Human Defense Mechanisms

Additional context

This document outlines the fundamental layers of the human immune system, starting with innate defenses and progressing to adaptive immunity. It builds upon foundational immunological principles established by pioneers like Metchnikoff, who first described phagocytosis, and Landsteiner, who elucidated blood groups and the concept of antigen specificity. The discussion of surface barriers and the microbiome relates to current research in commensalism and its role in immune homeostasis, as explored by researchers studying the gut-brain axis and mucosal immunology. Furthermore, the detailed breakdown of the inflammatory response, including the complement, clotting, and kinin systems, directly expands on the work of immunologists such as Paul Ehrlich and Waldemar Haffkine, who laid the groundwork for understanding humoral immunity and antimicrobial therapies, respectively. This foundational knowledge is critical for developing new strategies against infectious diseases and autoimmune disorders.

Ch 7

Human Defense Mechanisms

1. Innate defenses are the first line of defense, are present at birth, and include the surface barriers skin and mucous membranes.

2. Inflammation is the second line of defense and is activated with injury or infectious disease.

3. Adaptive (acquired) immunity is the third line of defense, is specific to particular antigens, and has memory.

Innate Immunity

1. There are three layers of human defense: physiologic barriers, the inflammatory response, and adaptive (acquired) immunity.

2. Physical barriers are the first lines of defense functioning to prevent damage to the individual and thwart the entrance of pathogens. These barriers include the skin and mucous membranes.

3. Antibacterial peptides are found in mucous secretions, perspiration, saliva, tears, and other secretions. They provide a biochemical barrier against pathogenic microorganisms.

Definition

commensal or mutualistic microorganisms: Microorganisms that live in close association with another organism, often providing a benefit to the host or existing without harming it.

4. The skin, mucous membranes, and the lining of the gastrointestinal (G.I) tract are colonized by commensal or mutualistic microorganisms called the microbiome. These microorganisms provide protection by releasing biochemical compounds which facilitate immune responses and prevent colonization by pathogens. Within the gut, they also facilitate digestion in the G.I tract.

Definition

vascularized tissues: Tissues that contain blood vessels, which are essential for the transport of blood cells and plasma proteins involved in the inflammatory response.

5. The second line of defense is the inflammatory response, a rapid and nonspecific protective response to cellular injury resulting from any cause. It can occur only in vascularized tissues.

Definition

plasma protein systems: A group of inactive protein precursors circulating in the blood that can be sequentially activated to mediate inflammatory and immune responses.

6. Inflammation is mediated by three key plasma protein systems: the complement system, the clotting system, and the kinin system. The components of all three systems are a series of inactive proteins which are activated sequentially in the presence of tissue injury.

2 Definitions

Definition 1: antigen–antibody reactions: The specific binding between an antigen and its corresponding antibody, a key event in adaptive immunity that can initiate various immune responses.

Definition 2: bacterial polysaccharides: Complex carbohydrate molecules found in the cell walls of bacteria, which can trigger immune responses through specific activation pathways.

7. The complement system can be activated by antigen–antibody reactions (through the classical pathway) or by other products, especially bacterial polysaccharides (through the lectin pathway or the alternative pathway). The lectin and alternative pathways do not require antibody activation to recruit phagocytes, activate mast cells, and destroy pathogens.

3 Definitions

Definition 1: opsonin: A molecule that enhances the ability of phagocytes to engulf and eliminate microorganisms or foreign particles by coating them.

Definition 2: anaphylatoxin: A substance that can trigger a type of allergic reaction and inflammation by promoting mast cell degranulation and releasing histamine.

Definition 3: chemotactic factor: A substance that attracts specific types of cells, particularly immune cells like phagocytes, to a site of injury or infection through a process called chemotaxis.

8. The most biologically potent products of the complement system are C.3.b (opsonin), C.3.a (anaphylatoxin), and C.5.a (anaphylatoxin, chemotactic factor).

9. The clotting system stops bleeding, localizes microorganisms, and provides a meshwork for repair and healing.

10. Bradykinin is the most important product of the kinin system and causes vascular permeability, smooth muscle contraction, and pain.

11. Control of inflammation regulates inflammatory cells and enzymes and localizes the inflammatory response to the area of injury or infection.

12. Carboxypeptidase, histaminase, kinase, and C.1 inhibitor are inactivating enzymes. The fibrinolytic system and plasmin facilitate clot degradation after bleeding is stopped.

13. Mast cells and macrophages are the most important cells for initiating the inflammatory response.

4 Definitions

Definition 1: pattern recognition receptors (P.R.R's): Cell surface or intracellular receptors that recognize conserved molecular structures found on microorganisms (P.A.M.P's) or released from damaged host cells (D.A.M.P's), initiating innate immune responses.

Definition 2: pathogen-associated molecular patterns (P.A.M.P's): Specific molecular structures that are conserved among different types of pathogens but are not found in host cells, serving as signals for the innate immune system to detect infection.

Definition 3: damage-associated molecular patterns (D.A.M.P's): Molecules released from damaged or dying host cells that alert the immune system to tissue injury or stress, triggering inflammatory responses.

Definition 4: cytokines: Small proteins secreted by cells that act as signaling molecules to regulate cell growth, differentiation, and immune responses, mediating communication between cells.

14. These cells express plasma membrane pattern recognition receptors (P.R.R's) which recognize molecules produced by infectious microorganisms. These molecules include pathogen-associated molecular patterns (P.A.M.P's) and damage-associated molecular patterns (D.A.M.P's). Toll-like receptors (T.L.R's) are transmembrane receptors and nucleotide-binding-like receptors (N.L.R-like), and nucleotide oligomerization domain-like (N.O.D-like) receptors are cytoplasmic receptors. They are expressed by many inflammatory cells and recognize both P.A.M.P's and D.A.M.P's. Upon recognition, they promote the release of cytokines and inflammatory mediators, which, in turn, eliminate damaged cells and protect against invasion by microbes.

15. Mast cells are near epithelial surfaces and capillaries. Mast cells initiate inflammation by releasing biochemical mediators (histamine and chemotactic factors) from cytoplasmic granules. They also synthesize other mediators (prostaglandins, leukotrienes, and platelet-activating factor (P.A.F)) in response to stimuli. Basophils, found in blood, function in a manner that is similar to mast cells.

16. Histamine is the major vasoactive amine released from mast cells. It increases vascular permeability through dilation of capillaries and retraction of endothelial cells lining the capillaries.

17. Tissue macrophages use P.R.R's to identify microorganisms and molecules from damaged tissue, and then secrete many biochemical mediators (cytokines), which are responsible for activating other cells and regulating the inflammatory response. These cytokines include T.N.F- alpha , interleukin, interferon, and other molecules.

18. T.N.F alpha is produced when P.R.R binding sends intracellular messengers to the nucleus of the macrophage which activates N.F kappa B. T.N.F alpha has multiple pro-inflammatory effects including vascular effects, chemotaxis, cellular proliferation, and systemic inflammatory changes.

19. Interleukins are produced primarily by lymphocytes and macrophages. They activate the growth and differentiation of leukocytes and contribute to systemic inflammatory changes such as fever.

20. The most important proinflammatory interleukin are interleukin-1 (I.L-1) and interleukin-6.

21. Interferons are produced by cells that are infected by viruses. Once released from infected cells, interferons can stimulate neighboring healthy cells to produce substances that prevent viral infection.

22. There are also anti-inflammatory cytokines such as T.G.F- beta and I.L-10 which downregulate the inflammatory response.

23. The vascular responses to inflammation are vasodilation, increased capillary permeability, and accumulation of fluid and cells at the inflammatory site.

24. The cellular response to inflammation includes neutrophils, monocyte-derived macrophages, and other inflammatory cells.

25. The endothelial cells lining the circulatory system (vascular endothelium) regulate circulating components of the inflammatory system, maintaining normal blood flow. During inflammation, the endothelium expresses receptors that stimulate leukocytes to exit the vessel. The endothelial cell body also retracts to allow fluid to pass into the tissues.

26. The polymorphonuclear neutrophil (P.M.N), the predominant phagocytic cell in the early inflammation, exits the circulation, through retracted endothelial junctions, by diapedesis. On exiting, it moves to the inflammatory site by chemotaxis.

27. The monocyte-derived macrophage, the predominant cell in the late inflammatory response, is highly phagocytic. Additionally, it is responsive to cytokines, which promote wound healing.

28. Phagocytosis is a multistep cellular process, which usually results in the destruction of pathogens and foreign debris. The steps include recognition and attachment, engulfment, formation of a phagosome, formation of a phagolysosome, and eventual destruction of the pathogen or foreign debris. Phagocytic cells engulf microorganisms, enclosing them within phagocytic vacuoles (phagolysosomes). The vacuoles contain toxins (especially metabolites of oxygen) and/or enzymes that kill and digest the microorganisms.

29. Opsonins are molecules which enhance phagocytosis by coating the antigen. This activity results in a stronger attraction between the microorganism and the phagocyte ("marking" the organism). It also enhances the affinity with which the phagocyte binds to the microorganism. Examples include antibodies and the complement component C.3.b.

30. Eosinophils release products that control the inflammatory response, and they are the principal cells that destroy parasitic organisms.

31. Other cells of innate immunity include dendritic cells which function as messengers between the innate and acquired (adaptive) immune systems, N.K cells which detect certain invaders and cancer cells, and innate lymphoid cells which modulate many aspects of innate immunity.

Acute and Chronic Inflammation

1. Acute inflammation is self-limiting and usually resolves within 8 to 10 days.

2. Local manifestations of inflammation include the classic signs of redness, heat, swelling, pain, and loss of function. They are the result of vascular changes associated with the inflammatory process, including vasodilation and increased capillary permeability.

3. The principal systemic effects of inflammation are fever, leukocytosis (increased levels of circulating leukocytes), and an increase in plasma proteins, primarily the acute-phase reactants, I.L-1, and I.L-6.

4. Chronic inflammation is the persistence of the inflammatory response often contributing to tissue damage.

5. Chronic inflammation is characterized by a dense infiltration of lymphocytes and macrophages. It can take two forms, nonspecific proliferative chronic inflammation and granulomatous chronic inflammation.

6. Nonspecific proliferative chronic inflammation occurs when the acute inflammatory response fails to eliminate the invader/injury or there is dysfunctional resolution of the acute inflammatory response.

7. Granuloma formation is a process wherein the body walls off and isolates certain infectious microorganisms or foreign bodies that could not be removed by acute inflammation. It serves to protect the body from further tissue damage.

8. Both forms of chronic inflammation can contribute to tissue dysfunction and organ damage and are the major causes of chronic disease.

Wound Healing

1. Resolution (regeneration) is the return of tissue to nearly normal structure and function. Repair is healing by scar tissue formation.

2. Resolution occurs when little tissue has been lost or where the injured tissue is capable of regeneration. This type of healing is called healing by primary intention.

3. Tissues that have sustained extensive damage or tissue types that are incapable of regeneration heal by repair, a process which results in the formation of a scar. This process is called healing by secondary intention.

4. Wound healing occurs in four overlapping phases; hemostasis, inflammation, proliferation with new tissue formation, and remodeling or maturation. Each of these phases is characterized by the complex interaction of multiple cells including platelets, neutrophils, macrophages fibroblasts, endothelial cells, and epithelial cells.

5. Dysfunctional wound healing can be secondary to ischemia, excessive bleeding, excessive fibrin deposition, predisposing disorders (e.g., diabetes mellitus), wound infection, inadequate nutrients, use of N.S.A.I.D's and steroids, or altered collagen synthesis.

6. Dehiscence is a disruption where the wound pulls apart at the suture line.

7. A contracture is a structural deformity caused by the excessive shortening of collagen in scar tissue.

Pediatric and Geriatric Considerations

1. Neonates often have transiently depressed inflammatory function, particularly decreased phagocyte chemotaxis and killing of microorganisms and limited complement activity.

2. Aging impairs the immune system due to a process called immunosenescence which causes impairment of cellular function in both immunity and wound healing.

3. Impaired wound healing in the aging population is multifactorial and includes changes in innate immunity, cellular metabolism, and tissue integrity.

4. The elderly are also at risk for excessive and disordered innate immune responses called inflammaging that contribute to many chronic diseases.

Ch 8

Overview of Adaptive Immunity

1. Adaptive immunity is a state of protection, primarily against infectious agents, that differs from inflammation by being slower to develop, being more specific, and having memory that makes it much longer lived.

2. The adaptive immune response is most often initiated by cells of the innate system. These cells process and present portions of invading pathogens (i.e., antigens) to lymphocytes in peripheral lymphoid tissue.

3. The adaptive immune response is mediated by two types of lymphocytes—B lymphocytes and T lymphocytes. Each has distinct functions. B cells are responsible for humoral immunity that is mediated by circulating antibodies, whereas T cells are responsible for cell-mediated immunity, in which they kill targets directly or stimulate the activity of other leukocytes.

4. B and T lymphocytes leaving the primary lymphoid organs are immunocompetent but have not been exposed to antigen, thus are naïve.

5. Clonal selection with cellular proliferation and further differentiation of T and B cells into active effort cells of the adaptive immune system is initiated when exposure to an antigen occurs.

Antigens

1. Antigens are molecules that bind and react with components of the immune response, such as antibodies and receptors on B and T cells.

2. Common antigens include infectious agents, allergens, chemical agents, and abnormal molecules on the surface of cells.

3. Large molecules, such as proteins, polysaccharides, and nucleic acids, are most immunogenic. Thus, molecular size is a crucial factor for antigen immunogenicity.

4. Haptens are antigens too small to be immunogens by themselves but become immunogenic after combining with larger molecules.

5. The antigenic determinant, or epitope, is the precise chemical structure with which an antibody or B-cell/T-cell receptor (B.C.R/T.C.R) reacts.

6. Self-antigens are antigens on an individual's own cells. The individual's immune system does not usually recognize self-antigens as immunogenic, a condition known as tolerance.

Lymphocyte Development

1. The generation of clonal diversity results in the production of B and T lymphocytes with receptors against millions of antigens that possibly will be encountered in an individual's lifetime occurs in the fetus in the primary lymphoid organs: the thymus for T cells and portions of bone marrow for B cells.

2. The generation of clonal diversity is the differentiation of lymphoid stem cells into B and T lymphocytes with specific B.C.R's and T.C.R's, respectively.

3. The enormous repertoire of B.C.R specificities is made possible by rearranging existing deoxyribonucleic acid (D.N.A) during B-cell development in the primary lymphoid organs, a process called somatic recombination.

4. Somatic rearrangement of the antibody variable regions will frequently result in a B.C.R that recognizes the individual's own antigens, which may result in attack on “self” antigens expressed on various tissue and organs. Many of these “autoreactive” B cells are eliminated in the bone marrow. Most of the developing B cells undergo apoptosis. This entire process is referred to as clonal deletion or central tolerance.

5. Treg cells are a diverse group of T cells that control the immune response, usually suppressing the response and maintaining tolerance against self-antigens. Treg cells produce very high levels of immunosuppressive cytokines, which induce tolerance.

6. The process of T-cell proliferation and differentiation is similar to that for B cells. The primary lymphoid organ for T-cell development is the thymus. Lymphoid stem cells travel through the thymus, where they gain a T.C.R, and receptors become immunocompetent. Self-reactive T cells undergo clonal deletion.

7. Proteins called C.D.4 and C.D.8 are expressed on the developing T cells. As the cell matures, it retains either the C.D.4 molecule or the C.D.8 molecule but not both. Eventually, C.D.4 cells develop into T-helper cells (Th cells), and C.D.8 cells become T-cytotoxic cells (Tc cells). Other mature T cells include T-regulatory cells (Treg cells) and memory cells.

8. The generation of clonal diversity concludes when immunocompetent T and B cells migrate from the primary lymphoid organs into the circulation and secondary lymphoid organs to await antigen.

Induction of the Adaptive Immune Response

1. The induction of an immune response, or clonal selection, begins when antigen enters the individual's body and interacts with antigen-presenting cells (A.P.C's) (e.g., dendritic cells, macrophages, and B cells).

2. To induce an optimal cellular or humoral immune response, A.P.C's must present antigens to Th cells. Antigen is processed in the A.P.C's and presented on the cell surface by molecules of the major histocompatibility complex (M.H.C). The particular M.H.C molecule (class I or class 2) that presents antigen determines which cell will respond to that antigen. Th cells require that the antigen be presented in a complex with M.H.C class 2 molecules. M.H.C class 2 molecules are found only on A.P.C's. Tc cells require that the antigen be presented by M.H.C class I molecules.

3. The T cell binds to the presented antigen through the T.C.R and accessory molecules: C.D.4 or C.D.8. C.D.4 is found on Th cells and reacts specifically with M.H.C class 2. C.D.8 is found on Tc cells and reacts specifically with M.H.C class I.

4. Further differentiation of these T.h.0 cells results in the formation of T.h.1 cells, which help Tc cells respond to antigen; T.h.2 cells, which help B cells develop into plasma cells; and T.h.17 cells, which help activate macrophages.

Humoral Immunity (Antibodies)

1. The humoral immune response consists of molecules (antibodies) produced by B cells. B cells are lymphocytes. B cells can detect antigen with their B.C.R molecules and differentiate into A.P.C's that interact closely with Th cells.

2. Th cell activation by B cells results in the production of I.L-4, which, along with costimulatory molecules C.D.40 and C.D.40.L, activate the B cell to become an antibody-producing plasma cell.

3. B cells can also be activated to become antibody-producing plasma cells through a T-cell independent process.

4. A typical antibody molecule is constructed of two identical heavy chains and two identical light chains (either kappa or lambda ) and has two Fab portions that bind antigen and an Fc portion that interacts with complement or receptors on cells.

5. Antibodies are plasma glycoproteins that can be classified by chemical structure and biologic activity as immunoglobulin G (IgG), IgM, IgA, IgE, or IgD.

6. The protective effects of antibodies may be direct through the action of antibody alone or indirect, requiring activation of other components of the innate immune response.

7. IgE is a special class of antibody produced against environmental antigens that are the primary cause of common allergies. It also protects the individual from infection by large parasitic worms (helminths).

8. The secretory immune system protects the external surfaces of the body through the secretion of antibodies in bodily secretions, such as tears, sweat, saliva, mucus, and breast milk. IgA is the dominant secretory immunoglobulin.

Cell-Mediated Immunity

1. The cells of cell-mediated immunity include Tc cells, N.K cells, and macrophages. These cells kill damaged, cancerous, or infected cells.

2. Tc cells bind with antigen presented on the M.H.C I molecule on an A.P.C. This, along with I.L-2 from Th cells, activates the Tc cell.

3. Tc cell attachment to a target cell activates multiple killing mechanisms through which the target cell is induced to undergo apoptosis.

4. Natural killer (N.K) cells are a special group of lymphoid cells that express various cell surface activation receptors that identify protein changes on the surface of cells infected with viruses or that have become cancerous. After attachment, the N.K cell kills its target like that of Tc cells.

5. Macrophages are activated by interferon gamma (I.F.N gamma). From T.h.1 cells. Activated M.1 macrophages secrete proinflammatory cytokines and kill infected cells within their phagolysosomes.

Immunologic Memory

1. When T and B cells are activated, they make long-lived copies of themselves called memory cells.

2. Upon re-exposure, these memory cells will rapidly become new plasma cells or effector T cells

Pediatric Considerations: Age-Related Factors Affecting Mechanisms of Self-Defense in the Newborn Child

1. Neonates often have a transiently depressed inflammatory function, particularly neutrophil chemotaxis and alternative complement pathway activity.

2. The T cell-independent immune response is adequate in the fetus and neonate, but the T cell-dependent immune response develops slowly during the first 6 months of life.

3. Maternal IgG antibodies are transported across the placenta into the fetal blood and protect the neonate for the first 6 months, after which they are replaced by the child's own antibodies.

Geriatric Considerations: Age-Related Factors Affecting Mechanisms of Self-Defense in the Elderly

1. Elderly persons are at risk for impaired wound healing, usually because of chronic illnesses.

2. T-cell function declines, and the relative kind of T cells produced is altered in elderly persons.

3. Elderly individuals also develop impaired humoral immunity and are at risk for increased levels of circulating autoantibodies (antibodies against self-antigens)

C.H 9

Hypersensitivity: Allergy, Autoimmunity, and Alloimmunity

1. Inappropriate immune responses are exaggerated misdirected responses innocuous environmental antigens (allergy), the host's own tissues (autoimmunity), or beneficial foreign tissues (alloimmunity); or insufficient responses to protect the host (immune deficiency).

2. Allergy, autoimmunity, and alloimmunity are collectively known as hypersensitivity reactions.

3. Mechanisms of hypersensitivity are classified as type I (IgE-mediated) reactions, type 2 (tissue-specific) reactions, type 3 (immune complex-mediated) reactions, and type 4 (cell-mediated) reactions.

4. Hypersensitivity reactions can be immediate (developing within minutes to a few hours) or delayed (developing within several hours or days).

5. Allergens are antigens that cause allergic responses.

6. Type 1 (IgE-mediated) hypersensitivity reactions are mediated through the binding of IgE to Fc receptors on mast cells and cross-linking of IgE by antigens that bind to the Fab portions of IgE. Cross-linking causes mast cell degranulation and the release of histamine (the most potent mediator) and other inflammatory substances.

7. Histamine, acting through the H.1 receptor, contracts bronchial smooth muscles, causing bronchial constriction; increases vascular permeability, causing edema; and increases blood flow into the affected area, causing vasodilation. Histamine with H.2 receptors results in increased gastric acid secretion and a decrease of histamine released from mast cells and basophils.

8. Type 2 (tissue-specific) hypersensitivity reactions are caused by five possible mechanisms: complement-mediated lysis, opsonization and phagocytosis, neutrophil-mediated tissue damage, antibody-dependent cell-mediated cytotoxicity, and modulation of cellular function.

9. Type 3 (immune complex–mediated) hypersensitivity reactions are caused by the formation of immune complexes that are deposited in target tissues, where they activate the complement cascade, generating chemotactic fragments that attract neutrophils into the inflammatory site. Neutrophils release lysosomal enzymes that result in tissue damage.

10. Immune complex disease can be a systemic reaction, such as serum sickness, or a localized response, such as the Arthus reaction.

11. Type 4 (cell-mediated) hypersensitivity reactions are caused by cytotoxic T lymphocytes (Tc cells), lymphokine-producing T.h.1 cells and activated macrophages.

12. Typical allergens include pollen, molds and fungi, certain foods (milk, eggs, fish, peanuts), animals, certain drugs, cigarette smoke, and house dust.

13. Clinical manifestations of allergic reactions usually are confined to the areas of initial intake or contact with the allergen. Ingested allergens induce gastrointestinal symptoms, airborne allergens induce respiratory tract or skin manifestations, and contact allergens induce allergic responses at the site of contact.

14. Autoimmune diseases originate from the coincidence of an initiating event in a genetically predisposed individual leading to an autoimmune mechanism that affects specific target tissues or cells. Central tolerance develops during the embryonic period. Peripheral tolerance is maintained in secondary lymphoid organs by regulatory T lymphocytes or antigen-presenting dendritic cells.

15. Heparin-induced thrombocytopenia is a condition in which heparin molecules attach to proteins in the surface of platelets resulting in the formation of autoantibodies that destroy platelets (bleeding) and promote clotting (thrombosis).

16. Systemic lupus erythematosus (S.L.E) is a chronic, multisystem, inflammatory disease and is one of the most serious of the autoimmune disorders. S.L.E is characterized by the production of a large variety of autoantibodies.

17. Alloimmunity is the immune system's reaction against antigens on the tissues of other members of the same species.

18. Alloimmune disorders include tran-zee-unt neonatal disease, in which the maternal immune system becomes sensitized against antigens expressed by the fetus; transplant rejection; and transfusion reactions, in which the immune system of the recipient of an organ transplant or blood transfusion reacts against foreign antigens on the donor's cells.

19. Red blood cell antigens may be the targets of autoimmune or alloimmune reactions. The most important of these, because they provoke the strongest humoral immune response, are the A.B.O and Rh systems.

20. Antigens on fetal red blood cells (Rh) can cause maternal antibodies to cross the placenta and cause severe anemia in the fetus.

21. Hyperacute graft rejection (preexisting antibody) is immediate and rare, acute rejection is both antibody and cell mediated and occurs days to months after transplantation, and chronic rejection is caused by inflammatory damage to endothelial cells as a result of a weak cell-mediated reaction.

Deficiencies in Immunity

1. Disorders resulting from immune deficiency are the clinical sequelae of impaired function of components of the immune or inflammatory response, phagocytes, or complement.

2. Immune deficiency is the failure of mechanisms of self-defense to function in their normal capacity.

3. Immune deficiencies are either congenital (primary) or acquired (secondary). Primary immune deficiencies are caused by genetic defects that disrupt lymphocyte development, whereas secondary immune deficiencies are secondary to disease or other physiologic alterations.

4. The clinical hallmark of immune deficiency is a propensity to unusual or recurrent severe infections. The type of infection usually reflects the immune system defect.

5. The most common infections in individuals with defects of the cell-mediated immune response are fungal and viral, whereas infections in individuals with defects of the humoral immune response or complement function are primarily bacterial.

6. Severe combined immunodeficiency is a total lack of T-cell function and a severe (either partial or total) lack of B-cell function. Other combined defects may result from deficiencies in antigen-presenting molecules (bare lymphocyte syndrome) or cytoskeletal proteins (W.A.S).

7. Chromosome 22q11.2 deletion syndrome (DiGeorge syndrome) is characterized by complete or partial lack of the thymus (resulting in depressed T-cell immunity) and the parathyroid glands (resulting in hypocalcemia) and the presence of cardiac anomalies.

8. Defects in B-cell function are diverse, ranging from a complete lack of the human bursal equivalent function, the lymphoid organs required for B-cell maturation (as in Bruton agammaglobulinemia), to deficiencies in a single class of immunoglobulins (e.g., selective IgA deficiency).

9. Defects in phagocyte function, which include insufficient numbers of phagocytes or defects of chemotaxis, phagocytosis, or killing, can result in recurrent life-threatening infections such as septicemia and disseminated pyogenic lesions.

10. Immune dysregulation disorders are characterized by abnormally high levels of inflammation secondary to mutations in control of inflammasome activation or in defects in cellular receptors of cytokines designed to decrease inflammation. These disorders are frequently related to diminished control of infections of epithelial surfaces.

11. Almost any portion of the complement cascade may be defective. The most severe defect is C.3 deficiency, which results in recurrent life-threatening bacterial infections. Defects in proteins of the membrane attack complex usually result in unusual, disseminated infections with bacteria of the Neisseria spp.

12. Bone marrow failure and somatic mutations in immune genes may also result in severe primary immunodeficiency states.

13. Primary immune deficiencies may sometimes be treated by replacement therapy. Deficient antibody production is treated by replacement of missing immunoglobulins with commercial gamma-globulin preparations. Lymphocyte deficiencies are treated with the replacement of host lymphocytes with bone marrow and stem cell transplants and gene therapies when available.

14. Acquired immunodeficiencies are caused by superimposed conditions, such as aging, malnutrition, infections, malignancies, physical or psychological trauma, environmental factors, some medical treatments, or other diseases chronic disease, or infections.

Ch 10

Microorganisms and Humans: A Dynamic Relationship

1. Infectious disease is a significant cause of morbidity and mortality in the United States and worldwide.

2. Pathogens have unique characteristics that influence their ability to overcome body defense mechanisms and cause disease.

3. The process of infection includes encounter and transmission, colonization, invasion, dissemination, and cellular or tissue damage by the pathogenic microorganisms.

4. There are four distinct stages of infection: incubation period, prodromal stage, invasion or acute illness stage, and convalescence.

Infectious Disease

1. Bacteria have virulence factors that promote their ability to cause infection and cell injury, including pili, flagella, capsules, enzymes, competition for iron, and toxins.

2. Bacteria produce exotoxins or endotoxins. Exotoxins are enzymes that can damage the plasma membranes of host cells or can inactivate enzymes critical to protein synthesis, and endotoxins activate the inflammatory response and produce fever.

3. Septicemia results from the proliferation of bacteria in blood. Toxins released by bloodborne bacteria cause the release of vasoactive enzymes that increase the permeability of blood vessels. Leakage from vessels causes hypotension that can result in septic shock.

4. Viruses are intracellular parasites. They enter host cells and use their metabolic processes to proliferate and cause disease.

5. Viral replication includes seven steps: recognition and attachment, penetration, uncoating, replication, translation, assembly, and release.

6. Viruses that have invaded host cells may decrease protein synthesis; disrupt lysosomal membranes; form inclusion bodies, where synthesis of viral nucleic acids is occurring; fuse with host cells to produce giant cells; alter antigenic properties of the host cell; transform host cells into cancerous cells; and promote bacterial infection.

7. Viruses can elude the immune system by making small changes to the genes that produce viral surface antigens, a process known as antigenic variation.

8. S.A.R.S-C.O.V-2 is a novel coronavirus that emerged in fall 2019 causing a severe respiratory illness pandemic in 2020. New and emerging viral infections pose global threats.

9. H.I.V is a blood-borne pathogen present in body fluids with typical routes of transmission: blood or blood products, intravenous drug abuse, heterosexual and homosexual activity, and maternal-child transmission before or during birth.

10. The primary surface receptor on H.I.V is the envelope glycoprotein gp120, which binds to the C.D.4 molecule found mostly on the surface of T-helper cells. Viral binding with chemokine coreceptors C.X.C.R.4 on T helper cells and C.C.R.5 on macrophages and dendritic cells is essential for viral fusion to the target cell membrane.

11. H.I.V is a member of the retrovirus family, which carries genetic information in the form of R.N.A. An enzyme, reverse transcriptase (R.T), converts R.N.A into a double-stranded D.N.A. Another enzyme, an integrase, inserts the new D.N.A into the infected cell's genetic material. On activation, translation of the viral information may be initiated, forming new virions, resulting in lysis and death of the infected cell, and shedding infectious H.I.V particles.

12. H.I.V infects macrophages, dendritic cells, and circulating Th cells. It also infects T helper cells in the gut. T helper memory cells serve as reservoirs for H.I.V infection that persist for life, even in those who are treated with antiretroviral drugs.

13. The major immunologic finding in AIDS is a decrease in the number of C.D.4+ Th cells resulting in decreasing immune competence.

14. AIDS is characterized by immunocompromise and the development of opportunistic infections and cancers.

15. The COVID-19 pandemic is caused by infection with S.A.R.S-C.O.V-2 which has caused serious illness and death for millions of people worldwide.

16. S.A.R.S-C.O.V-2 is spread primarily by respiratory droplets produced when infected individuals cough, sneeze, or talk.

17. S.A.R.S-C.O.V-2 attaches to respiratory epithelial cells via its spike protein. Upon entering the cell, it sets of an immunologic response that can escalate to a cytokine storm which may cause severe lung disease and death.

18. Diseases caused by fungi are called mycoses, and fungi occur in two forms: yeasts (spheres) and molds (filaments or hyphae).

19. Dermatophytes are fungi that infect skin, hair, and nails with diseases, such as ringworm and athlete's foot.

20. Candida albicans is the most common cause of fungal infections in humans. Other important fungal pathogens include Aspergillus fumigatus and Pneumocystis jiroveci.

21. Parasitic microorganisms range from unicellular protozoa to large worms. Although less common in the United States, parasites and protozoa are common causes of infection worldwide.

22. Parasitic and protozoal infections are rarely transmitted from human to human. Infection mainly spreads through vectors (e.g., through mosquito bites) or through contaminated water.

23. Plasmodium falciparum is the most common cause of malaria.

24. Toxoplasma gondii and Trichomonas vaginalis are the two most common parasitic infections in the United States.

Antibiotic/Antimicrobial Resistance

Pathogens can use various mechanisms to resist the effects of antibiotics, including transmission of resistance genes to new generations of bacteria, enzyme degradation of the antibiotic, ejection of the antibiotic from the pathogen, modification of the cell wall to prevent binding or uptake of the antibiotic, or modification of the target of the antibiotic.

Vaccines and Protection Against Infection

1. Vaccines are biologic preparations of antigens that, when administered, stimulate production of protective antibodies or cellular immunity against a specific pathogen.

2. Passive immunotherapy is the administration of preformed antibodies for protection against a specific pathogen, such as hepatitis A and B or rabies.

Ch 11

Background and General Concepts of Stress

1. Stress is broadly defined as a perceived or anticipated threat that activates stress-related systems in the body and the brain (the stress response).

2. The term fight-or-flight response was coined by Walter Cannon to describe how the brain's perception of threat and rapid physiologic responses prepares the body to deal with threat.

3. Cannon's view was further developed by Hans Selye in 1946 by demonstrating that internal or external stressors could result in adrenal gland enlargement, immune alterations (increased leukocytes), and gastrointestinal manifestations (ulcers). These global physiologic responses, characterized by Selye, were labeled general adaptation syndrome (G.A.S).

4. G.A.S occurs in three stages: the alarm stage; the stage of resistance or adaptation; and the stage of exhaustion. The latter stage is now referred to as allostatic overload. Diseases of adaptation develop if the stage of resistance or adaptation does not restore homeostasis. Although important, this approach is now thought to be greatly oversimplified.

5. Stress research continued into the mid-1950s to show that psychological stressors are as effective as physical stressors in activating adrenal gland hormone secretion.

Psychological stressors can be anticipatory and triggered by expectations of an upcoming negative event or can be reactive to a stressor. Both of these psychological stressors are capable of eliciting a physiologic stress response.

6. The emerging link between stress and disease became the basis for the concept of allostasis (stability through change; monitoring the environment for adaptive response). This allostasis concept differs from a “fixed homeostasis model” (i.e., stress-induced heightened physiologic responses eventually returning to a narrow step point range) by involving a dynamic adaptation of the brain to constantly adjust its physiologic operating range to meet future anticipated demands. In other words, returning stress-induced hormone levels to prestress levels may not be the most adaptive strategy to cope with impending stressful encounters.

7. Chronic activation of regulatory stress systems has the potential to tax the body and the brain and lead to the emergence of diseases and disorders. In allostatic overload, chronic overactivation of adaptive regulatory physiologic systems may lead to pathophysiology and onset of disease.

The Stress Systems

1. The perception or anticipation of threat activates three major physiologic stress systems: the hypothalamic–pituitary–adrenal (H.P.A) axis, (2) the sympathetic nervous system (S.N.S), and the immune system (I.S). Acute stress-induced activation of these stress systems modulates a broad range of mediators in the body and the brain to protect and meet the physiologic and behavioral demands of the stressor to facilitate recovery.

2. Key physiologic changes involved in allostatic overload include exaggerated or chronic secretion of adrenal cortisol, catecholamines from the sympathetic nervous system, and proinflammatory cytokines that may initiate gene expression changes with widespread effects on the body, and neurobiologic structures and processes.

3. Becoming “stressed out” by allostatic overload may lead to sleep deprivation, heightened insulin and blood glucose levels, increased blood pressure, and reduced parasympathetic activity. These physiologic consequences are often linked to insomnia, depression, chronic pain and fatigue syndromes, obesity, metabolic syndrome, essential hypertension, type 2 diabetes, atherosclerosis and its cardiovascular consequences, osteoporosis, and autoimmune inflammatory and allergic disorders.

4. Activation of the H.P.A system involves sequential secretion of corticotropin-releasing hormone from the hypothalamus, which stimulates receptors in the anterior pituitary to secrete adrenocorticotropic hormone (A.C.T.H), which, in turn, stimulates the adrenal cortex to secrete the glucocorticoid cortisol.

5. Cortisol secretion induced by acute stress binds to glucocorticoid receptors to activate diverse biologic actions throughout the body and the brain. The many adaptive functions include, but are not limited to, arousal, cognition, mood, metabolism, maintenance of cardiovascular tone, and effects on the immune system.

6. Cortisol's main effects involve metabolic processing by mobilizes glucose, amino acids, lipids, and fatty acids and delivers them to the bloodstream. As an example, anabolic effects of cortisol increase the rate of protein synthesis in the liver, whereas the catabolic effects of cortisol increase levels of amino acids, ultimately depleting protein stores in muscle, bone, skin, and connective tissue.

7. Chronic dysregulation of the H.P.A axis, especially abnormal elevated secretion of cortisol, is linked to a wide variety of disorders, including obesity, metabolic syndrome, sleep deprivation, lipid abnormalities, coronary heart disease, diabetes, atherosclerosis, and loss of bone density. In the brain, chronic glucocorticoid secretion may lead to cognitive impairments and emotional disorders, such as depression. For example, depression is accompanied by shrinkage of the hippocampus and the prefrontal cortex.

8. Activation of the autonomic nervous system (A.N.S) consists of sympathetic stimulation of the adrenal medulla and nerve endings to rapidly secrete catecholamines (norepinephrine, epinephrine).

9. Epinephrine exerts its chief effects on the cardiovascular system by increasing cardiac output and blood flow to the heart, brain, and skeletal muscles by dilating vessels that supply these organs. It also dilates the airways, thereby increasing delivery of oxygen to the bloodstream. Norepinephrine and epinephrine contribute to arteriolar vasoconstriction to other parts of the body raising blood pressure.

10. The parasympathetic nervous system balances or restrains the sympathetic system, resulting in slowed heart rates and antiinflammatory effects. During prolonged stress (allostatic overload), the parasympathetic system becomes less effective in opposing the sympathetic system.

11. Acute stress-induced secretion of H.P.A hormones and catecholamines (C.A's) directly influences the immune system, which plays an adaptive role as a signal organ to alert other systems from internally threatening stimuli (e.g., infection, tissue damage, tumor cells). The release of immune inflammatory mediators (e.g., interleukin-6 (I.L-6), tumor necrosis factor- beta [T.N.F- beta ], interferon (I.F.N)) [T.N.F- beta ], interferon (I.F.N)) serves to protect the body from bacterial or viral infections, cancer, tissue injury, and other stressors.

12. Chronic stress induced by prolonged, intrusive, and/or negative thoughts may lead to pathophysiology of the immune system. Persistent secretion of proinflammatory cytokines and inflammation is linked to cardiovascular disease, osteoporosis, arthritis, type 2 diabetes mellitus, chronic obstructive pulmonary disease (C.O.P.D), and other diseases associated with aging.

13. Clear examples of the adverse effects of chronic psychosocial stress are burnout, a syndrome associated with a number of negative impacts on workers' well-being and health, as well as loneliness and social isolation. Mechanisms contributing to the effects of psychosocial stress include dysregulation of the H.P.A axis and the A.N.S which are accompanied by impaired immune function and inflammation.

Chronic Stress at an Early Age Increases the Risk of Developing Long-Lasting Pathophysiologic Alterations Linked to Poor Health and to Disease

1. Children exposed to prenatal or postnatal stressors increase the risk of developing long-lasting pathophysiologic alterations linked to poor health and to disease.

2. High levels of stress-induced maternal cortisol secretion could cross the placental barrier and enter the fetus to cause low birth weight and increase the risk of disease in later life, including obesity, cardiovascular conditions (e.g., hypertension), and behavioral disorders (e.g., depression and attention-deficit/hyperactivity disorder).

3. Early exposure to psychosocial stressors (e.g., parental, sexual, or emotional abuse, low socioeconomic status (S.E.S) or poverty) are linked to the development of dysregulated H.P.A and A.N.S leading to a chronic proinflammatory state that increases the risk of disease.

4. Early life stressors may impair brain systems that govern executive functions involved in attention, self-awareness, impulse control behavior that regulate emotions, and adaptive coping behavior.

Negative Effects of Stress on Telomere Length, Aging, and Disease

1. Telomeres are deoxyribonucleic acid (D.N.A)−based caps located at the end of chromosomes to protect genetic information and degradation during cell division.

2. Telomere shortening or attrition is linked to biologic aging and can be accelerated by a number of conditions associated with inflammation and oxidative stress. Shorter telomere length found in white blood cells reflects an increased risk of aging-related morbidity and mortality and is associated with a range of conditions in people with obesity, smoking, type 2 diabetes, and low S.E.S.

3. Stress has a major role on telomere shortening that can begin in yoo-tuh-roh by increasing early telomere damage, inflammation, and greater rate of leukocyte division.

4. Studies showed that childhood psychosocial stress predicts telomere erosion and increased risk of developing depression and metabolic disorders.

Coping and Intervention Strategies

1. Coping styles affect the ability of a person to handle stress. Personality characteristics, such as academic achievement, motivation, and optimism, increase the likelihood of successfully dealing with stress. In addition, people who engage in coping strategies that receive social support develop greater stress resilience and improved psychological and physiologic outcomes.

2. Maladaptive coping responses to stress, such as increased smoking, decreased exercise and sleep, and poor diets, are likely to alter adaptive immune functions and increase susceptibility to disease.

3. Engagement in exercise as a means of coping with stress has beneficial effects at all ages. Exercise has the potential to rebalance neurotransmitter effects that were altered by stress. Exercise also may improve the neuroimmune status (i.e., inflammation) by inhibiting the secretion of proinflammatory cytokines. Exercise increases brain metabolism that improves cognitive functions that could be compromised by chronic exposure to stress.

4. Another major benefit of exercise is to reduce obesity, a major contributor of the pathophysiology of diabetes, heart disease, metabolic disorders, liver disease, cancer, inflammatory disorders, mental illnesses, and premature death. Coping with stress and obesity by exercising reduces adipose tissue, attenuates serum proinflammatory cytokine levels, and creates an antiinflammatory environment.

5. Mindfulness therapy is increasingly used to reduce the chronic impact of allostatic load on health. This therapy involves monitoring current experiences with acceptance and is effective in coping with various medical conditions, including chronic pain, depression, and attenuating the negative perception of stress.

6. Mindfulness appears to improve health by modulating the stress-induced secretion of cortisol by the H.P.A and by dampening brain regions activated by stress that facilitate a range of stress reactions.

7. In children and adolescents experiencing chronic stress, mindfulness training can result in improvement in sleep, self-esteem, well-being, and reduction in depression and anxiety. Mindfulness teaches valuable coping skills that potentially reduce the likelihood of at-risk children developing chronic diseases in adulthood.

You have reached the end of the document.