Brief Survey Of The Immune System

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Introduction

The immune system plays a crucial role in human health, but one that has two sides. On the one hand, it is absolutely indispensable for protection against pathogens; on the other, malfunctions in the immune system can result in serious disease. Earlier sections of this book have mentioned the involvement of the immune system in inflammatory diseases such as arthritis and asthma, and also in autoimmune diseases such as type 1 diabetes (diabetes mellitus) and Addison's disease. As medicine becomes more molecular in character, the cellular and molecular details of immunity must be clarified if truly effective treatments are to be discovered.

Human life and health depend on the ability of the immune system to distinguish between self and non-self and selectively to destroy viruses, bacteria, fungi, multicellular parasites, or other foreign invaders. That discrimination involves the sensing of foreign matter by receptors on the surface of various immune cells. Such receptors can detect foreign matter that exhibits telltale, non-self chemical features. The body also uses outer defenses wherever it is directly exposed to the environment. These include antimicrobial enzymes and molecules in skin and in the respiratory and digestive tracts, and also sentinel immune cells that effectively destroy microorganisms.1"4

Innate immunity

The inner defense mounted by the immune system when foreign invaders enter the body is broadly of two types, depending on the kind of immune cell that is involved. The first response is a predetermined defensive system that deals with a broad assortment of invaders. These cells make up the innate arm of the immune response. Members of this class include monocytes, macrophages, dendritic cells, granulocytes, and natural killer cells. They all originate in bone marrow from a common hemopoietic stem cell precursor. These cells often carry surface receptors that bind surface components of microbes, a form of pattern recognition selected for by evolution.

Adaptive Immunity

The second line of cells form the "adaptive arm" of the immune response which includes

B- and T-lymphocytes, and the various subtypes derived from them. The response of these cells is highly specific and exquisitely tailored to be effective against the foreign agent. In addition, some of those cells are unusually long-lived and remember a previous encounter with a particular invading microorganism. They are primed for later action.

Complexity of Immunity

The many component cells of the immune system are linked together in a functional network by chemical messengers that influence their activation or suppression, their migration to the site of infection, and also their proliferation or demise. The various immune cells express a large number of surface receptors that receive and transmit a huge variety of informational signals from the cell's environment. The direction, coordination and regulation of the immune reaction to infection involves multiple levels of chemical signaling and redundancy that add up to an enormously complex system. For this reason, it has taken many decades to attain our present understanding of its operation and the molecular basis for the exquisite distinction between the cells of our own body and those of a foreign organism. Although there is still much to learn, we are beginning to appreciate the ways in which the immune system malfunctions in inflammatory and autoimmune diseases.

A brief summary of the working elements of the immune system is challenging because of the many types of cells that are involved and the large cast of biochemical agents that serve as weapons, messengers, activators, deactivators or regulators. The interactions of these components are complex and dynamic. For these reasons we shall consider first the various mediators that guide cell action and their general properties, and then discuss the actions of the different classes of immune cells and the role of the mediators in these actions.

Mediators

1. Chemotactic agents. These attract immune cells to the site where the immune defense needs to be focused. The attraction arises from sensing receptors on a target cell that stimulate its movement toward increasing concentrations of the agent.

IA. Chemokines. These are small signaling proteins (8-10 kDa molecular weight) secreted by several types of immune cells, especially to attract monocytes, macrophages, and dendritic (phagocytic) cells of the innate response, and the T- and B-cells of the adaptive response. There are roughly 50 chemokines and numerous receptors (about 20) for them.

IB. Products of the complement system. "Complement" is a large family of proteins, made in liver and in certain immune cells, that has several functions, for example:

(1) to effect proteolytic cleavage of proteins,

(2) to provide reactive fragments that can tag foreign or abnormal host cells and

(3) to generate small peptide fragments (e.g., complement peptides C3a, C5a and N-formyl-Met-Leu-Phe) that serve as chemotactic agents.

IC. Fragments from degradation of microbes or viruses or from blood clotting or fibrinolysis.

ID. Other small molecules, e.g., leuko-trienes B4 and C4 (see page 41), which are powerfully attractive to immune cells.

2. Cytokines. These are proteins secreted by immune cells that regulate and coordinate the immune response, but also play a role in inflammation and cell proliferation. Subtypes include monokines (made by monocytes), lymphokines (made by lymphocytes), chemokines (see above) and interleukins (made by leukocytes to act on other leukocytes). Examples include:

(1) TNF-a which activates cells such as macrophages and T-cells,

(2) IL-1 which activates T-cells,

(3) IL-2 which activates T, B and also natural killer (NK) cells and

(4) interferons which are produced by a variety of cells and serve to upregulate antiviral defenses. There are about 30 different interleukins now known.

3. C-reactive protein (CRP). The production of this protein which circulates in blood is increased by about two orders of magnitude after an infection. CRP binds to bacteria synergistically with the C3b fragment of complement and stimulates monocytes and macrophages to attack the cells so tagged.

4. Antibodies (Ab). Antibodies are proteins of the immunoglobulin type that recognize and bind to foreign agents including microbes, cell fragments and foreign molecules, effectively tagging these species for destruction or elimination. There are five classes of immunoglobulins: IgG (most abundant in blood, ca. 75%), IgM (ca. 10%), IgA (15-20%), IgD (<1%) and IgE (<1%), all synthesized by B-cells. IgE mainly targets mast cells and basophils. As if this were not complex enough, there are 4 subclasses of IgG and 2 of IgA in humans.

A close-up X-ray structure of the antigen binding site of an IgG molecule with riboflavin as the bound antigen. The crystal used for this structural analysis was obtained from the serum of a patient with the cancerous disease multiple myeloma. (2FL5)
class I HLA molecule. (1IAK)
A space-filling representation of the class I HLA molecule-peptide binary complex shown above. The peptide is shown in red. (1IAK)

The structures of the various classes have been determined by X-ray crystallographic studies. These proteins are roughly Y-shaped with the stem being a fixed structural domain that binds to a specific cell surface receptor for each class.

Their receptors occur, for example, on B-cells (for IgG) and mast cells (for IgE). The uppermost part of the slanting Y arms of the immunoglobulin are highly variable in amino acid sequence and contain the antigen binding region. One particular B-cell clone produces only one antibody species, specific for that clone. Every day millions of non-identical immunoglobulins are produced in the body by the total population of ca. 1012 cells. When an antigen is bound to an Ig molecule attached to the surface of the B-cell, it is internalized and broken down. Each B-cell clone deals with only one particular antigen.

Human Leukocyte Antigen Molecules (HLA)

Human leukocyte antigens, also known as major histocompatibility complex (MHC), are proteins that, at one end, function as ligands which bind to cognate receptors and, at the other end, possess grooves that always carry one specific small peptide in a stretched-out condition, and only that particular peptide. There are two broad classes of human leukocyte antigens, class I HLAs and class II HLAs. The peptides which fit class I HLAs are 8-11 amino acid long, whereas those that are recognized by class II HLAs are 10-30 amino acid long. The peptides may be derived from the host's own proteins (self peptides) or from foreign proteins (non-self or antigenic peptides). The HLA-peptide complexes are expressed by antigen presenting cells (APC). When these HLA-peptide complexes are activated by pathogens, they migrate to lymph nodes. Once there, the APC-HLA-peptide complex can bind to a T-cell causing its activation. An X-ray structure of a binary complex of class I HLA and a small peptide is shown on the left.

mediated hydrogen bonding between the class I HLA molecule and peptide ligand. The peptide is shown in red (without its side chains), the a and (3 subunits of the HLA molecule are shown in yellow and cyan, the water molecules are shown as small spheres in magenta, and the hydrogen bonds are depicted as blue dotted lines. (1IAK)

mediated hydrogen bonding between the class I HLA molecule and peptide ligand. The peptide is shown in red (without its side chains), the a and (3 subunits of the HLA molecule are shown in yellow and cyan, the water molecules are shown as small spheres in magenta, and the hydrogen bonds are depicted as blue dotted lines. (1IAK)

The binding of class II HLA molecules to peptides is generally similar to that shown for class I HLA-peptide complex.

Families of Immune Cells

1. Phagocytes are immune cells that recognize, engulf and digest viruses, microbes, and foreign cells or organic materials. There are three principle subtypes, which are part of the innate response: monocytes, macrophages and dendritic cells. In addition, there is another family of phagocytic cells, the granulocytes, that contain subcellular enzyme packets.

1A. Monocytes. Roughly 5% of the circulating white blood cells in the body are monocytes. These cells have lifetimes of just a few days, after which they develop into macrophages, which reside in body tissues. Monocytes selectively destroy cells or materials that are tagged by having surface labels such as antibodies or a complex of complement fragment C3b and C-reactive protein. Monocytes are attracted to sites of infection or damage by the various chemotactic factors mentioned above.

IB. Macrophages. The name macrophage derives from the Greek for "big eater", which is appropriate since they devour foreign cells or fragments and since one macrophage can ingest dozens of microorganisms over their lifetime, which can vary from months to years. Because they produce a variety of noxious enzymes and chemicals, macrophages cause significant collateral damage to surrounding cells and tissues, thereby resulting in inflammation and, also, in their own demise.

Macrophages are activated by mediators secreted by other immune cells; they also produce their own mediators to stimulate the immune response of other cells.

Macrophages are guided to their prey by a variety of attractant molecules. They play a role as a viral reservoir in HIV infection since the human immunodeficiency virus can gain surreptitious entry by binding to a surface receptor to form a complex which is then taken up by the macrophage (endocytotic internalization). Once inside, the HIV guest enjoys safe haven since it is protected from attack by the immune system.

IC. Dendritic cells migrate from blood to tissues that are exposed to the environment (e.g., airways, gastrointestinal tract and skin). They are attracted to sites of infection, and if they sense a tagged foreign invader, they are activated to ingest and break down the various constituents.

Dendritic cells, in common with ordinary human cells, contain a cylindrically shaped assembly of 28 protein subunits (the "proteasome") that can cleave any protein which carries a polyubiquitin chain (a general tag for disposal) to small fragments (mostly 812 amino acids). These then are transported to the surface of the dendritic cells where they are held by a human leukocyte antigen (HLA) protein. The dendritic cell so equipped next migrates to a lymph node where it awaits an encounter with a T-cell that possesses a surface receptor, which provides a matching fit with the HLA-peptide complex. The dendritic cell then functions as an antigen presenting cell which activates the T-cell. Most dendritic cells carry small peptides derived from self that do not activate T-cells. There are actually three types of dendritic cells with respect to origin, but they all function in the same general way as antigen presenting cells.

2. Granulocytes. This class of white blood cells, also known as polymorphonuclear leukocytes, comprises the subclasses neutrophils, eosinophils, basophils and mast cells. These cells contain, in addition to nuclei, granules that hold enzymes which break down DNA, RNA, triglycerides and other lipids, complex carbohydrates and proteins. These enzymes (e.g., a-amylase, elastase and collagenase) can break down not only organic materials but also bacterial cell walls (using the enzyme lysozyme), and tissues. Other granule products are (1) lactoferrin which binds iron strongly and deprives bacteria of this element which is essential for their proliferation and (2) an array of enzymes that break down bacterial cells and their contents, and powerful bacteriocidal oxidants such as peroxide-derived oxygen radicals and hypochlorite (NaOCI). The latter (the active ingredient in chlorine bleach) is especially lethal to bacteria. One milliliter of bleach will kill 1 gram of E. coli bacteria in seconds.

2A. Neutrophils. The most abundant of the phagocytic white blood cells (about 50-70%, roughly 1010 cells in the average human), neutrophils circulate in blood and are drawn to sites of infection by cytokines, chemokines and other mediators. They arrive rapidly (ca. 1 hour) and in force at the site of infection because they are widely distributed and mobile. Neutrophils have half lives of roughly 7-8 hours, which is fortunate because they are not only deadly to invading microorganisms, but very destructive to the body's own cells and tissues.

2B. Eosinophils. Although they comprise less than 5% of the white blood cell population, eosinophils can effectively deal with parasites and viruses because they possess not only protein digesting enzymes and oxidants but an abundance of DNAase and RNAase enzymes. An elevated eosinophil blood count can accompany various disease states, e.g., parasitic infection, Hodgkin's malignancy and rheumatoid arthritis (in which they contribute to tissue and joint damage).

2C. Basophils and mast cells. These immune cells have many common features including surface receptors for IgE and granules containing inflammatory mediators such as histamine, leukotrienes B and C, PGD2 and various cytokines. These mediators are released when the cells are activated. Mast cells are found In most tissues and are considerably more abundant than basophils. Full activation of these cells occurs when IgE-bound surface receptors are cross-linked by an antigen. The IgE is provided by a B-cell which can interact with the basophil or mast cell. Mast cells appear to be important in asthma and rhinitis and in various allergies.

3. Natural killer (NK) cells. NK cells of the immune system are very cytotoxic, and consequently, highly regulated weapons against infection. Their outer surfaces are studded with regulatory receptors that bind either activating or deactivating mediators. Activation can be effected by cytokines such as TNF-a (released, for example, by macrophages which are stimulated by microbial lipopolysaccharides), viral double stranded RNA and interferons (especially IF-« and IF-p, which are secreted by virally infected cells). These bind to activation receptors on the surface of the NK cells. NK cells contain granules that release at least two types of attack mediators: (1) perforin proteins which enter the membranes of target cells and form pores, and (2) proteolytic enzymes that then invade the target cell through these pores. The activity of NK cells is eventually downregulated by mediators, including the body's own HLA proteins that bind to inhibitory receptors on the outer surface of the NK cells.

NK cells are especially well suited to the removal of the body's own cells that become malignant or infected by viruses, or any other cells whose surfaces are tagged by IgG,

4. Lymphocytic T-cells. The white blood cells known as T- and B-cells, originating in the thymus and bone marrow, respectively, are major components of the adaptive immune response. The daily human production of these cells is about 10s each per day, and each population consists of many millions of distinctly different clones. This enormous diversity is combinatorial and is the result of gene-segment shuffling during cell formation. The diversity is manifested in T-cells by the huge variety of binding domains of Immunoglobulin-like T-cell receptors (TCR) on the surface of the T-cell. These receptors recognize and bind to specific HLA-peptide complexes on the antigen presenting cells. The diversity-producing gene shuffling occurs in Ig/TCR genes of T-cells (and for B-cells in genes coding for Igs). In general, T-cells and B-cells require two different signals for full activation. One of these is directly related to interaction with an antigen. The maturation and proliferation of T-cells is greatly increased in those cells that are bound to HLA-peptide complexes and also receive a co-stimulatory signal from the activated APC's. As a result, there is an exponential expansion of those highly competent cells and an elimination of any incompetent T-cells.

A negative selection also occurs in the thymus during T-cell generation for any subset of T-cells that happen to bind strongly with HLA molecules bearing a "self nonapeptide. Those T-cells which could be toxic to the body's own cells are caused to undergo biochemically programmed cell death (apoptosis) and thus depart from the immune system or are rendered innocuous. (See section below on discrimination between self and non-self.)

T-cells can be distinguished by two differentiating surface proteins, CD4 and CD8. CD4-bearing T-cells (CD4*) bind class II HLAs and CD8-bearing T-cells (CD81) bind class I HLAs. CD8* cells are cytotoxic T-cells (Tc) whereas CD41 cells are helper T-cells which are involved in activating other immune cells or cytokine release (Th). Cytotoxic T-cells are powerful destroyers of foreign cells, but also sources of inflammation. There are two subsets of Th-cells. Th1 and Th2, which produce different cytokines and affect different components of the immune response. Th1-cells produce IF-y and are highly stimulating to phagocytes. Th2-cel!s produce IL-4. IL-5, and IL-13 and stimulate the immune response of mast cells, basophils and eosinophils, effectively upregulating antiparasitic and allergic respon ses. Another type of Th-cell, Th17, makes IL-17, and seems to play a role in autoimmune diseases such as multiple sclerosis and inflammatory bowel disease.

There are T-cells that carry both CD4 and CD25 surface protein markers and serve as regulatory cells (Tr). One important function of Tr-cells, which contributes to the ability of the immune system to distinguish between self and non-self, is to cause apoptosis (biochemically programmed cell death) of self-reactive Tc-cells. A second critical role of Tr -cells is to hasten the death of activated Tc-cells after an infection has been cleared. This process supplements another control on Tc-cells in which apoptosis of the Tc-cell occurs spontaneously after it has been activated multiple times.

Finally, there are long-lived T-cells that are termed "memory cells" because they live for several years and are able to deal rapidly with an agent from an earlier Infection. Normally Tc-cells survive only for a few weeks, and even less if they have been activated several times.

5. Lymphocytic B-cells. B-cells recognize foreign organic matter including microbes and viruses, produce high affinity immunoglobulin antibodies that attach to these foreign entities, and cooperate with other immune cells to eliminate such threats. B-cells originate from stem cells in bone marrow and progress through a multi-stage maturation process, which only a small fraction survive. Humans have at any one time about 1012 B-cells and a huge diversity of B-cell clones, approximately 10'. Each one produces a different antibody which may be of the IgG, IgM, IgA, IgD or IgE class, as mentioned in the section on antibodies above. The enormous number of different B-cell clones, and Igs arises because of very extensive, random shuffling of certain segments of the genes that code for the variable, antigen-binding, portion of the immunoglobulins. This genetic shuffling is all the more remarkable because the genes coding for the Igs consist of many segments that are separated by intervening, non-coding DNA and are even on different chromosomes. It is clear that great B-cell diversity is required because there are 209 or 5.12 x 1011 possible nonapeptides with the 20 genetically coded amino acids.

Another reason for the effectiveness of the B-cells in combating infection is the existence of a mechanism for expanding the population of those clones that produce Igs which recognize antigens and bind with high affinity to the HLAs of antigen presenting cells. Those B-cells that find matching antigen are stimulated to proliferate, thereby greatly increasing that clonal population. This selection mechanism for clonal expansion continues until the foreign invader has been dealt with. The sequence of events for clonal expansion of B-cells is as follows: (1) encounter with an antigen presenting cell for which the B-cell has affinity, (2) ingestion of the antigen, (3) display of the antigen on a B-cell class II HLA protein, and (4) binding to a primed helper T-cell that also recognizes the antigen and secretes cytokines which stimulate B-cell proliferation.

Many millions of B-cells are manufactured daily by humans. Some B-cells have large nuclei and are large-scale producers of antibodies. Furthermore, other special purpose B-cells are so long lived that they function as memory cells, since they rapidly spring into action, even at a much later time, if their triggering antigen reappears. Still another B-cell subtype expresses lower affinity, but less specific IgM antibodies.

B-cells are distributed in tissues throughout the body, but they have a major presence in the lymph nodes, like T-cells. A small fraction circulate in the vasculature. Activated B-cells are cleared in the liver and spleen and survive only a matter of days, but "naive" or memory B-cells are protected from this fate. Peripheral B-cells also secrete immunoglobulins such as IgE (which goes mainly to mast cells and basophils) and IgM. The latter is prone to form stable pentameric structures. The binding of IgM to bacterial surfaces causes aggregation to a large polycellular clump which is attacked and destroyed by macrophages.

antibodies

A graphical summary of the interactions and functions of lymphocytes. Tc-cells that are self-reactive or no longer needed are disposed of by Trcells; otherwise Tc-cells undergo spontaneous apoptosis after multiple cycles of activation.

antibodies

A graphical summary of the interactions and functions of lymphocytes. Tc-cells that are self-reactive or no longer needed are disposed of by Trcells; otherwise Tc-cells undergo spontaneous apoptosis after multiple cycles of activation.

Discrimination Between Self and Non-Self

If a student of biological chemistry were to undertake the theoretical task of designing an immune system that, in principle, can distinguish an individual's own cells (self) from those of invading microbes or viruses (non-self), the result might be along the following lines. Each cell of the person would have to be tagged by a surface molecule that is unique to that individual, in the same way that a combination lock is coded by a unique set of numbers. The molecular tag might be a particular protein or a particular protein that is further garnished by a branching chain of carbohydrate units to ensure even greater diversity. Any immune cell that happened to have a receptor which allows it to bind to the tag, or self-antigen, would then have to be dealt with because such proximity would probably lead to attack and destruction by the immune cell. The individual's cell could deal with the inappropriate recognition and binding by the immune cell in various ways. First, it might simultaneously repel the immune cell and tag it for destruction. Or, it might send a biochemical signal to the cell that renders it incapable of producing any damage. Finally, it might label the immune cell with a marker that would allow regulatory cells to trigger the death of the self-reactive immune cell. This conceptually simple model is not very different from the picture that has emerged after decades of study of this central question in immunology.

We now know that a person's cells do indeed carry surface tags that are unique to the individual and genetically determined. These self- or tolerogenic antigens induce tolerance by the immune system and are essential for distinguishing between self and non-self. Severe failure of this system leads to autoimmune disease. T- and B-lymphocytes and dendritic cells are key players in immunological tolerance.

This discussion will be simplified by focusing on T-cells. Each day about 100 immune-cell precursors enter the thymus and undergo multiple cell divisions to generate about 107-108 T-cells. However, only about 5% of these T-cells survive the selection process in the thymus which weeds out those T-cells that show an affinity for self-antigens. About 95% of the total production of T-cells either die by apoptosis or by conversion to a harmless (anergic) state. This selection-driven tolerance ("central tolerance") is crucial to the establishment of a properly balanced immune system. If the selection process were to be too severe, a weak immune system incapable of dealing with infection would result. On the other hand, if the selection were to be too lenient, autoimmune disease would become more likely. In general, the immune system seems to err on the side of leniency, because it has developed another level of defense against autoimmunity involving regulatory T-cells (Tr). It has been mentioned in the earlier section on T-cells (page 116) that Tr-cells can induce apoptosis in Tc-cells after an infection has been cleared or inactivate these cells.

The control of self-reactive circulating T-cells by Tr-cells occurs in the periphery (and is sometimes called "peripheral tolerance"). The subpopulation of Tr-cells carrying both CD4 and CD25 surface proteins is more effective for the elimination of self-reactive T-cells than the Tr-cells that carry surface CD4 but not CD25. The molecular mechanisms by which T-cells are downregulated or disposed of involve interleukins as the active agents. T-cell anergy can be induced by inhibition of a tyrosine kinase signaling pathway that downregulates calcium influx into the cell and also by another pathway that blocks IL-2 receptor-mediated activation. There is a whole family of proteins produced by the immune system that suppress cytokine signaling.

Most cancer cells avoid attack by the immune system because they carry self-antigens on their surface.

In summary the immune system has evolved a multilevel quality-control mechanism to minimize damage to host cells by self-reactive T- and B-lymphocytes.

Immunologic Profile of an Infection

The vast majority of pathogens in the environment are held at bay by the body's physical barriers to infection (e.g., skin, mucus, gastric acidity, and antimicrobial chemicals and enzymes). However, once these outer defenses are breached and an infection sets in, a variety of effective immunological countermeasures emerge. One simplified scenario can be outlined for a bacterial infection. The presence of foreign organic matter (e.g., lipopolysaccharide of microbial origin) may provoke attack by components of the innate immune response (e.g., dendritic cells or macrophages), which can lead to activation of the complement system and release of chemotactic agents and cytokines. The activated dendritic cells then generate surface antigen from the target and migrate to a nearby lymph node. There they meet T-cells and B-cells which recognize the antigen as foreign, become activated and mount a response. Immunoglobulins are formed and secreted, and reactive complement fragments and C-reactive protein are generated. Activated monocytes, macrophages, NK cells, Tc-cells and B-cells then converge on the invading microbes and clear the infection, at which point the destructive immune cells are caused to die. However, memory B- and T-cells persist and remain in long-term reserve against reinfection.

Disorders of the Immune System

There are at least one hundred illnesses involving abnormal function of the immune system. These cover a spectrum ranging from systemic immune malfunction (e.g., rheumatoid arthritis) to highly localized organ destruction, such as of pancreas (type I diabetes), adrenals (Addison's disease) or thyroid (Hashimoto's thyroiditis). The susceptibility of an individual may vary with genetic inheritance, gender, history of infection, or age. Causation is almost always complex and multifactorial, but leads pathologically to the harmful action of autoantibodies, autoreactive T-cells or phagocytes on the tissues and organs. Autoimmunity is basically a failure of immune tolerance that can, in principle, stem from:

(1) functional defects in any one of the immune cell types,

(2) the improper secretion of the mediators which coordinate or regulate them,

(3) failure to recognize invaders as foreign,

(4) failure to distinguish self from non-self,

(5) failure to control populations of effective, non-effective or deleterious cells,

(6) failure to generate adequate diversity of immunoglobulins and/or HLA molecules,

(7) purely random events such as the chance similarity of self and non-self antigens.

Autoimmune diseases can be diagnosed in various ways, including by the nature of the symptoms of the illness or the detection of autoantibodies (often termed "antinuclear antibodies" or ANAs). If high blood levels of ANAs are detected, more precise diagnostic tests are used to determine the type, e.g., rheumatoid arthritis, lupus or Sjogren's syndrome subtype. In addition, elevated levels of C-reactive protein, reactive complement fragments, cytokines or other inflammatory species are indicative. The therapies of autoimmunity are still limited. The most commonly used of these are glucocorticoids such as prednisone, immunosuppressants, or monoclonal antibodies against specific cytokines such as antl-TNF-a or anti-IL-1 antibodies.

Allergy

Allergy, now termed type 1 hypersensitivity, is characterized by excessive production of IgE in response to harmless common antigens by mast cells and basophils, and their overactivation. As a result, inflammatory mediators (e.g., histamine, PGD2, and leuko-trienes) are released causing symptoms ranging from mild to life-threatening (anaphylaxis).

The Immune System and Aging, Immuno-senescence

The intensity and effectiveness of the human immune response to infection increases from birth to a maximum in middle age. In the elderly (>70 years) there is a substantially increased susceptibility to infection, which is especially serious for viral infections such as flu, pneumonia and shingles (Varicella zoster). The protective effect of vaccines is reduced in the elderly with regard to the level of the resulting antibodies and the duration of the protective effect. The production of immune-stimulating cytokines (e.g., IL-2) is diminished. In addition, the antibodies generated by elderly individuals exhibit lowered affinity for antigen than those measured for young adults. The levels of antinuclear antibodies are on average considerably higher for individuals between the ages of 70 and 80 than those in their 40s, and the incidence of autoimmune disease is increased. In the elderly much of the thymic tissue is lost by age 70 and the clonal diversity of CD8-bearing Tc-cells is diminished. The factors that determine the decline in immune function with age are especially difficult to evaluate because there are so many, and because animal models (e.g., mice) have been unreliable.

1. Abbas, A. K.. Lichtman, A. H. Cellular and Molecular Immunology, 5th Edition (2005), 2. Cruse, J. M., Lewis, J. R. E. & Editors. Illustrated Dictionary of Immunology (1995); 3. Janeway, C. A., Travers, P., Walport, M. & Shlomchik. M. Immunobiology: The Immune System in Health and Disease, 6th Edition (2004); 4. Paul, W. E. & Editor. Fundamental Immunology (1986); Refs. p. 173

The medical repair or replacement of damaged or non-functioning organs, now in Its infancy, is likely to play a much more important role in the treatment of human illnesses in the coming decades.

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