IMMUNE SYSTEM

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 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

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 suppressive 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.

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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 direct 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].

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.

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 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 for immune cells and protein synthesis. 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 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. 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].