Curcumin, the active component of turmeric, is a polyphenol with anti-inflammatory, antiamyloid, antiseptic, antitumor, and antioxidative properties. Curcumin was reported to have anti-allergic properties with inhibitory effect on histamine release from mast cells. The effectiveness of curcumin in allergy and asthma has been further investigated using a murine model. The results indicate a marked inhibition of allergic response in animals treated with curcumin suggesting a major role for curcumin in reducing the allergic response [Kurup & Barrios 2008]. Curcumin also elicits immune-modulatory effects on lymphoid cell populations, antigen presentation, humoral and cell-mediated immunity, and cytokine production [Gautam et al 2007]. Curcumin interferes with inflammation partly through inhibition of the chemokine expression and through direct inhibition of neutrophil motility [Larmonier et al 2011].

Quercetin, a bio-flavonoid, naturally found in foods such as apples, berries, red grapes, red onions, capers, garlic, cayenne peppers and black tea, is potent anti-histamine agent. Mast cells are immune cells critical in the pathogenesis of allergic diseases through release of many pro-inflammatory cytokines such as IL-8 and TNF. Inhibition of mast cell cytokine release could be effective therapy for allergy. In two pilot, open-label, clinical trials, quercetin significantly decreased contact dermatitis and photosensitivity [Weng et al 2012]. Dendritic cells (DCs) play a crucial role in linking innate and adaptive immunity. Thus, DCs have been regarded as a major target of immune-suppressants for the control of harmful immune responses. Quercetin effectively inhibits DC activation by reducing the production of pro-inflammatory cytokines/chemokines [Huang et al 2010].

Lactic acid bacteria and other probiotic organisms exert many beneficial health effects. Probiotics prevent adherence, establishment, and replication of several enteric mucosal pathogens through several antimicrobial mechanisms. Specific cellular components in lactobacill strains can induce strong adjuvant effects including modulation of cell-mediated immune responses, augmentation of cytokine pathways and regulation of interleukins, and tumor necrosis factors. Probiotics also decrease the prevalence of allergies in susceptible individuals and inhibit the inflammatory responses in the gut. [Naidu et al 1999]. Probiotics can interact with mucosal immune cells or epithelial cells lining the mucosa to modulate innate and adaptive immune responses in the host. The most well understood mechanisms involve interaction with pattern recognition receptors expressed on on immune cells and many other tissues including the intestinal epithelium. Binding of probiotic bacteria to these receptors can activate antigen presenting cells and modulate their function through the expression of surface receptors, secreted cytokines and chemokines. Several factors have been identified in probiotics that influence the immune response including cell surface carbohydrates, enzymes modifying the structure of lipoteichoic acids and metabolites. Other probiotic mechanisms include modulation of the T cells, enhancement of humoral immunity and interactions with dendritic cells and macrophages [Wells 2011].

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III. Immune System Replenishment

Life is a ‘self operating program’ that maintains a fixed cellular/molecular design in an open frame. Openness of this frame, allows physical (i.e. light, temperature) and chemical (in gaseous, liquid, colloidal and solid states) forces pass through its structural space. The “on-or-off” mode of a ‘self operating program’, will govern the ultimate fate (capture, transfer, retention or expulsion) of the physico-chemical encounters from its environment. Continuous transformation of random components of environment into organized segments of a fixed cellular/molecular design will regulate either life or death of an organism. In multi-cellular life forms, humans in particular, the extra-ordinary ability to differentiate ‘self’ from its macro-molecular environmental influx, evolved another vital self operating program – the immune system.

Immune system is designed with a unique computational program to operate four strategic levels of defense management: i) Recognition of non-self, ii) Processing of non-self, iii) Development of memory, and iv) Tolerance to self. These vital characteristics empower the immune response to become scalable, resilient to subversion, robust, and flexible. Also, the host defense needs to be widely distributed, highly responsive, potentially effective and readily degradable in the human body. Self and non-self refer to chemical structures (tissue, cells, molecules, etc) inherent to the body and entities that are encountered through a foreign source, respectively. Immune efficiency is further dependent on the ability to distinguish between harmful non-self (i.e. bacteria, viruses and toxins), and everything else (i.e. food, water and air). The overall success in self defense is contingent upon the ability of the immune system to recognize a large variety of foreign bodies. The system also needs to detect and react to pathogens that the body has never encountered before. Thus, devising efficient defense strategies to discriminate self versus non-self has been pivotal in the molecular evolution of the immune system.

Immune system is based on a multi-layered arrangement of membranes (skin, epithelial, and mucus), cells, and molecules that collectively perform a balancing act, which is lethal enough to kill pathogens or cancer cells, yet specific enough not to cause any collateral damage to “self”. Accordingly, immunity is a super intelligent process that deals with a magnificent variety of unknowns in the environment.

Immunity and host defense are similar to an “arms race,” since an offensive intruder may have an ability to multiply at a rate, several-fold faster than the immune cell cascade. Accordingly, the immune cells should quickly respond to pathogenic threats by shifting from a dormant state to a highly active phase within a short period. Accordingly, immune cells must dramatically alter their metabolism to face the combat. Thus, a normal immune cell needs to effectively “reprogram” its metabolism and directs nutrients to the synthesis of nucleotides, lipids, amino acids, and other biosynthetic products needed for the proliferation – the arms race [van stipdonk et al 2003, Wang et al 2011].

Recognition of Non-self: Since the foreign body exposure is potentially large, while the system has only limited cellular and molecular resources; recognition of the non-self is performed on the basis of chemistry. Instead of whole foreign body identification, the immune system detects only tiny fragments (molecular structures or “antigens”) from a non-self entity. Accordingly, the detectors used by the system are small, efficient, highly distributed, and are not subject to centralized control or co-ordination.

Lymphocytes are the immune cells responsible for recognition (detection) of antigens. Non-self detection is achieved through interactions, when chemical bonds are formed between the antigen and “receptors” that cover the surface of the lymphocyte. Due to the large size and complexity of most antigens, only discrete sites (“epitopes”) get bound to the lymphocyte receptors. A typical lymphocyte has approximately 100,000 receptors on its surface. The number of receptors that bind to an antigen will determine the “affinity” (detection threshold) of a lymphocyte to its target.

Processing of Non-self: Immune system singles out self from non-self by various mechanisms through multi-layered architecture with protection lined up at multi-level. The first line of defense includes skin and other physical barriers (i.e. acid and temperature) to restrain foreign insult. If the first line of defense is compromised, the innate and acquired immune barriers come into effect. The “innate” defense involves roaming scavenger cells, such as phagocytes, that ingest extracellular molecules and materials, clearing the system of both debris and pathogens. The “acquired” immune response is a sophisticated defense that involves a myriad of cells, chemicals and molecules. Any foreign body (pathogens, in particular) that evades the previous layers of host defense will be much harder to detect and eliminate.

A successful acquired immune response involves specialized B-cells (lymphocytes that mature in the bone marrow), which are activated upon binding to pathogens. The B-cell activation has a two-fold effect: i) it results in secretion of soluble form of its receptors, the “antibodies”, which bind and inactivate pathogens, or ii) to submit the bound pathogen to phagocytes and other innate defense systems for kill and removal. The B-cells are short-lived and disappear when a pathogen is eliminated, which means that the immune system would have to repeat the whole affinity maturation/activation process in case of re-infection. The immune system circumvents this process lapse by retaining a “memory” of the information encoded in the adapted B-cells.

Development of Memory: Immune system can learn and memorize the structures of foreign agents that come across. When a new pathogen is encountered, the body mounts a primary immune response which usually takes some time to clear the infection. During such process, various immune mechanisms enable the lymphocytes to learn about the chemical structures of specific antigen molecules and remember the infectious agent. If the body is re-infected, the host memory recalls a secondary immune response to generate high-affinity lymphocytes against specific antigens of the previously encountered pathogen. Such memory-induced immune responses are significantly rapid and effectively protect the body from harmful insults from the environment.

Tolerance to Self: Generally the immune system is tolerant to self and does not attack itself. Tolerance is implemented via another class of lymphocytes, called helper T-cells that mature in thymus, an organ located just behind the breastbone. Most self proteins circulate through thymus and any T-cells maturing in this organ are exposed to most self proteins. If a maturing T-cell binds (recognizes) to any of these self proteins, it will be censored, or removed, in a process called clonal deletion. T-cells that survive the maturation process and leave the thymus are tolerant to most self proteins.

Self and non-self recognition in human body is also achieved by a cellular marker based on the major histocompatibility complex (MHC). Any cell not displaying this marker is treated as non-self, attacked and eliminated. The tolerance control so effective to the extent that any self protein, which is under or over digested, is treated as an antigen. Seldom the tolerance control may break down and the immune system could attack self-cells, resulting in autoimmune diseases (i.e. rheumatoid arthritis, multiple sclerosis, etc).

Immunity is fundamental for the prevention or elimination of foreign invasion, as well as in the overall repair and recovery of the host from pathogenic encounters. However, mounting any type of immune response triggers a huge metabolic and nutritional demand on the host physiology. Such potential threat triggers a significant boost in the replication of immune cells, synthesis of defense molecules and amplification of hydrolytic enzymes, which cumulatively require high energy consumption. In order to mount and maintain an efficient immune response, several physiological trade-off decisions come into force [Lochmiller and Deerenberg 2000].

Immune Replenishment - Maintenance and Emergency: Regular maintenance of the immune system includes an uninterrupted supply of nutrients to support biosynthesis of immune cells, immunoglobulins and other plasma proteins, in order to replenish those that were expended during a normal turnover. However, the cost of using immune system during emergency attacks to impede a potential invader, is manifested at two levels: i) loss in tissue function due to damage when immune cells break tissue integrity and host cell viability (collectively, the collateral damage); ii) nutritional costs to mobilize specific cell types and energy costs in fueling the activity of such recruited cells. The primary cost of a pathogen challenge is in the systemic acute phase response, especially involvement of other organs (i.e. liver), to assist the immune system.

Metabolic requirements of immune cells and indirect consequences of mounting an antigen-induced immune response (e.g. acute inflammatory response) are critical for host survival. Accordingly, the immune replenishment takes into account: i) the bio-energetics to fuel the emergency (sudden) process of antigen recognition, and ii) the nutrient requirements to expedite the system during an immune response. From a bio-replenishment standpoint, immune system is analogous to the female reproductive system, where the costs of maintenance are minor compared to the expenses of actually using it!

Life has evolved with a conservative energy budget for its survival, growth and multiplication. During an immune response, however, balancing an energy budget becomes a challenge – it a question of life and death, after all. Immunity requires substantial energy to mount an effective response that could provide a strong host defense. Considering the profit (life) and loss (death) balances, the host metabolism re-routes a significant part of its bio-energetic output (sparing the basal metabolic rate) to meet the demands of immune defense. Since, the aging process is associated with a progressive decline in bio-energetic grid (with deteriorating basal metabolic rate and depreciating energy resources for host defense); immune compromised condition and susceptibility to infections are common among the elderly population. Interestingly, metabolism and immunity share a common purpose; both processes must engulf other particles, however, one for energy and the other to stop a harmful invader!

Immune cells originating from different lineage meet their bio-energetic demand through distinct mechanisms. Such metabolic disparity defines the energy efficiency and specificity of an immune response. Cells of myeloid lineages derive their energy exclusively from the glycolytic pathway. In contrast, T and B cells from lymphoid origin, obtain energy predominantly utilizing the oxidative phosphorylation [Fox et al 2005].

Bio-energetics of Myeloid Cells: Myeloid cells that proliferate within tissues, such as neutrophils, macrophages, and dendritic cells, are recruited to the inflammatory sites during an immune response. In the transit, these cells expend tremendous amounts of energy. Cell migration, for example, requires large amounts of protein (“actin”) turnover, which is ATP demanding event. After reaching the inflammatory site, the nutrient, energy, and oxygen demands of myeloid cells spike up to performs tasks such as phagocytosis and microbial killing. It is known that neutrophils are primarily glycolytic cells with few mitochondria; therefore, generate limited energy from respiration [Borregaard & Herlin, 1982]. An active inflammatory site with high immune activity can rapidly deplete both nutrients and oxygen. Activated neutrophils, for example, demonstrate an increased oxygen demand, as much as 50-fold in the generation of reactive oxygen intermediates (the so-called respiratory burst) necessary to kill bacteria after phagocytosis [Gabig et al 1979].

Macrophages are also nutrient demanding cells. During hyper-metabolic state, these cells demonstrate a markedly elevated rate of glucose and glutamine utilization compared to other host cells. Based on in vitro oxygen consumption rates, activated macrophages turn over its cellular ATP about 10 times per minute, which is comparable to maximally functioning heart muscle [Newsholme and Newsholme 1989]. Thus, immunity demands fuel in terms of nutrients and energy at remarkable proportions to ensure host survival. Accelerated breakdown of lipids (lipolysis), proteins (proteolysis), and sugars (glycolysis) supply the fuel necessary for mounting the initial immune responses against infection, resulting in substantial loss of body weight if infections are severe (“acute”) and persist for a long time (“chronic”).

Bio-energetics of Lymphoid Cells: Lymphoid cells, both T and B types, by contrast, use amino acids, glucose and lipids as energy substrates during oxidative phosphorylation. Mitogenic stimulation of thymocytes (or native T cells) is substantially energy-demanding process. During proliferation, lymphocytes become increasingly dependent on glucose uptake. Stimulated proliferation of thymocytes can result in nearly 20-fold increases in glucose uptake, which is accomplished by elevated expression of glucose transporter-1in the plasma membrane [Greiner et al 1994], When glucose becomes a limiting factor (which often occurs at sites of high immune activity), T cells can use alternative energy sources, such as glutamine, within the Kreb’s (TCA) cycle [Fox et al 2005].

Bio-energetics of Immunity – Cost Equation: Severity, type, and duration of infection, ambient temperature, and gender, age and nutritional status of the host, collectively influence the cost of mounting an immune response [Klasing 2004]. In humans, severe infections commonly lead to losses of 15–30% body weight, with 25–55% increases in resting metabolic rates [Kreymann et al 1993]. The energy cost for synthesis of new proteins to replace those lost in skeletal muscle must be added to the overall cost of mounting an immune response. Thus, about 20% of protein mobilized from the skeletal muscle meets the metabolic demand of an immune response [Duke et al 1970]. About 50% of rise in metabolic rate during an infection can be attributed to the increased energy costs with protein synthesis (acute-phase inflammatory proteins, antibodies) [Borel et al 1998]. Glucose utilization can increase 68% during the acute-phase immune response [Klasing 1988]. Fever, a hallmark of infection, usually elicits a 10–15% increase in basal metabolic rate for each 1°C rise in body temperature [Roe and Kinney 1965]. Mild immune challenges such as those associated with vaccination with protein antigen or attenuated organisms can result in 15–30% increases in the metabolic rate [Cooper et al 1992, Demas et al 1997, Svensson et al 1998]. Finally, the recovery period has a substantial nutritional demand associated with the replenishment of the body tissue reserves that were expended through catabolic processes during the immune response. An estimated 24 kcal is required by the host to deposit a single gram of protein [Scrimshaw 1991].

Inflammatory and immune responses lead to drastic shifts in tissue metabolism. These changes include local depletion of nutrients, increased oxygen consumption and generation of large quantities of reactive nitrogen and oxygen intermediates [Demas et al 1997, Kominsky et al 2010].The negative consequence of fighting an infection is a reduction in dietary intake. Sepsis-induced anorexia is a striking example, which occurs at a time when the body needs a surplus of nutrients to support the increased demands of mounting an immune response [Scrimshaw 1991]. Consequently, catabolic processes activate and come into force to provide additional nutrients for immune cells and protein synthesis (acute-phase proteins, antibodies). To meet such nutritional demand, catabolic pathways breakdown the body’s protein reserves to provide glutamine, carbohydrates, and lipids to the immune cells [Michie 1996, Crouser and Dorinsky 1996]. Moderate infections can easily lead to 150–200% increases in rates of gluco-neogenesis in the host, often cause severe wasting of lean tissue. A host typically becomes insulin-resistant as an adaptation mechanism to ensure that glucose levels in circulation remain high for the insulin-independent immune cells that are involved in wound healing and combating infection [Chiolero et al. 1997].

During infection, energy demands need to be met very rapidly with an immediate response from the host physiology. Adipose tissue supplies immune cells with fatty acids to serve as energy fuel. It also provides arachidonic acid and docohexanoic acid, the two lipid-derived messenger molecules originating from polyunsaturated fatty acids (PUFAs), both of which are key factors in innate immune defense. These two fatty acids are the precursors for prostaglandins and leukotrienes, critical for an effective inflammatory response [Schmedtje et al 1997].

Nitrogen demand also increases during an acute immune response. Nitrogen excretion in the form of urea can elevate up to 160% above normal during sepsis [Carlson et al. 1997]. Protein synthesis falls short in keeping pace with accelerated rates of protein loss from skeletal muscle, therefore, results in loss of total body protein [Biolo et al. 1997]. Even mild challenges of the immune system such as those induced by vaccinations can reduce nitrogen retention by as much as 30% in the host [Hentges et al. 1984].

It is well known that caloric restriction with diet, if prolonged, can lead to suppression of the immune system and increased risk of infection, especially with opportunistic pathogens. The importance of caloric restriction to sustain the immune system has also become evident from the space program where the minimal energy demands manifested by zero-gravity environments can result about 90% decline in cytotoxic T-lymphocyte function in astronauts [Tanner 1992].

The interaction involving nutrition and immunity and ability of the host to deal with infectious agents is a strategic determinant in immune replenishment. Almost all nutrients in the diet play a fundamental role in sustaining an optimal immune response, such that deficient and excessive intakes can have negative consequences on immune status and susceptibility to a variety of pathogens. Dietary components can regulate physiological functions of the body; interacting with the immune response is one of the most important functions of nutrients.

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