The above overview of innate and adaptive immunity depicts a multicomponent interactive system that protects the host from infectious diseases and from cancer. This overview would not be complete without mentioning that the immune system can function improperly. Sometimes the immune system fails to protect the host adequately or misdirects its activities to cause discomfort, debilitating disease, or even death. There are several common manifestations of immune dysfunction:
■ Allergy and asthma
■ Graft rejection and graft-versus-host disease
Allergy and asthma are results of inappropriate immune responses, often to common antigens such as plant pollen, food, or animal dander. The possibility that certain substances increased sensitivity rather than protection was recognized in about 1902 by Charles Richet, who attempted to immunize dogs against the toxins of a type of jellyfish, Physalia. He and his colleague Paul Portier observed that dogs exposed to sublethal doses of the toxin reacted almost instantly, and fatally, to subsequent challenge with minute amounts of the toxin. Richet concluded that a successful immunization or vaccination results in phylaxis, or protection, and that an opposite result may occur—anaphylaxis—in which exposure to antigen can result in a potentially lethal sensitivity to the antigen if the exposure is repeated. Richet received the Nobel Prize in 1913 for his discovery of the ana-phylactic response.
Fortunately, most allergic reactions in humans are not rapidly fatal. A specific allergic or anaphylactic response usually involves one antibody type, called IgE. Binding of IgE to its specific antigen (allergen) releases substances that cause irritation and inflammation. When an allergic individual is exposed to an allergen, symptoms may include sneezing, wheezing, and difficulty in breathing (asthma); dermatitis or skin eruptions (hives); and, in more extreme cases, strangulation due to blockage of airways by inflammation. A significant fraction of our health resources is expended to care for those suffering from allergy and asthma. The frequency of allergy and asthma in the United States place these complaints among the most common reasons for a visit to the doctor's office or to the hospital emergency room (see Clinical Focus).
When the immune system encounters foreign cells or tissue, it responds strongly to rid the host of the invaders. However, in some cases, the transplantation of cells or an organ from another individual, although viewed by the immune system as a foreign invasion, may be the only possible treatment for disease. For example, it is estimated that more than 60,000 persons in the United States alone could benefit from a kidney transplant. Because the immune system will attack and reject any transplanted organ that it does not recognize as self, it is a serious barrier to this potentially life-saving treatment. An additional danger in transplantation is that any transplanted cells with immune function may view the new host as nonself and react against it. This reaction, which is termed graft-versus-host disease, can be fatal. The rejection reaction and graft-versus-host disease can be suppressed by drugs, but this type of treatment suppresses all immune function, so that the host is no longer protected by its immune system and becomes susceptible to infectious diseases. Transplantation studies have played a major role in the development of immunology. A Nobel prize was awarded to Karl Landsteiner, in 1930, for the discovery of human blood groups, a finding that allowed blood transfusions to be carried out safely. In 1980, G. Snell, J. Dausset, and B. Benacerraf were recognized for discovery of the major histocompatibil-ity complex, and, in 1991, E. D. Thomas and J. Murray were awarded Nobel Prizes for advances in transplantation immunity. To enable a foreign organ to be accepted without suppressing immunity to all antigens remains a challenge for immunologists today.
In certain individuals, the immune system malfunctions by losing its sense of self and nonself, which permits an immune attack upon the host. This condition, autoimmunity, can cause a number of chronic debilitating diseases. The symptoms of autoimmunity differ depending on which tissues and organs are under attack. For example, multiple sclerosis is due to an autoimmune attack on the brain and central nervous system, Crohn's disease is an attack on the tissues in the gut, and rheumatoid arthritis is an attack on joints of the arms and legs. The genetic and environmental factors that trigger and sustain autoimmune disease are very active areas of immunologic research, as is the search for improved treatments.
If any of the many components of innate or specific immunity is defective because of genetic abnormality, or if any immune function is lost because of damage by chemical, physical, or biological agents, the host suffers from immunodeficiency. The severity of the immunodeficiency disease
TABLE 1-4l Immunity in multicellular organisms
Innate Adaptive enzymes Pattern-
immunity immunity and enzyme Antimicrobial recognition Graft T and B
Taxonomic group (nonspecific) (specific) cascades Phagocytosis peptides receptors rejection cells Antibodies
Invertebrate animals Porifera (sponges)
Arthropods (insects, crustaceans)
Vertebrate animals Elasmobranchs (cartilaginous fish; e.g., sharks, rays)
Teleost fish and bony fish (e.g., salmon, tuna) Amphibians Reptiles Birds
equivalent agents probable
KEY: + = definitive demonstration;
: failure to demonstrate thus far; ? = presence or absence remains to be established.
SOURCES: L. Du Pasquier and M. Flajnik, 1999, "Origin and Evolution of the Vertebrate Immune System," in Fundamental Immunology, 4th ed. W. E. Paul (ed.), Lippincott, Philadelphia; B. Fritig, T. Heitz, and M. Legrand, 1998, Curr. Opin. Immunol. 10:16; K. Soderhall and L. Cerenius, 1998, Curr. Opin. Immunol. 10:23.
CLI N ICAL FOCUS
CLI N ICAL FOCUS
Allergy and Asthma as Serious Public Health Problems
Although the m mune system serves to protect the host from infection and cancer, inappropriate responses of this system can lead to disease. Common among the results of immune dysfunction are allergies and asthma, both serious public health prob lems. Details ofthe mechanisms that underlie allergic and asthmatic responses to environmental antigens (or allergens) will be considered in Chapter 16. Simply stated, allergic reactions are responses to antigenic stimuli that result in immunity based mainly on the IgE class of immunoglobulin. Exposure to the antigen
(or allergen) triggers an IgE-mediated release of molecules that cause symptoms ranging from sneezing and dermatitis to inflammation of the lungs in an asthmatic attack. The sequence of events in an allergic response is depicted in the accompanying figure.
The discomfort from common allergies such as plant pollen allergy (often called ragweed allergy) consists of a week or two of sneezing and runny nose, which may seem trivial compared with health problems such as cancer, cardiac arrest, or life-threatening infections. A more serious allergic reaction is asthma,
CLINICAL FOCUS (continued)
CLINICAL FOCUS (continued)
Allergy and Asthma as Serious Public Health Problems a chronic disease of the lungs in which inflammation, mediated by environmental antigens or infections, causes severe difficulty in breathing. Approximately 15 million persons in the United States suffer from asthma, and it causes about 5000 deaths per year. In the past twenty years, the prevalence of asthma in the Western World has doubled.*
Data on the frequency of care sought for the most common medical complaints in the United States show that asthma and allergy together resulted in more than 28 million visits to the doctor in 1995. The importance of allergy as a public health problem is underscored by the fact that the annual number of doctor visits for hypertension, routine medical examinations, or normal pregnancy, are each fewer than the number of visits for allergic conditions. In fact, the most common reason for a visit to a hospital emergency room is an asthma attack, accounting for one third of all visits. In addition to those treated in the ER, there were about 160,000 hospitalizations for asthma in the past year, with an average stay of 3 to 4 days.
Although all ages and races are affected, deaths from asthma are 3.5 times more common among African-American children. The reasons for the increases in number of asthma cases and for the higher death rate in African-American children remain unknown, although some clues may have been uncovered by recent studies of genetic factors in allergic disease (see Clinical Focus in Chapter 16).
An increasingly serious health problem is food allergy, especially to peanuts and tree nuts (almonds, cashews, and walnuts).1 Approximately 3 million Americans are allergic to these foods and they are the leading causes of fatal and near-fatal food allergic (anaphylactic) reactions. While avoidance of these foods can prevent harmful consequences, the ubiquitous use of peanut protein and other nut products in a variety of foods makes this very difficult for the allergic individual. At least 50% of serious reactions are caused by accidental exposures to peanuts, tree nuts, or their products. This has led to controversial movements to ban peanuts from schools and airplanes.
Anaphylaxis generally occurs within an hour of ingesting the food allergen and the most effective treatment is injection of the drug epinephrine. Those prone to anaphylactic attacks often carry injectable epinephrine to be used in case of exposure.
In addition to the suffering and anxiety caused by inappropriate immune responses or allergies to environmental antigens, there is a staggering cost in terms of lost work time for those affected and for caregivers. These costs well justify the extensive efforts by basic and clinical immunologists and allergists to relieve the suffering caused by these disorders.
First contact with an allergen (ragweed)
Production of large amounts of ragweed IgE antibody
IgE molecules attach to mast cells
Production of large amounts of ragweed IgE antibody
IgE molecules attach to mast cells
Subsequent contact with allergen
*Holgate, S. T. 1999. The epidemic of allergy and asthma, Nature Supp. to vol. 402, B2.
'Hughes, D. A., and C. Mills. 2001. Food allergy: A problem on the rise. Biologist (London) 48:201.
IgE-primed mast cell releases molecules that cause wheezing, sneezing, runny nose, watery eyes, and other symptoms
Sequence of events leading to an allergic response. When the antibody produced upon contact with an allergen is IgE, this class of antibody reacts via its constant region with a mast cell. Subsequent reaction of the antibody binding site with the allergen triggers the mast cell to which the IgE is bound to secrete molecules that cause the allergic symptoms.
depends on the number of affected components. A common type of immunodeficiency in North America is a selective immunodeficiency in which only one type of immunoglob-ulin, IgA, is lacking; the symptoms may be minor or even go unnoticed. In contrast, a rarer immunodeficiency called severe combined immunodeficiency (SCID), which affects both B and T cells, if untreated, results in death from infection at an early age. Since the 1980s, the most common form of immunodeficiency has been acquired immune deficiency syndrome, or AIDS, which results from infection with the retrovirus human immunodeficiency virus, or HIV. In AIDS, T helper cells are infected and destroyed by HIV, causing a collapse of the immune system. It is estimated that 35 million persons worldwide suffer from this disease, which is usually fatal within 8 to 10 years after infection. Although certain treatments can prolong the life of AIDS patients, there is no known cure for this disease.
This chapter has been a brief introduction to the immune system, and it has given a thumbnail sketch of how this complex system functions to protect the host from disease. The following chapters will concern the structure and function of the individual cells, organs, and molecules that make up this system. They will describe our current understanding of how the components of immunity interact and the experiments that allowed discovery of these mechanisms. Specific areas of applied immunology, such as immunity to infectious diseases, cancer, and current vaccination practices are the subject matter of later chapters. Finally, to complete the description of the immune system in all of its activities, a chapter addresses each of the major types of immune dysfunction.
■ Immunity is the state of protection against foreign organisms or substances (antigens). Vertebrates have two types of immunity, innate and adaptive.
■ Innate immunity is not specific to any one pathogen but rather constitutes a first line of defense, which includes anatomic, physiologic, endocytic and phagocytic, and inflammatory barriers.
■ Innate and adaptive immunity operate in cooperative and interdependent ways. The activation of innate immune responses produces signals that stimulate and direct subsequent adaptive immune responses.
■ Adaptive immune responses exhibit four immunologic attributes: specificity, diversity, memory, and self/nonself recognition.
■ The high degree of specificity in adaptive immunity arises from the activities of molecules (antibodies and T-cell receptors) that recognize and bind specific antigens.
■ Antibodies recognize and interact directly with antigen. T-cell receptors recognize only antigen that is combined with either class I or class II major histocompatibility complex (MHC) molecules.
■ The two major subpopulations of T lymphocytes are the CD4+ T helper (TH) cells and CD8+ T cytotoxic (TC) cells. TH cells secrete cytokines that regulate immune response upon recognizing antigen combined with class II MHC. TC cells recognize antigen combined with class I MHC and give rise to cytotoxic T cells (CTLs), which display cyto-toxic ability.
■ Exogenous (extracellular) antigens are internalized and degraded by antigen-presenting cells (macrophages, B
cells, and dendritic cells); the resulting antigenic peptides complexed with class II MHC molecules are then displayed on the cell surface.
■ Endogenous (intracellular) antigens (e.g., viral and tumor proteins produced in altered self-cells) are degraded in the cytoplasm and then displayed with class I MHC molecules on the cell surface.
■ The immune system produces both humoral and cell-mediated responses. The humoral response is best suited for elimination of exogenous antigens; the cell-mediated response, for elimination of endogenous antigens.
■ While an adaptive immune system is found only in vertebrates, innate immunity has been demonstrated in organisms as different as insects, earthworms, and higher plants.
■ Dysfunctions of the immune system include common maladies such as allergy or asthma. Loss of immune function leaves the host susceptible to infection; in autoimmu-nity, the immune system attacks host cells or tissues,
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If you suffer with asthma, you will no doubt be familiar with the uncomfortable sensations as your bronchial tubes begin to narrow and your muscles around them start to tighten. A sticky mucus known as phlegm begins to produce and increase within your bronchial tubes and you begin to wheeze, cough and struggle to breathe.