Micro Exam 3

C2: phagocytosis

chemotaxis adherence ingestion phagolysosome formation digestion elimination(exocytosis)+ antigen presentation on MHC

the mechanism of phagocytosis

chemotaxis, adherence, ingestion, and digestion

defensive cells of innate immunity

macrophages and dendritic cells provide a link between innate immunity and adaptive immunity When the TLRs on these cells encounter the PAMPs of microbes, such as the LPS of gram-negative bacteria, the TLRs induce the defensive cells to release chemicals called cytokines.

Pattern-recognition receptors

receptors of sentinel cells that can detect PAMPs and trigger a response against pathogen: -phagocytosis -releasing cytokins to alert -recruit immune cells, and trigger inflammation

interleukins

serve as communicators primarily between leukocytes. ILs often target immune cells to stimulate cell proliferation, maturation, migration, or activation during an immune response. This type of cytokine may sometimes be useful as a drug treatment designed to stimulate the immune system and treat certain infectious diseases or cancers.

thymus

serves as a site for T cell maturation. It also contains dendritic cells and macrophages.

second line defense

slow/destroy invader

alternative pathway

so named because it was discovered after the classical pathway. Unlike the classical pathway, it does not involve antibodies. The alternative pathway is activated by contact between certain complement proteins and a pathogen

Adaptive immunity

specific response to a specific microbe once a microbe has breached the innate immunity defense adjust to handle a particular microbe slower to respond has memory-allowing the body to more effectively target the same pathogens in the future involves lymphocytes-called T cells and B cells

basophiles

stain blue-purple with the basic dye methylene blue. Basophils release substances, such as histamine, that are important in inflammation and allergic responses.

eosinophils

stain red or orange with the acidic dye eosin. Eosinophils are somewhat phagocytic and also have the ability to leave the blood. Their major function is to kill certain parasites, such as helminths. Although eosinophils are physically too small to ingest and destroy helminths, they can attach to the outer surface of the parasites and discharge peroxide ions that destroy them (see Figure 17.16). Their number increases significantly during certain parasitic worm infections and hypersensitivity (allergy) reactions.

cytokine storm

stimulate cells to produce yet more cytokines. This feedback loop occasionally gets out of control, overabundance of cytokines can do significant damage to tissues, which appears to be a factor in the pathology of certain diseases such as influenza, Ebola virus disease, graft- versus-host disease, and sepsis **COVID**.

chronic inflammation

the signs and symptoms develop more slowly and can last for up to several months or years. It is often severe and progressive, and the principal defensive cells are monocytes and macrophages. Examples of chronic inflammation are mononucleosis, peptic ulcers, tuberculosis, rheumatoid arthritis, and ulcerative colitis.

acute inflammation

the signs and symptoms develop rapidly and usually last for a few days or even a few weeks. It is usually mild and self-limiting, and the principal defensive cells are neutrophils. Examples of acute inflammation are a sore throat, appendicitis, cold or flu, bacterial preumonia, and a scratch on the skin.

adaptive immunity

which involves a range of microbial defenses that target specific pathogens after exposure. A crucial element of the adaptive immune system is its ability to differentiate between normal "self" cells and "nonself." Without this ability, the immune system might attack components of the body it is designed to protect. In fact, this is exactly what occurs with certain immune disorders, when the body's own tissues are erroneously targeted and damaged by immune cells. the adaptive system tailors its fight to specific pathogens, toxins, or other substances. The first time the adaptive immune system meets and combats a particular antigen is called the primary response, which involves a lag or latent period of 4 to 14 days. Later interactions with that same cell or substance will cause a secondary response, which is faster and more effective as a result of the "memory" formed during the primary response. This memory component is also exclusive to the adaptive immune system.

dual system

with humoral and cellular components that also contribute to the innate immune system. Cells of the adaptive immune system originate from pluripotent stem cells in the bone marrow or the fetal liver Although cells of humoral and cellular immunity mature differently, the cells of the adaptive immune system are all found primarily in blood and lymphoid organs.

interferons

Because viruses hijack host cells to carry out viral multiplication, it is difficult for the immune system to inhibit viral infections without affecting body cells too. One way an infected host cell counters viral infections is with a family of cytokines called interferons (IFNs). These are a class of proteins produced by certain animal cells, such as lymphocytes and macrophages. Just as different animal species produce different interferons, different types of cells within the same animal also produce different interferons. Interferons produced by people protect human cells, but they produce little antiviral activity for cells of other species, such as mice or chickens. However, the interferons of a species are active against a number of different viruses. They typically play a major role in infections that are acute, such as colds and influenza. There are three main types of human interferons: alpha interferon (IFN-α), beta interferon (IFN-β), and gamma interferon (IFN-γ). There are also various subtypes of interferons within each of the principal groups. In humans, interferons are produced by fibroblasts in connective tissue and by lymphocytes and other leukocytes. All interferons are small proteins, with molecular masses between 15,000 and 30,000. They are quite stable at low pH and are fairly resistant to heat. Both IFN-α and IFN-β are produced by virus-infected host cells only in very small quantities that diffuse to uninfected neighboring cells (Figure 16.14). Both types are host-cell-specific but not virus-specific. They react with plasma or nuclear membrane receptors, inducing the uninfected neighboring cells to manufacture mRNA for the synthesis of antiviral proteins (AVPs). These proteins are enzymes that disrupt various stages of viral multiplication. For example, one AVP, called oligoadenylate synthetase, degrades viral mRNA. Another, called protein kinase, inhibits protein synthesis. Both IFN-α and IFN-β stimulate NK cells, which produce IFN-γ. Gamma interferon is produced by lymphocytes and induces neutrophils and macrophages to kill bacteria. IFN-γ causes macrophages to produce nitric oxide that appears to kill bacteria as well as tumor cells by inhibiting ATP production. IFN-γ increases the expression of MHC molecules and antigen presentation. Interferons would seem to be ideal antiviral substances, but certain problems do exist. They are stable for short periods of time in the body, so their effect is limited. When injected, interferons have side effects such as nausea, fatigue, headache, vomiting, weight loss, and fever. High concentrations of interferons are toxic to the heart, liver, kidneys, and red bone marrow. Another problem is that interferons have no effect on viral multiplication in cells already infected, and some viruses (such as adenoviruses) have resistance mechanisms that inhibit antiviral proteins. The importance of interferons in protecting the body against viruses, as well as their potential as anticancer agents, has made their production in large quantities a top health priority. Several groups of scientists have successfully applied recombinant DNA technology in inducing certain species of bacteria to produce interferons. (This technique is described in Chapter 9.) The interferons produced with recombinant DNA techniques, called recombinant interferons (rIFNs), are important for two reasons: they are pure, and they are plentiful. In clinical trials, IFNs have exhibited no effects against some types of tumors and only limited effects against others. Alpha interferon (Intron® A) is approved in the United States for treating several virus-associated disorders. One is Kaposi's sarcoma, a cancer that often occurs in patients infected with HIV. Other approved uses for IFN-α include treating hepatitis B and C, malignant melanoma, and hairy cell leukemia. A form of IFN-β (Betaseron®) slows the progression of multiple sclerosis (MS) and lessens the frequency and severity of MS attacks. Another form of IFN-β (Actimmune®) is being used to treat osteoporosis.

4 major categories of cytokines

-chemokines: chemotaxis of leukocytes -interferons(IFNs):cytokines produced in response to viruses. they alert the neighboring host cells, stimulate NK cells, macrophages -colony stimulating factors: induce hematopoiesis -interleukins: activates immune cells proliferation, maturation, activation, and migration during immune response.

normal microbiota/flora(biological barrier)

-normal flora: microorganisms colonizing body surfaces in healthy humans, preventing the overgrowth of harmful microbes by: **competitive exclusion: -cover binding/attachment sites and consume available nutrients -especially effective against salmonella, shigella **production of toxic compounds: -fermentation products inhibit intestinal pathogens( esp. salmonella) -lactobacillus produce lactic acid in vagina(low pH) and hydrogen peroxide(effects against chlamydia, candida albicans) ***disruption of flora can predispose to infections - oral candidiasis or thrush, vulvovaginal candidiasis or yeast infection, caused by candida albicans

3 major types of PRRs

-toll-like receptors:membrane-bound and monitor cell's surrounding -RIG-like receptors & NOD-like receptors: soluble and monitor cell's cytoplasm

inflammation

1. Activated C3 splits into C3a and C3b. 2. C3a and C5a bind to mast cells and cause them to release histamine and other chemicals that increase blood vessel permeability during inflammation. C5a also functions as a very powerful chemotactic factor that attracts phagocytes to the site of an infection.

clonal expansion, or proliferation.

B cells selected to mature can be activated. This allows activated B cells to produce plasma cells that make antibodies as well as memory cells.

monomer

Because a bivalent antibody has the simplest molecular structure, A typical antibody monomer has four protein chains: two identical light chains two identical heavy chains. ("Light" and "heavy" refer to the relative molecular masses.) The chains are joined by disulfide links and other bonds to form a Y-shaped molecule. The Y-shaped molecule is flexible and can assume a T shape

phagocytosis

Cells that perform phagocytosis is the ingestion of a microorganism or other substance by a cell. We have previously mentioned phagocytosis as the method of nutrition of certain protozoa. Phagocytosis is also involved in clearing away debris such as dead body cells and denatured proteins. In this chapter, phagocytosis is discussed as a means by which cells in the human body counter infection as part of the second line of defense.

big picture immunity

Every day the human body wages war with microbial pathogens needing a place to live.

first-line defenses

First-line defenses keep pathogens on the outside or neutralize them before infection begins. The skin, mucous membranes, and certain antimicrobial substances are part of these defenses.

phagocyte migration and phagocytosis

Generally, within an hour after the process of inflammation is initiated, phagocytes appear on the scene. 4 As the flow of blood gradually decreases, phagocytes (both neutrophils and monocytes) begin to stick to the inner surface of the endothelium (lining) of blood vessels. This sticking process in response to local cytokines is called margination. The cytokines alter cellular adhesion molecules on cells lining blood vessels, causing the phagocytes to stick at the site of inflammation. (Margination is also involved in red bone marrow, where cytokines can release phagocytes into circulation when they are needed.) 5 Then the collected phagocytes begin to squeeze between the endothelial cells of the blood vessel to reach the damaged area. This migration, which resembles ameboid movement, is called diapedesis; it can take as little as 2 minutes. 6 The phagocytes then begin to destroy invading microorganisms by phagocytosis. As mentioned earlier, certain chemicals attract neutrophils to the site of injury (chemotaxis). These include chemicals produced by microorganisms and even other neutrophils; other chemicals are kinins, leukotrienes, chemokines, and components of the complement system. Chemokines are cytokines that are chemotactic for phagocytes and T cells and thus stimulate both the inflammatory response and an adaptive immune response. The availability of a steady stream of neutrophils is ensured by the production and release of additional granulocytes from red bone marrow. As the inflammatory response continues, monocytes follow the granulocytes into the infected area. Once the monocytes are contained in the tissue, they undergo changes in biological properties and become free macrophages. The granulocytes predominate in the early stages of infection but tend to die off rapidly. Macrophages enter the picture during a later stage of the infection, once granulocytes have accomplished their function. They are several times more phagocytic than granulocytes and are large enough to phagocytize tissue that has been destroyed, granulocytes that have been destroyed, and invading microorganisms. After granulocytes or macrophages engulf large numbers of microorganisms and damaged tissue, they themselves eventually die. As a result, pus forms, and its formation usually continues until the infection subsides. At times, the pus pushes to the surface of the body or into an internal cavity for dispersal. On other occasions the pus remains even after the infection is terminated. In this case, the pus is gradually destroyed over a period of days and is absorbed by the body. As effective as phagocytosis is in contributing to innate resistance, there are times when the mechanism becomes less functional in response to certain conditions. For example, with age, there is a progressive decline in the efficiency of phagocytosis. Recipients of heart or kidney transplants have impaired innate defenses as a result of receiving drugs that prevent the rejection of the transplant. Radiation treatments can also depress innate immune responses by damaging red bone marrow. Even certain diseases such as AIDS and cancer can cause defective functioning of innate defenses. Finally, individuals with certain genetic disorders produce fewer or impaired phagocytes.

neutralization

IgG antibodies inactivate microbes by blocking their attachment to host cells. IgG can neutralize toxins in a similar manner. By surrounding specific pathogenic components of a microbe, the antibodies can reduce pathogenicity or toxicity.

skin

It consists of the dermis and the epidermis

vasodilation and increased permeability of blood vessels

Immediately following tissue damage (Figure 16.9a), blood vessels dilate (increase in diameter) in the area of damage, and their permeability increases (Figure 16.9b). Dilation of blood vessels, called vasodilation, is responsible for the redness (erythema) and heat associated with inflammation.

the classical pathway

The classical pathway begins with an antigen-antibody reaction. The alternative pathway begins by contact between certain complement proteins and a pathogen; it doesn't involve antibodies. In the lectin pathway, lectin binds to mannose on the surface of a microbe.

the diversity of antibodes

The human immune system is capable of creating a mind-boggling number of antibodies—an estimated minimum of 1 × 1015 (quadrillion) of them. The number of genes required for this amount of diversity is actually relatively small, thanks to random rearrangement of gene segments that code for antigen receptors, resulting in variations of the amino acid sequence at the antigen-binding site (the variable site, or V site). These rearrangements occur before antigen is present, during the early stages of the differentiation of each B cell. Due to the random nature of their creation, some of the B cell antigen receptors made would ultimately lead to antibodies that could harm our own tissues. However, these harmful B cells are usually eliminated at the immature lymphocyte stage by a process called clonal deletion.

mucus

The respiratory and gastrointestinal tracts have many physical forms of defense traps many of the microorganisms that enter these tracts has mucus coated hairs- filter inhaled air and trap particles greater than 10 μm. Smaller (to 2 μm) **these particle will be trapped in the lower respiratory tract

immunoglobulin classes

The simplest and most abundant immunoglobulins are monomers, but they can also assume some different sizes and arrangements. The five classes of Igs are designated IgG, IgM, IgA, IgD, and IgE. Each class has a different role in the immune response. The structures of IgG, IgD, and IgE molecules are Y-shaped monomers. Molecules of IgA and IgM are aggregates of two or five monomers, respectively, that are joined together.

first-line defenses: skin and mucous membranes

The skin and mucous membranes are the body's first line of defense against environmental pathogens. This function results from both physical and chemical factors.

keratin

The top layer of epidermal cells is dead and contains a protective protein The periodic shedding of the top layer helps remove microbes at the surface. In addition, the dryness of the skin is a major factor in inhibiting microbial growth on the skin. When the skin is frequently moist, as in hot, humid climates, skin infections are quite common, especially fungal infections such as athlete's foot. These fungi hydrolyze keratin when water is available.

third-line defenses

Third-line defenses, shown in the table below, include lymphocytes that target specific pathogens for destruction when the second-line defenses don't contain infections. It includes a memory component that allows the body to more effectively respond to that same pathogen in the future. First- and second-line defenses are part of the innate immune system, whereas the third-line defenses are referred to as the adaptive immune system. Many leukocytes (white blood cells) coordinate efforts in controlling infections in the second and third lines of immune defense.

immune system and blood

WBCs count measure leukocytes in the blood. Leukocytes coordinate efforts in controlling infections in the second and third lines of defense. a high or low WBC can indicate infection, autoimmune disease, cancer, side-effects to medications/treatment or other medical conditions.

White blood cell counts

White blood cell (WBC) counts measure the number of leukocytes found in the blood. A related test, called differential white blood cell count, breaks down the white blood cell count further, identifying the percentages of eosinophils, basophils, neutrophils, monocytes, and lymphocytes. Abnormal blood cell counts give health care providers important clues for diagnosing infections and other conditions.

chemokines

a family of small cytokines, induce leukocytes to migrate to areas of infection or tissue damage where they can begin to act against an infection. The name is based on chemotaxis, the term for movement of an organism in response to a chemical stimulus. Chemokines are especially important for infections by HIV

IgA

accounts for only about 13% of the antibodies in serum, but it is by far the most common form in mucous membranes and in body secretions such as mucus, saliva, tears, and breast milk. most abundant immunoglobulin in the body. The form of IgA that circulates in serum, serum IgA, is usually in the form of a monomer. The most effective form of IgA, however, consists of two connected monomers that form a dimer called secretory IgA. It is produced in this form by plasma cells in the mucous membranes—as much as 15 grams per day, mostly by intestinal epithelial cells. Each dimer then enters and passes through a mucosal cell, where it acquires a polypeptide called secretory component that protects it from enzymatic degradation. The main function of secretory IgA is probably to prevent the attachment of microbial pathogens to mucosal surfaces. This is especially important in resistance to intestinal and respiratory pathogens. relatively short-lived, the length of immunity to many respiratory infections is correspondingly short. IgA's presence in a mother's milk, especially the colostrum, probably helps protect infants from gastrointestinal infections.

cell communication: Cytokines(pg.477)

act as "voice" of cells allowing a coordinated immune response regulate timing, intensity, duration of immune response produced mostly by immune cells

T helper (TH) cell

antigen required to activate a B cell is known as a T-dependent antigen. T-dependent antigens are mainly proteins of the type found on viruses, bacteria, red blood cells, and haptens with their carrier molecules. antibodies to be produced in response to a T-dependent antigen, both B and T cells must recognize and interact with different epitopes on a given antigen. This ensures specificity of the attack and also helps prevent an unintentional autoimmune response. B cells can be activated directly by some antigens, called T-independent antigens, without assistance of T cells. First, we'll walk through the steps involved with responding to a T-dependent antigen.

dendritic cells

are also believed to be derived from the same precursor cells as monocytes. They have long extensions that resemble the dendrites of nerve cells, thus their name. Dendritic cells are especially abundant in the epidermis of the skin, mucous membranes, the thymus, and lymph nodes. Dendritic cells destroy microbes by phagocytosis and initiate adaptive immune responses

kinins

are another group of substances that cause vasodilation and increased permeability of blood vessels. Kinins are present in blood plasma, and once activated, they play a role in chemotaxis by attracting phagocytic granulocytes, chiefly neutrophils, to the injured area.

leukotrienes

are substances produced by mast cells (cells especially numerous in the connective tissue of the skin and respiratory system, and in blood vessels) and basophils. Leukotrienes cause increased permeability of blood vessels and help attach phagocytes to pathogens. Various components of the complement system produced by the liver stimulate the release of histamine, attract phagocytes, and promote phagocytosis.

macrophages

are usually found in a resting state. We have already discussed the function of these cells related to phagocytosis. They are important for innate immunity and for ridding the body of worn-out blood cells (about 200 billion per day) and other debris, such as cellular remnants from apoptosis. Their motility and phagocytic capabilities are greatly increased when they are stimulated to become activated macrophages (Figure 17.11). This activation can be initiated by ingestion of antigenic material. Other stimuli, such as cytokines produced by an activated T helper cell, can further enhance the capabilities of macrophages. Once activated, macrophages are more effective as phagocytes and as APCs. Activated macrophages are important factors in the control of cancer cells, virus-infected cells, and intracellular pathogens such as the tubercle bacillus. Their appearance becomes recognizably different as well—they are larger and become ruffled. How do macrophages become activated? After taking up an antigen anywhere in the body, APCs tend to migrate to lymph nodes or other lymphoid centers on the mucosa, where they present the antigen to T cells located there. T cells carrying receptors that are capable of binding with any specific antigen are present in relatively limited numbers. Migration of APCs increases the opportunity for these particular T cells to encounter the antigen for which they are specific.

antigen-presenting cells(APCs)

associated with cellular immunity include B cells, dendritic cells, and activated macrophages. All APCs have MHCs on their surfaces that presents potential antigenic fragments to T cells. T cells interacting with the antigenic epitope and MHC will lead to T cell activation. APCs produce IL-12, which activates TH1 cells.

granular leukocytes

basophiles (stain blue w/ basic dye) -involved in allergic reactions and inflammation; release heparin, and histamine -similar in appearance and function to mast cells, found in tissues instead eosinophiles(stain orange-red w/ acidic dye) -found mostly in specific tissues (not the lungs) -involved in allergic reactions, inflammation and combatting parasites via ADCC

urine

cleansing of the urethra by the flow of urine physical factor that prevents microbial colonization in the genitourinary tract. urine flow is obstructed—by catheters, for example—urinary tract infections may develop. Vaginal secretions likewise move microorganisms out of the female body. in addition to containing lysozyme, has an acidic pH (average 6) that inhibits microbes.

saliva

contains not only the enzyme salivary amylase that digests starch, but also a number of substances that inhibit microbial growth. These include lysozyme, urea, and uric acid. The slightly acidic pH of saliva (6.55-6.85) also inhibits some microbes. Saliva additionally contains an antibody (lgA) that prevents attachment of microbes so that they cannot penetrate mucous membranes.

lower respiratory tract

covered with cilia moving synchronously, these cilia propel inhaled dust and microorganisms that have become trapped in mucus upward toward the throat.

second line of defense

defensive cells, such as phagocytic cells; inflammation; fever; and antimicrobial substances.

similarities between systems

dendritic cells and macrophages

IgG

derived from the part of blood, called gamma globulin, that contains antibodies. accounts for about 80% of all antibodies in serum. In regions of inflammation, these monomer antibodies readily cross the walls of blood vessels and enter tissue fluids. Maternal IgG antibodies, for example, can cross the placenta and confer passive immunity to a fetus. They protect against circulating bacteria and viruses, neutralize bacterial toxins, trigger the complement system, and, when bound to antigens, enhance the effectiveness of phagocytic cells.

third line defense

destroy invader and memorize response (humoral and cellular immunity)

sensor systems

detect invasion

naturally acquired active immunity

develops from exposure to antigens, illness, and recovery. Once acquired, immunity is lifelong for some diseases such as measles. In other cases, especially for intestinal diseases, immunity may last only a few years. Subclinical infections, or inapparent infections (those that produce no noticeable symptoms or signs of illness), can also confer immunity.

skin

difficult for microbes to penetrate; chemical and physical barrier *impermeable, inhospitable -epidermis: tightly packed layers of epithelial cells(keratinocytes); outermost: dead,repels water, filled with keratin, shedding -Dermis: connective tissue, sweat, sweat glands(salty), sebum, sebaceous glands (acidic) **moist skin has a greater chance at infection***

activation of complement system

either IgG or IgM antibodies may trigger For example, inflammation is caused by infection or tissue injury. One aspect of inflammation is that it will often cause microbes in the inflamed area to become coated with certain proteins. This, in turn, leads to the attachment to the microbe of an antibody-complement complex. This complex lyses the microbe, which then attracts phagocytes and other defensive immune system cells to the area.

Peristalsis, defecation, vomiting, and diarrhea

expel microbes Peristalsis is a series of coordinated contractions that propels food along the gastrointestinal tract. Mass peristalsis of large intestinal contents into the rectum results in defecation. In response to microbial toxins, the muscles of the gastrointestinal tract contract vigorously, resulting in vomiting and/or diarrhea, which may also rid the body of microbes.

the lymphatic system

fluid called lymph, vessels called lymphatic vessels, a number of structures and organs containing lymphoid tissue, and red bone marrow, where stem cells develop into blood cells, including lymphocytes Lymphoid tissue contains large numbers of lymphocytes, including T cells, B cells, and phagocytic cells that participate in immune responses. Lymph nodes are the sites of activation of T cells and B cells, which destroy microbes by immune responses . Also within lymph nodes are reticular fibers, which trap microbes, and macrophages and dendritic cells, which destroy microbes by phagocytosis.

C1: the complement system

functions as a sensor system and a second line defense through the complement proteins (C1-C9+ factors) must be actuvated to mount the comlement response some are activated by a split (a,b) **each pathway includes a detection step, activation of C3 and C5, all three of the following outcomes: 1.inflammatory response induced by C3a and C5a 2. opsonization by C3b(lectin)-> phagocytosis 3.Cytolysis-> lysis if foreign cells by the membrane attack complexes (MACs) formed by C5b,C6,C7,C8 and C9 1-detect 2-activate 3-respond

affinity maturation

genetic recombination locks the genes in a sequence b cell gets activated and goes through expansion plasma cell stops wasting energy making BCR to instead make antibodies B cells go through to fine tune and increase affinity class switching

arganular leukocytes

granules not visible with light microscope after staining **monocytes: circulate in blood and migrate into tissues to diffeentiate into either macrophages- highest phagocytic activity or dendritic cells. both are antigen-presenting cells(APCs) that act as sentinel phagocytic cells. **lymphocytes: NK cells are sentinel cells that target infected body cells, tumor cells and parasites by releasing toxic substances T and B cells- highly specific, play key role in adaptive immunity

granular leukocytes

granulocytes- are named based on staining properties of granules(active chemicals) neutrophiles(polymorphs)->stain poorly; pale lilac -most numerous: 60% of blood WBCs -important in inflammation: *first responders->diapedesis *intracellular killing by phagocytosis *extracellular killing by degranulation of NET release

physical factors

include barriers to entry and processes that remove microbes from the body's surface The intact skin is the human body's largest organ in terms of surface area and weight and is an extremely important component of the first line of defense.

lymphocytes

include natural killer cells, T cells, and B cells. Natural killer (NK) cells are found in blood and in the spleen, lymph nodes, and red bone marrow. NK cells have the ability to kill a wide variety of infected body cells and certain tumor cells. NK cells attack any body cells that display abnormal or unusual plasma membrane proteins. The binding of NK cells to a target cell, such as an infected human cell, causes the release of toxic substances from lytic granules in NK cells. Lytic granules are a secretory organelle unique to NK cells. Some granules contain a protein called perforin, which inserts into the plasma membrane of the target cell and creates channels (perforations) in the membrane. As a result, extracellular fluid flows into the target cell and the cell bursts, a process called cytolysis (sī-TOL-i-sis; cyto- = cell; -lysis = loosening). Other granules of NK cells release granzymes, which are protein-digesting enzymes that induce the target cell to undergo apoptosis, or self-destruction. This type of attack kills infected cells but not the microbes inside the cells; the released microbes, which may or may not be intact, can be destroyed by phagocytes.

what do blood cells counts tell us about patient health?

infection

chapter 16

innate immunity: nonspecific defense of the host

susceptibility

lack of immunity

T regulatory cells

make up about 5-10% of the T cell population. They are a subset of the T helper cells and are distinguished by carrying an additional CD25 molecule. Their primary function is to combat autoimmune reactions by suppressing T cells that escape deletion in the thymus without the necessary "education" to avoid reacting against the body's self. They are also useful in protecting the resident microbiota that live in our intestines and aid digestion. Similarly, in pregnancy they may play a role in protecting the fetus from rejection as nonself. Recently, researchers have discovered evidence of Treg involvement in establishing the skin microbiome

normal microbiota and innate immunity

preventing the overgrowth of harmful microbes.

innate immunity

refers to defenses that are present at birth always available to provide rapid responses to protect us against disease does not involve recognition of a specific microbe no memory response first-line defense: skin and mucous membranes second line defense: natural killer cells, phagocytes, inflammation, fever and antimicrobial substances early warning system prevent microbes from gaining access into the body and help eliminate those that do gain access

dermis

the skin's inner, thicker portion, is composed of connective tissue.

interferons

were originally named for one of their functions: the ability to interfere with viral infections in host cells A number of antiviral interferons are available as commercial products in treating disease conditions, including hepatitis and some cancers. Gamma interferon (IFN-γ) stimulates the immune system.

artificially acquired active immunity

s the result of vaccination—which will be discussed in Chapter 18. Vaccines, also called immunizations, introduce antigens to the body. For example, killed or inactivated bacteria can be injected into the body resulting in an immune response without causing infection.

antimicrobial substances(chemical barrier)

-sebum/cerumen(skin/ear): rich in fatty acids-> low pH -acid kills most bacteria and toxins **exception: clostridium botulinum toxin -lactoferrin: binds iron (saliva, tears, mucus,milk,nasal secreations) -AMPs: borad spectrum antimicrobial peptides produced by our cells **defensins form pores in microbial membranes-> cytolysis **lysozyme(sweat,tears, saliva, urine) degrades PG

functions of inflammation

(1) to destroy the injurious agent, if possible, and to remove it and its by-products from the body; (2) if destruction is not possible, to limit the effects on the body by confining or walling off the injurious agent and its by-products; and (3) to repair or replace tissue damaged by the injurious agent or its by-products.

mucous membranes (outside boarder)

*epithelial layer bathed in mucus lining: -digestive -respiratory -genitourinary tracts *mucous moistens tracts while trapping and washing off pathogens: -ciliary escalator: beating action of cilia of propels microbes upward away from lungs -peristalsis: muscular contraction of intestinal wall resulting in movement of content into the rectum for defecation.

cytosis

1. Activated C3 splits into C3a and C3b. 2. C3b splits C5 into C5a and C5b. 3. Fragments C5b, C6, C7, and C8 bind together sequentially and insert into the plasma membrane of the invading cell. C5b through C8 act as a receptor that attracts a C9 fragment. Additional C9 fragments are added to form a transmembrane channel. Together, C5b through C8 and the multiple C9 fragments form the membrane attack complex (MAC) (Figure 16.11). The MAC creates a hole on a pathogen's cell membrane and makes transmembrane channels, allowing for flow of extracellular fluid into the pathogen. The fluid inflow bursts the microbial cell. Plasma membranes of the host cell contain proteins that protect against lysis by preventing the MAC proteins from attaching to their surfaces. Also, the MAC forms the basis for the complement fixation test used to diagnose some diseases. This is explained in the Clinical Focus box on page 470 and in Chapter 18 (see Figure 18.10). Gram-negative bacteria are more susceptible to cytolysis because they have only one or very few layers of peptidoglycan to protect the plasma membrane from the effects of complement. Gram-positive bacteria have many layers of peptidoglycan, which limit complement's access to the plasma membrane and thus interfere with cytolysis. Bacteria that are not killed by the MAC are said to be MAC resistant.

resistance to disease

1. They are well adapted to a limited number of attachment sites on which they live and have a competitive advantage over pathogenic microbes for these colonization sites by competing for available space and nutrients (competitive exclusion). This colonization resistance is especially effective against microbes such as Clostridium difficile, Salmonella, Shigella, and Candida albican. 2.Normal microbiota produce substances that inhibit or kill pathogens. For example, E. coli bacteria in the large intestines produce bacteriocins that inhibit or kill bacteria of the same or closely related species. Some normal microbiota, such as Lactobacillus in the vagina, produce hydrogen peroxide under anaerobic conditions. This has shown to be effective against infections caused by Chlamydia trachomatis, Gardnerella vaginalis, and Candida albicans. 3.Development of the immune system is dependent on the presence of microbiota even before birth.

Antigen-Presenting Cells (APCs)

1. a bacterium is engulfed by phagocytosis into a dendritic cell and is encased in a phagosome 2. lysosomes fuse with the phagosome and digest the bacterium 3.immunodominant epitopes are associated with MHC II and presented in the cell surface.

chemotaxis

1. is the chemical attraction of phagocytes to microorganisms. Among the chemotactic chemicals that attract phagocytes are microbial products, components of white blood cells and damaged tissue cells, cytokines released by other white blood cells, and, finally, peptides derived from complement—a system of host defense proteins

ingestion

2.Following adherence, ingestion occurs. The plasma membrane of the phagocyte extends projections called pseudopods that engulf the microorganism. 3.Once the microorganism is surrounded, the pseudopods meet and fuse, surrounding the microorganism with a sac called a phagosome, or phagocytic vesicle. The membrane of a phagosome has enzymes that pump protons (H+) into the phagosome, reducing the pH to about 4. At this pH, hydrolytic enzymes are activated.

high white blood cells counts

A high white blood cell count shows the patient is producing a higher than average number of leukocytes. This typically occurs when the patient battles a bacterial infection. High white blood cell counts may also stem from autoimmune disorders that result in too much inflammatory response, such as rheumatoid arthritis, and from leukemia, a cancer of the blood. Some drugs can cause high white blood cell counts as a side effect; these include certain asthma medications such as albuterol, epinephrine, and corticosteroids.

low white blood cells counts

A low white blood cell count shows the patient has fewer leukocytes than expected. A low neutrophil count, in particular, is instructive. Even bacteria that generally live in the mouth and digestive track without being pathogenic may result in disease when the patient's neutrophil count drops below 500 neutrophils per mm3 of blood. Low white blood cell counts may result from viral infections or pneumonia. They may also be caused from autoimmune diseases such as lupus; certain cancers, such as lymphoma; and radiation and other cancer treatments. White blood cell counts may also be low when a patient has an extremely severe bacterial infection, such as septicemia. Finally, numerous drugs may also cause low white blood cell counts, including a variety of antibiotics, diuretics, and anticancer medications.

vaccination

A vaccine formulated with a harmless version of a pathogen incites an adaptive response, rendering people immune to the illness without the damage and danger of a full-blown infection that are otherwise needed to obtain these benefits. Vaccination against smallpox, the first disease for which the procedure was developed, actually predated the establishment of the germ theory of disease by nearly a hundred years

cytokines: chemical messengers of immune cells

Adaptive immunity requires complex interactions between different cells. This communication is mediated by chemical messengers called cytokines, which are soluble proteins or glycoproteins. They are produced by nearly all types of immune cells in response to a stimulus. More than 200 cytokines are thought to exist. Most have common names that reflect functions known at the time of the discovery; some are now known to have multiple functions. A cytokine only acts on a cell that has a receptor for it. Cytokines are classified by structure or function. Several important types include interleukins, chemokines, interferons, tumor necrosis factors, and hematopoietic cytokines.

phagolysosome formation and digestion

4.On contact, the phagosome and lysosome membranes fuse to form a single, larger structure called a phagolysosome. 5.The contents of the phagolysosome brought in by ingestion are digested in the phagolysosome. Lysosomal enzymes that attack microbial cells directly include lysozyme, which hydrolyzes peptidoglycan in bacterial cell walls. Lipases, proteases, ribonuclease, and deoxyribonuclease hydrolyze other macromolecular components of microorganisms. Lysosomes also contain enzymes that can produce toxic oxygen products such as superoxide radical (O2−˙O2−˙), hydrogen peroxide (H2O2), nitric oxide (NO), singlet oxygen (1O2−), and hydroxyl radical (OH·) Toxic oxygen products are produced by an oxidative burst. Other enzymes can make use of these toxic oxygen products in killing ingested microorganisms. For example, the enzyme myeloperoxidase converts chloride (Cl−) ions and hydrogen peroxide into highly toxic hypochlorous acid (HOCl). The acid contains hypochlorite ions, which are found in household bleach and account for its antimicrobial activity 6.After enzymes have digested the contents of the phagolysosome brought into the cell by ingestion, the phagolysosome contains indigestible material and is called a residual body. 7.This residual body then moves toward the cell boundary and discharges its wastes outside the cell.

antimicrobial proteins

Although fairly recently discovered, antimicrobial peptides (AMPs) may be one of the most important components of innate immunity (see also Chapter 20, page 585). Antimicrobial peptides are short peptides that consist of a chain of about 12 to 50 amino acids synthesized on ribosomes. They were first discovered in the skin of frogs, the lymph of insects, and human neutrophils; to date, over 600 AMPs have been discovered in nearly all plants and animals. AMPs have a broad spectrum of antimicrobial activities, including activity against bacteria, viruses, fungi, and eukaryotic parasites. Synthesis of AMPs is triggered by protein and sugar molecules on the surface of microbes. Cells produce AMPs when chemicals in microbes attach to Toll-like receptors (see page 448). The modes of action of AMPs include inhibiting cell wall synthesis; forming pores in the plasma membrane, resulting in lysis; and destroying DNA and RNA. Among the AMPs produced by humans are dermcidin, produced by sweat glands; defensins and cathelicidins, produced by neutrophils, macrophages, and epithelium; and thrombocidin, produced by platelets. Scientists are especially interested in AMPs for a number of reasons. Besides their broad spectrum of activity, AMPs have shown synergy (working together) with other antimicrobial agents, so that the effect of them working together is greater than that of either working separately. AMPs are also very stable over a wide range of pH. What is particularly significant is that microbes do not appear to develop resistance even though the microbes are exposed to them for long periods of time. In addition to their killing effect, AMPs also participate in a number of other immune functions. For example, AMPs can sequester the LPS shed from gram-negative bacteria preventing endotoxic shock. AMPs have been found to vigorously attract dendritic cells, which destroy microbes by phagocytosis and initiate an adaptive immune response. AMPs have also been shown to recruit mast cells, which increase blood vessel permeability and vasodilation. This brings about inflammation, which destroys microbes, limits the extent of damage, and initiates tissue repair.

Immunological Memory

Antibody-mediated immune responses intensify after the primary response, where a particular antigen is first met and corresponding antibodies are produced. This secondary response is also called the memory response, or anamnestic response. As shown in Figure 17.17, this response is comparatively more rapid, reaching a peak in only 2 to 7 days, longer in duration, and considerably greater in magnitude than the primary response. The secondary response is due to the portion of activated B cells that, instead of transforming into antibody-secreting plasma cells, become memory cells. As mentioned earlier, IgM is the first antibody that B cells make during the primary response to an antigen. But an individual B cell is also capable of making different classes of antibody, such as IgG, IgE, or IgA, all with unchanged antigenic specificity. Termed class switching, this is observed, especially, in the case of the primary and secondary immune response (compare IgG and IgM in Figure 17.17). Generally speaking, when IgG begins to be produced in the secondary response, the production of IgM will decrease or be sharply curtailed.

Nonspecific Cells and Extracellular Killing by the Adaptive Immune System

CTLs are not the only cells that can lead to the destruction of a target cell. Natural killer (NK) cells can also destroy certain virus-infected cells and tumor cells and can attack parasites, which are normally much larger than bacteria (Figure 17.16). NK cells are large granular leukocytes (10-15% of all circulating lymphocytes). In contrast to CTLs, NK cells are not immunologically specific, meaning that they do not need to be stimulated by a particular antigen. Instead, NK cells distinguish normal cells from transformed cells, or cells infected with intracellular pathogens. NK cells first contact the target cell and determine whether it expresses MHC class I self-antigens. If it does not—which is often the case in the early stages of viral infection and with some infecting viruses that have developed a system of interfering with the usual presentation of antigens on an APC—they kill the target cell by mechanisms similar to that of a CTL. Tumor cells also have a reduced number of MHC class I molecules on their surfaces. NK cells cause pores to form in the target cell, which leads to either lysis or apoptosis. With the help of antibodies produced by the humoral immune system, the cell-mediated immune system can stimulate natural killer cells and cells of the innate defense system, such as macrophages, to kill targeted cells. In this way, an organism such as a fungus, protozoan, or helminth that is too large to be phagocytized can be attacked by immune system cells. This is referred to as antibody-dependent cell-mediated cytotoxicity (ADCC). As is illustrated in Figure 17.16, the target cell is first coated with antibodies. A variety of cells of the immune system bind to the Fc regions of these antibodies and, thus, to the target cell. The attacking cells secrete substances that then lyse the target cell.

inflammation

Damage to the body's tissues triggers a local defensive response component of second-line defense The damage can be caused by microbial infection, physical agents (such as heat, radiant energy, electricity, or sharp objects), or chemical agents (acids, bases, and gases). Certain signs and symptoms are associated with inflammation, which you can remember by thinking of the acronym PRISH:

class II MHC

Displaying antigen fragments bound to attracts the appropriate T helper cell to the APC cell. The TH cell makes contact with the fragment presented on the APC, and then the T helper cell produces cytokines that activate a B cell, which divides into a large clone of cells. Some of the B cell clones differentiate into antibody-producing plasma cells. Others become long-lived memory cells responsible for the enhanced secondary response to an antigen. T-independent antigens stimulate B cells directly, without the help of T cells. T-independent antigens tend to be molecules consisting of repeating subunits, such as polysaccharides or lipopolysaccharides. Bacterial capsules are a common example of T-independent antigens. can bind to multiple B cell receptors, which is probably why this class of antigens doesn't require T cell assistance. these antigens tend to provoke a weaker immune response than T-dependent antigens do. The T-independent response is composed primarily of IgM, and no memory cells are generated. *The immune system of infants may not be stimulated by T-independent antigens until about age 2.

lymphoid tissues and organs

scattered throughout the mucous membranes that line the gastrointestinal, respiratory, urinary, and reproductive tracts. They protect against microbes that are ingested or inhaled. Multiple large aggregations of lymphoid tissues are located in specific parts of the body. These include the tonsils in the throat and Peyer's patches in the small intestine

cellular immunity response

Humoral antibodies are effective against pathogens that are circulating freely in the body, where the antibodies can make contact with them. intracellular antigens, such as a virus, certain bacteria, and some parasites, are not exposed to these circulating antibodies since they enter host cells. T cells likely evolved to combat the problem posed by these intracellular pathogens. They are also the way in which the immune system recognizes other cells that are abnormal—especially cancer cells. Like B cells, each T cell is specific for only a certain antigen. T cells will recognize only antigen fragments bound to MHC. About 98% of immature T cells are eliminated in the thymus, which is akin to clonal deletion in B cells. This reflects a weeding-out process, called thymic selection, that allows only those T cells that correctly recognize foreign materials and host cells to continue. Once mature, T cells migrate from the thymus by way of the blood and lymphatic system to various lymphoid tissues, where they are most likely to encounter antigens. Pathogens destined to live intracellularly most frequently enter the body via the gastrointestinal or respiratory tracts. Each of these tracts is lined with a barrier of epithelial cells. Normally, something can pass this barrier in the gastrointestinal tract only by way of a scattered array of gateway cells called microfold cells, or M cells Instead of the myriad of fingerlike microvilli found on the surface of absorptive epithelial cells of the intestinal tract, M cells have microfolds. M cells are located over Peyer's patches, which are secondary lymphoid organs located on the intestinal wall. M cells take up antigens from the intestinal tract and allow their transfer to the lymphocytes and antigen-presenting cells of the immune system found throughout the intestinal tract, just under the epithelial-cell layer but especially in the Peyer's patches. It is also here that antibodies, mostly IgA essential for mucosal immunity, are formed and migrate to the mucosal lining.

hummoral immunity response process

Humoral immune actions take place in the extracellular spaces within the body. So-called free antigens found here need to be identified and processed, so that specific antibodies can be created to neutralize them. these antibodies need to be remembered so that future interactions with the same type of antigen result in a quicker immune response the next time. Both these processes begin with an inactivated B cell. Each B cell carries immunoglobulins on its surface. The majority are IgM and IgD, all of which are specific for recognition of the same epitope (portion of an antigen). Some B cells may have other immunoglobulin families on their surface. For example, B cells in the intestinal mucosa are rich in IgA. B cells may carry more than 100,000 identical immunoglobulin molecules, all recognizing the same epitope.

What is the function of keratin in the epidermis?

If we consider the closely packed cells, continuous layering, the presence of keratin, and the dryness and shedding of the skin, we can see why the intact skin provides such a formidable barrier to the entrance of microorganisms. Microorganisms rarely, if ever, penetrate the intact surface of healthy epidermis. However, when the epithelial surface is broken as a result of burns, cuts, puncture wounds, or other conditions, a subcutaneous (below-the-skin) infection often develops. The bacteria most likely to cause infection are the staphylococci that normally inhabit the epidermis, hair follicles, and sweat and oil glands of the skin. Epithelial cells called endothelial cells that line blood and lymphatic vessels are not closely packed like those of the epidermis. This arrangement permits defensive cells to move from blood into tissues during inflammation, but it also permits microbes to move into and out of blood and lymph.

Types of Adaptive Immunity

Immunity is acquired actively when a person is exposed to microorganisms or foreign substances and the immune system responds. Immunity is acquired passively when antibodies are transferred from one person to another. Passive immunity in the recipient lasts only as long as the antibodies are present—in most cases, a few weeks. Both actively acquired immunity and passively acquired immunity can be obtained by natural or artificial means

complement and disease

In addition to its importance in defense, the complement system assumes a role in causing disease as a result of inherited deficiencies. C1, C2, or C4 deficiencies cause collagen vascular disorders that result in hypersensitivity (anaphylaxis); deficiency of C3, though rare, results in increased susceptibility to recurrent infections with pyogenic (pus-producing) microbes; and C5 through C9 defects result in increased susceptibility to Neisseria meningitidis and N. gonorrhoeae infections. Complement may play a role in diseases with an immune component, such as systemic lupus erythematosus, asthma, various forms of arthritis, multiple sclerosis, and inflammatory bowel disease. Complement is also implicated in Alzheimer's disease and other neurodegenerative disorders.

iron binding proteins

Most pathogenic bacteria require iron for their vegetative growth and reproduction (see Chapter 15). Humans use it as a component of cytochromes in the electron transport chain, a cofactor for enzyme systems, and as a part of hemoglobin, which transports oxygen in the body. Many pathogens also require iron to survive. So an infection creates a situation where pathogens and humans compete for available iron. The concentration of free iron in the human body is low because most of it is bound to iron-binding proteins—molecules such as transferrin, lactoferrin, ferritin, and hemoglobin—whose function is to transport and store iron. Transferrin is found in blood and tissue fluids. Lactoferrin is found in milk, saliva, and mucus. Ferritin is located in the liver, spleen, and red bone marrow, and hemoglobin is located within red blood cells. The iron-binding proteins not only transport and store iron but also, by doing so, deprive most pathogens of the available iron. To survive in the human body, many pathogenic bacteria obtain iron by secreting proteins called siderophores (see Figure 15.3 on page 430). Recall that siderophores compete to take away iron from iron-binding proteins by binding it more tightly. Once the iron-siderophore complex is formed, it is taken up by siderophore receptors on the bacterial surface and brought into the bacterium; then the iron is split from the siderophore and utilized. (In some cases, the iron enters the bacterium while the siderophore remains outside.) A few pathogens do not use the siderophore mechanism to obtain iron. For example, Neisseria meningitidis produces receptors on its surface that bind directly to human iron-binding proteins. Then the iron-binding protein, along with its iron, is taken into the bacterial cell. Some pathogens, such as Streptococcus pyogenes, release hemolysin, a protein that causes the lysis (destruction) of red blood cells. The hemoglobin is then degraded by other bacterial proteins to capture the iron.

regulation of complement

Once complement is activated, its destructive capabilities usually cease very quickly to minimize the destruction of host cells. This is accomplished by various regulatory proteins in the host's blood and on certain cells, such as blood cells. The regulatory proteins are present at higher concentrations than the complement proteins. The proteins bring about the breakdown or inhibition of activated complement. One example of a regulatory protein is CD59, which prevents the assembly of C9 molecules to form the MAC.

opsonization

Opsonization, or immune adherence, promotes attachment of a phagocyte to a microbe. 1. Activated C3 splits into activated C3a and C3b. 2. C3b binds to the surface of a microbe, and receptors on phagocytes attach to the C3b.

PRISH

Pain due to the release of certain chemicals. Redness because more blood goes to the affected area. Immobility that results from local loss of function in severe inflammations. Swelling caused by an accumulation of fluids. Heat, which is also due to an increase in blood flow to the affected area.

pathogen-associated molecular patterns (PAMPs)

Pathogenic bacteria characteristically possess a number of recognizable antigens PAMPs serve as warning flags of an invading organism that the host can recognize by means of receptors. The best-known of these receptors is the extended family of Toll-like receptors (TLRs).

sebum

Sebaceous (oil) glands of the skin produce an oily prevents hair from drying and becoming brittle. orms a protective film over the surface of the skin. One of the components of sebum is unsaturated fatty acids, which inhibit the growth of certain pathogenic bacteria and fungi. The low pH of the skin, between pH 3 and 5, is caused in part by the secretion of fatty acids and lactic acid. The skin's acidity probably discourages the growth of many other microorganisms. Certain bacteria commonly found on the skin metabolize sebum, and this metabolism forms free fatty acids that cause the inflammatory response associated with acne Isotretinoin, a derivative of vitamin A that prevents sebum formation, is a treatment for a very severe type of acne called cystic acne.

second-line defenses

Second-line defenses slow or contain infections when first-line defenses fail. They include proteins that produce inflammation, fever that enhances cytokine activity, and phagocytes and natural killer (NK) cells, which attack and destroy cancer cells and virus-infected cells.

evading the compliment system

Some bacteria evade the complement system by means of their capsules, which prevent complement activation. For example, some capsules contain large amounts of a monosaccharide called sialic acid, which discourages opsonization and MAC formation. Other capsules inhibit the formation of C3b and C4b and cover the C3b to prevent it from making contact with the receptor on phagocytes. Some gram-negative bacteria, such as Salmonella, can lengthen the O polysaccharide of their LPS (see page 81), which prevents MAC formation. Other gram-negative bacteria, such as Neisseria gonorrhoeae, Bordetella pertussis, and influenzae type b, attach their sialic acid to the sugars in the outer membrane, ultimately inhibiting MAC formation. Gram-positive cocci release an enzyme that breaks down C5a, the fragment that serves as a chemotactic factor that attracts phagocytes. With respect to viruses, some viruses, such as the Epstein-Barr virus, attach to complement receptors on body cells to initiate their life cycle.

antigens

Substances that induce production of antibodies Most antigens are either proteins or large polysaccharides. Lipids and nucleic acids are usually antigenic only when combined with proteins and polysaccharides. Pathogens can have multiple antigenic sites. Components of invading microbes—such as capsules, cell walls, flagella, fimbriae, bacterial toxins, and viral coats—all tend to be antigenic. a compound doesn't have to be part of an invading pathogen to be deemed antigenic by the immune system. Nonmicrobial antigens may include pollen, egg white, blood cell surface molecules, serum proteins from other individuals or species, and surface molecules of transplanted tissues and organs. Detection of an antigen provokes production of highly specific, corresponding antibodies Antigens that cause such a response are often known as immunogens. antibodies react with specific regions on antigens called epitopes or antigenic determinants The nature of the interaction depends on the size, shape, and chemical structure of the binding site on the antibody molecule. epitopes can be displayed by antigen presenting cells (such as when macrophages and dendritic cells present them to T cells). A bacterium or virus may have several epitopes that cause the production of different antibodies. Most antigens have a molecular mass of 10,000 da or higher. Which would have more epitopes: a protein or a lipid? Why?

T helper cells (CD4+ T Cells)

T helper cells can recognize an antigen presented on the surface of a macrophage and activate it, making the macrophage more effective in both phagocytosis and in antigen presentation. Dendritic cells are especially important in the activation of T helper cells and in developing their effector functions For a T helper cell to become activated, its T cell receptor recognizes antigen fragments held in a complex with proteins of MHC class II on the surface of the APC. This is the initial signal for activation; a second, costimulatory signal that comes from either the APC or T helper cell is also required for activation. The activated T helper cell begins to proliferate and secrete cytokines. Secretion of cytokines causes the proliferating T helper cells to differentiate into populations of T helper cell subsets, such as TH1, TH2, and TH17. These subsets act on different cells of the body's defensive systems. They also form a population of long-lived memory cells. The cytokines produced by TH1 cells, especially IFN-γ, activate cells related to delayed hypersensitivity (see page 535) and are responsible for activation of macrophages (see page 487). They also stimulate the production of antibodies that promote phagocytosis and are especially effective in enhancing the activity of complement, such as opsonization and inflammation (see Figure 16.12, page 466). As shown in Figure 17.13, the generation of cytotoxic T lymphocytes requires action by a TH1 cell. TH2 cells produce cytokines, including IL-4. They are associated primarily with the production of antibodies, especially IgE, that are important in allergic reactions (see the discussion of hypersensitivity on page 525). They are also important in the activation of the eosinophils that defend against infections by extracellular parasites, such as helminths A third subset is named TH17 cells because of their production of large quantities of the cytokine IL-17. The discovery of TH17 cells answered the questions raised by the observation that TH1 and TH2 cells were not effective in dealing with certain infections by extracellular bacteria and fungi. IL-17 acts as a chemokine to recruit neutrophils. Excessive amounts of TH17 cells probably contribute to the inflammation and injury to tissue found in certain autoimmune diseases such as multiple sclerosis, psoriasis, rheumatoid arthritis, and Crohn's disease. They may be associated with the pathologic effects of diseases such as asthma and allergic dermatitis. But they also serve, helpfully, to combat microbial infections of the mucosa by the production of cytokines such as IL-22, which stimulate epithelial cells to produce antimicrobial proteins. Therefore, a severe deficiency of TH17 cells may make one more susceptible to opportunistic infections. The functions of the three subsets directly involved in the body's defenses against external microbial threats

cellular immunity

T lymphocytes, or T cells, are the basis of cellular immunity, also called cell-mediated immunity. T cells do not directly bind to antigens. Instead, phagocytic cells, such as macrophages or dendritic cells, process and present antigenic peptides to them. T cells have T cell receptors (TCRs) that recognize an antigenic peptide attached to a specialized presenting molecule on a cell. When T cells are activated, some destroy target cells that present a particular antigenic peptide. Others can proliferate and secrete chemical messengers, called cytokines (discussed next), that induce other cells to perform a function. T cells owe their name to the thymus, the organ where these particular cells mature (Figure 17.1). Once mature, T cells are found in the same places as B cells—primarily in the blood and lymphoid organs. Cellular immune responses focus on recognizing antigens that have already entered a cell. This immunity is generally best at fighting viruses and some intracellular bacteria such as Listeria monocytogenes or Mycobacterium leprae.

tissue repair

The final stage of inflammation is tissue repair, the process by which tissues replace dead or damaged cells (Figure 16.9c). Repair begins during the active phase of inflammation, but it cannot be completed until all harmful substances have been removed or neutralized at the site of injury. The ability to regenerate, or repair, depends on the type of tissue. For example, skin has a high capacity for regeneration, whereas cardiac muscle tissue has a low capacity to regenerate. A tissue is repaired when its stroma or parenchyma produces new cells. The stroma is the supporting connective tissue, and the parenchyma is the functioning part of the tissue. For example, the capsule around the liver that encloses and protects it is part of the stroma because it is not involved in the functions of the liver; liver cells (hepatocytes) that perform the functions of the liver are part of the parenchyma. If only parenchymal cells are active in repair, a perfect or near-perfect reconstruction of the tissue occurs. A familiar example of perfect reconstruction is a minor skin cut, in which parenchymal cells are more active in repair. However, if repair cells of the stroma of the skin are more active, scar tissue is formed. As noted earlier, some microbes have various mechanisms that enable them to evade phagocytosis. Such microbes often induce a chronic inflammatory response, which can result in significant damage to body tissues. The most significant feature of chronic inflammation is the accumulation and activation of macrophages in the infected area. Cytokines released by activated macrophages induce fibroblasts in the tissue stroma to synthesize collagen fibers. These fibers aggregate to form scar tissue, a process called fibrosis. Because scar tissue is not specialized to perform the functions of the previously healthy tissue, fibrosis can interfere with the normal function of the tissue.

valence

The number of antigen-binding sites on an antibody For example, most human antibodies have two binding sites; therefore, they are bivalent.

classes of T cells

There are classes of T cells that have different functions, rather like the classes of immunoglobulins. As mentioned previously, T helper cells (TH cells) cooperate with B cells in the production of antibodies, mainly through cytokine signaling. For their role in cellular immunity, T cells interact more directly with antigens. T cells are also classified by certain glycoproteins on their cell surface called clusters of differentiation, or CD. These are membrane molecules that are especially important for adhesion to receptors. The CDs of greatest interest are CD4 and CD8; T cells that carry these molecules are named CD4+ and CD8+ cells, respectively. (For the importance of these molecules in HIV infection, see Figure 19.14 on page 545.) T helper cells are classified as CD4+, which bind to MHC class II molecules on B cells and other APCs. CTL cells are classified as CD8+, which bind to MHC class I molecules. T cells that have not encountered a pathogen are called naïve. After contact with a pathogen, the T cell is activated and can form effector and memory cells.

lymphatic vessels

These vessels, like veins, have one-way valves to keep lymph flowing in one direction only. At intervals along the lymphatic vessels, lymph flows through bean-shaped lymph nodes All lymph eventually passes into the thoracic (left lymphatic) duct and right lymphatic duct and then into their respective subclavian veins, where the fluid is now called blood plasma. The blood plasma moves through the cardiovascular system and ultimately becomes interstitial fluid between tissue cells, and another cycle begins.

results of the antigen- antibody interaction

When an antibody encounters an antigen for which it is specific, their binding forms an antigen-antibody complex. The strength of the bond between antigen and antibody is called affinity. the closer the physical fit between antigen and antibody, the higher the affinity. Antibodies tend to recognize the amino acid sequence of the antigen's epitope, giving specificity to the antigen-antibody interaction. Antibodies can distinguish between minor differences in the amino acid sequence of a protein and even between two amino acid isomers Clinically speaking, this means that antibodies can be used in diagnostic tests to differentiate between hepatitis B and hepatitis C viruses and between different strains of bacteria. The antibody molecule itself is not damaging to the antigen. the binding marks foreign cells and molecules for destruction or neutralization by phagocytes and complement. Foreign organisms and toxins are rendered harmless by several mechanisms These are agglutination, opsonization, neutralization, antibody-dependent cell- mediated cytotoxicity, and activation of complement

activation and clonal expansion of antibody producing cells(APCs)

When an antigen-presenting cell makes contact with an antigen that can combine with its particular receptor, the APC and antigen bind. The APC then internalizes the antigen and digests it. Next, the APC displays digested antigen fragments on its surface by combining them with its major histocompatibility complex (MHC),

actions of phagocytic cells

When an infection occurs, both granulocytes (especially neutrophils, but also eosinophils) and monocytes migrate to the infected area. These leave the blood and migrate into tissues where they enlarge and develop into macrophages. Some macrophages, called fixed macrophages, or histiocytes are resident in certain tissues and organs of the body. Fixed macrophages are found in the liver (Kupffer's cells), lungs (alveolar macrophages), nervous system (microglial cells), bronchial tubes, spleen (splenic macrophages), lymph nodes, red bone marrow, and the peritoneal cavity surrounding abdominal organs (peritoneal macrophages). Other macrophages are motile and are called free (wandering) macrophages, which roam the tissues and gather at sites of infection or inflammation. The various macrophages of the body constitute the mononuclear phagocytic (reticuloendothelial) system

responses on the innate immune system

activated by protein receptors in the plasma membranes of defensive cells toll-like receptors(TLRs)-attach to various components commonly found on pathogens that are called pathogen-associated molecular patterns (PAMPs) can also attach to fungi and parasites **Examples include the lipopolysaccharide (LPS) of the outer membrane of gram-negative bacteria, the flagellin in the flagella of motile bacteria, the peptidoglycan in the cell wall of gram-positive bacteria, the DNA of bacteria, and the DNA and RNA of viruses.**

two types of immunity

adaptive innate

chapter 17: adaptive immunity, specific defenses of the host

adaptive immunity is designed to recognize self from nonself, and it mounts reactions that are specific to the particular substance or pathogen at hand. The cells and chemical factors involved in adaptive immunity come into play when first- and second-line defenses of the innate system fail. The first time these cells and chemicals encounter a pathogen, responses can take days or longer to develop. However, the adaptive immune system also has a memory component, which engages future defenses against the same pathogen much more quickly. Adaptive immunity is described as a dual system, with humoral and cellular components. Humoral immunity primarily involves B cells and neutralizes threats outside human cells. Cellular immunity primarily involves T cells and deals with threats inside cells. Both involve specialized immune cell receptors that recognize antigens, followed by activation and production of cells, chemical messengers, and other factors that help destroy the antigen in question or allow the body to remember it later, for speedier future interactions.

immunity

also called resistance ability to ward off disease caused by microbes or their products and to protect against environmental agents such as pollen, chemicals, and animal dander

agranulocytes

also have granules in their cytoplasm, but the granules are not visible under the light microscope after staining. There are three different types of agranulocytes: monocytes, dendritic cells, and lymphocytes.

aggutination

antibodies cause antigens to clump together. For example, the two antigen-binding sites of an IgG antibody can combine with epitopes on two different foreign cells, aggregating the cells into clumps that are more easily ingested by phagocytes. Because of its more numerous binding sites, IgM is more effective at cross-linking and aggregating particulate antigens IgG requires 100 to 1000 times as many molecules for the same results.

IgD

antibodies make up only about 0.02% of the total serum antibodies. Their structure resembles that of IgG molecules. found in blood, lymph, and particularly on the surfaces of B cells. Serum IgD has no well-defined function; on B cells it assists in the immune response.

antibodies

are compact, relatively soluble proteins. They are designed to recognize and bind to a specific antigen. Antibodies are either secreted by plasma cells or attached to the cell membrane of a B cell. Each antibody has at least two identical antigen-binding sites that bind to identical epitopes.

activated fixed macrophages

secrete cytokines, which bring about vasodilation and increased permeability. Vasodilation and the increased permeability of blood vessels also help deliver clotting elements of blood into the injured area.

probiotics

are live microbial cultures applied to or ingested that are intended to exert a beneficial effect. Probiotics may be administered with prebiotics, which are chemicals that selectively promote the growth of beneficial bacteria. If lactic acid bacteria (LAB) colonize the large intestine, the lactic acid and bacteriocins they produce can inhibit the growth of certain pathogens. Several studies have shown that ingesting certain LAB can alleviate diarrhea and prevent colonization by Salmonella enterica during antibiotic therapy. Researchers are also testing the use of LAB to prevent surgical wound infections caused by S. aureus and vaginal infections caused by E. coli. In a Stanford University study, HIV infection was reduced in women treated with LAB that were genetically modified to produce CD4 protein that binds to HIV. Results of several studies suggest that giving probiotics with antibiotics reduces the risk of developing Clostridium difficile-associated diarrhea. However, probiotics may not always work. A recent French study found that although use of probiotics reduced incidence of pneumonia acquired in intensive care units (ICUs) and length of ICU stay, probiotics did not significantly reduce hospital mortality rates.

monocytes

are not actively phagocytic until they leave circulating blood, enter body tissues, and mature into macrophages In fact, the proliferation of lymphocytes is one factor responsible for the swelling of lymph nodes during an infection. As blood and lymph that contain microorganisms pass through organs with macrophages, the microorganisms are removed by phagocytosis. Macrophages also dispose of worn out blood cells.

t cells and b cells

are not usually phagocytic but play a key role in adaptive immunity They occur in lymphoid tissues of the lymphatic system and also circulate in blood. During many kinds of infections, especially bacterial infections, the total number of white blood cells increases as a protective response to combat the microbes; this increase is called leukocytosis. During the active stage of infection, the leukocyte count might double, triple, or quadruple, depending on the severity of the infection. Diseases that might cause such an elevation in the leukocyte count include meningitis, infectious mononucleosis, appendicitis, pneumococcal pneumonia, and gonorrhea. Other diseases, such as salmonellosis and brucellosis, and some viral and rickettsial infections may cause a decrease in the leukocyte count, called leukopenia. Leukopenia may be related to either impaired white blood cell production or the effect of increased sensitivity of white blood cell membranes to damage by complement, antimicrobial serum proteins discussed later in the chapter. Leukocyte increase or decrease can be detected by a differential white blood cell count, which is a calculation of the percentage of each kind of white cell in a sample of 100 white blood cells. The percentages in a normal differential white blood cell count are shown in parentheses

cytokins

are proteins that regulate the intensity and duration of immune responses. recruit other macrophages and dendritic cells; as well as other defensive cells they isolate and destroy microbes as part of the inflammatory response activate the T cells and B cells involved in adaptive immunity

lymphatic vessels

begin as microscopic lymphatic capillaries located in spaces between cells

earwax

besides serving as a physical barrier, also functions as a chemical protectant. It is a mixture of secretions from glands producing earwax as well as from the sebaceous glands, which produce sebum. The secretions are rich in fatty acids, giving the ear canal a low pH, between 3 and 5, which inhibits the growth of many pathogenic microbes. Earwax also contains many dead cells from the lining of the ear canal.

First line defense

block entry through inside borders and outside borders: -physical -chemical -biological barriers 1. skin -provides a physical barrier to the entrance of microbes -acid pH discourages the growth of organisms -sweat,oil, and fatty acid secretions kill many bacteria 2. mucous membranes 3.antimicrobial substances 4.normal flora

first line defense

block/neutralize entry

blood cells

blood cells originate from hematopoeitic stem cells in the bone marrow in a process called hematopoiesis **3 general categories from hematopoiesis - RBCs - platelets -WBCs always found in normal blood move around the body can move against flow of blood or lymph to reach infection site can move through walls of capillaries(diapedesis/emigration/extravasation) to enter infected tissues some reside in specific tissues

super system

both adaptive and innate combined produce a combined response that is more effective that either component produced separately

IgM

class (the M refers to macro, reflecting their relatively large size) make up 6% of the antibodies in serum. IgM has a pentamer structure, with five monomers held together by a polypeptide called a joining (J) chain. The large size of the molecule prevents IgM from moving about as freely as IgG does, so IgM antibodies generally remain in blood vessels and do not enter surrounding tissues or cross the placenta. IgM is the predominant type of antibody involved in the response to the ABO blood group antigens on the surface of red blood cells. It is much more effective than IgG in causing the clumping of cells and viruses and in reactions involving the activation of complement. appears first in response to a primary infection and is relatively short-lived makes it uniquely valuable in diagnosing disease. If high concentrations of IgM against a pathogen are detected in a patient, it is likely that the symptoms observed are caused by that pathogen. The detection of IgG, which is relatively long-lived, may indicate only that immunity against a particular pathogen was acquired in the more distant past.

IgE

class where shown to be potent inducers of erythema (superficial reddening or rash of the skin). IgE molecules are slightly larger than IgG molecules; they constitute only 0.002% of the total serum antibodies. IgE molecules bind tightly by their Fc (stem) regions to receptors on mast cells and basophils, specialized cells that participate in allergic reactions When an antigen such as pollen links with the IgE antibodies attached to a mast cell or basophil, that cell releases histamine and other chemical mediators. These chemicals provoke a response—for example, an allergic reaction such as hay fever. the response can be protective as well, for it attracts complement and phagocytic cells. This is especially useful when the antibodies bind to parasitic worms. The concentration of IgE is greatly increased during some allergic reactions and parasitic infections, which is often diagnostically useful.

major histocompatibility complex (MHC),

collection of glycoproteins embedded in the plasma membrane. Class I MHC are found on all mammalian nucleated cells. Their presence identifies a cell as "self," preventing the immune system from making antibodies that would be harmful to our own tissues. Class II MHC are found on APCs (B cells, macrophages, and dendritic cells).

antimicrobial substances

complement system, interferons, iron-binding proteins, and antimicrobial peptides.

mucous membranes

consist of an epithelial layer and an underlying connective tissue layer. line the entire gastrointestinal, respiratory, and genitourinary tracts. The epithelial layer of a mucous membrane secretes a fluid called mucus, a slightly viscous (thick) glycoprotein produced by goblet cells of a mucous membrane. Among other functions, mucus prevents the tracts from drying out. Some pathogens that can thrive on the moist secretions are able to penetrate the membrane if the microorganism is present in sufficient numbers. Treponema pallidum is such a pathogen. This penetration may be facilitated by toxic substances produced by the microorganism, prior injury by viral infection, or mucosal irritation.

haptens

low-molecular-mass compounds foreign substance that has a low molecular mass is often not antigenic unless it is attached to a carrier molecule. Once an antibody against the hapten has been formed, the antibody will react with the hapten independent of the carrier molecule. Penicillin is a good example of a hapten. *This drug is not antigenic by itself, but some people develop an allergic reaction to it. (Allergic reactions, are a type of hypersensitivity reaction that occurs when the immune system reacts to something that is normally nonpathogenic, such as pollen.) In these people, when penicillin combines with host proteins, the resulting combined molecule initiates an immune response. This concept has therapeutic applications. *Conjugated vaccines, which combine an antigen with a protein, work in the same fashion

the complement system

consists of over 30 proteins produced by the liver that circulate in blood serum and within tissues throughout the body. (See the box on page 470.) The system is so named because it "completes," or enhances, cells of the immune system in destroying microbes. The complement system is not adaptable, never changing over a person's lifetime. Therefore it is considered part of the innate immune system. However, it can be recruited into action by the adaptive immune system. This is another example of the cooperation between the innate and adaptive immune systems. Together, proteins of the complement system destroy microbes by cytolysis, opsonization, and inflammation (see Figure 16.12), and they also prevent excessive damage to host tissues. Complement proteins are inactive until split into fragments (products), which activates them. Activated fragments carry out the destructive actions. Complement proteins are usually designated by an uppercase letter C and are numbered C1 through C9, named for the order in which they were discovered. Activated fragments are indicated by lowercase letters a and b. For example, inactive complement protein C3 is split into activated fragments, C3a and C3b. Complement proteins act in a cascade, where one reaction triggers another, which in turn triggers another. More product is formed with each succeeding reaction in the cascade, amplifying the effects. The cascade of complement proteins that occurs during an infection is called complement activation. It may occur in three pathways that end in the activation of C3.

spleen

contains lymphocytes and macrophages that monitor the blood for microbes and secreted products such as toxins, much like lymph nodes monitor lymph.

humoral immunity

derives from the word humors, an ancient name for body fluids such as blood, phlegm, black bile, and yellow bile. Humoral immunity describes immune actions taking place in these extracellular fluids, brought about by protective molecules called antibodies. Another term for antibody is immunoglobulin (Ig). Antibodies recognize and combat foreign molecules called antigens. Humoral immunity involves B lymphocytes, more commonly known as B cells. Immunoglobulins corresponding to specific antigens coat the surfaces of B cells. Activated B cells secrete the same specific immunoglobulin that reacts with a particular antigen component of a virus, bacterium, toxin, or other extracellular material in body tissue fluids and blood. Because humoral immunity fights invaders outside cells, efforts tend to focus on bacteria that live extracellularly (as well as their toxins) and on viruses before they penetrate a target cell. B cells were named for the bursa of Fabricius, the specialized organ of birds where researchers first observed these cells. In humans, lymphocytes are initially produced in the fetal liver. By about the third month of fetal development, the site of B cell creation and maturation (known as schooling) becomes the red bone marrow. Once mature, B cells are found primarily in the blood and lymphoid organs.

dendritic cells

have long extensions called dendrites (Figure 17.10) because they resemble nerve cell dendrites. Dendritic cells are the main APCs that induce immune responses by T cells. Dendritic cells in the skin and genital tract are called Langerhans cells or Langerhans DCs. Other dendritic cell populations are found in the lymph nodes, spleen, thymus, blood, and various tissues—except the brain. Dendritic cells that act as sentinels in these tissues engulf invading microbes, degrade them, and transfer them to lymph nodes for display to T cells located there.

hematopoietic cytokines

help control the pathways by which stem cells develop into red blood cells or different white blood cells Some of these are interleukins (mentioned above). Others are termed colony-stimulating factors (CSFs). An example is granulocyte colony-stimulating factor (G-CSF). This particular CSF stimulates the production of neutrophils from the granulocyte precursors. Another, granulocyte macrophage colony-stimulating factor (GM-CSF), is used therapeutically to increase the numbers of protective macrophages and granulocytes in patients undergoing red bone marrow transplants.

innate immune system

immediate non-specific immunity no learning process no memory

artificially acquired passive immunity

involves the injection of antibodies (rather than antigens) into the body. These antibodies come from an animal or a human who is already immune to the disease. This is used for postexposure prophylaxis from diseases such as rabies or in immunotherapy **When an individual is given artificially acquired passive immunity, it confers an immediate passive protection against the disease. However, although artificially acquired passive immunity is immediate, it is short-lived because antibodies are degraded by the recipient. The half-life of an injected antibody (the time required for half of the antibodies to disappear) is typically about 3 weeks.

gastric juices

is produced by the glands of the stomach. It is a mixture of hydrochloric acid, enzymes, and mucus. The very high acidity of gastric juice (pH 1.2-3.0) is sufficient to destroy bacteria and most bacterial toxins, except those of Clostridium botulinum and Staphylococcus aureus. However, many enteric pathogens are protected by food particles and can enter the intestines via the gastrointestinal tract. In contrast, the bacterium Helicobacter pylori neutralizes stomach acid, thereby allowing the bacterium to grow in the stomach. Its growth initiates an immune response that results in gastritis and ulcers.

naturally acquired passive immunity

is the transfer of antibodies from a mother to her infant. Maternal antibodies cross the placenta to the fetus (transplacental transfer). If the mother is immune to diphtheria, rubella, or polio, for example, the newborn will be temporarily immune to these diseases as well. Certain antibodies are also passed from the mother to her nursing infant in breast milk, especially in the first secretions, called colostrum. Passive immunity in the infant generally lasts only as long as the transmitted antibodies persist—usually a few weeks or months. These maternal antibodies are essential for providing immunity to the infant until its own immune system matures. Colostrum is even more important to some other mammals; calves, for example, do not have antibodies that cross the placenta and rely on colostrum ingested during the first day of life. Researchers often specify fetal calf serum for certain experimental uses because it does not contain maternal antibodies.

ciliary escalator

keep the mucus blanket moving toward the throat at a rat of 1 to 3 cm per hour coughing and sneezing speed up the escalator **Some substances in cigarette smoke are toxic to cilia and can seriously impair the functioning of the ciliary escalator by inhibiting or destroying the cilia.** **Mechanically ventilated patients are vulnerable to respiratory tract infections because the ciliary escalator mechanism is inhibited.** Microorganisms are also prevented from entering the lower respiratory tract by a small lid of cartilage called the epiglottis, which covers the larynx (voicebox) during swallowing. The external ear canal contains hairs and earwax (cerumen), which help prevent microbes, dust, insects, and water from entering the ear. What can happen if the ciliary escalator is inhibited?

protects eyes

lacrimal apparatus, a group of structures that manufactures and drains tears lacrimal glands, located toward the upper, outermost portion of each eye socket, produce the tears and pass them under the upper eyelid. From here, tears pass toward the corner of the eye near the nose and into two small holes that lead through tubes (lacrimal canals) to the nose. The tears are spread over the surface of the eyeball by blinking. Normally, the tears evaporate or pass into the nose as fast as they are produced. This continual washing action helps keep microorganisms from settling on the surface of the eye. If an irritating substance or large numbers of microorganisms come in contact with the eye, the lacrimal glands start to secrete heavily, and the tears accumulate more rapidly than they can be carried away. This excessive production is a protective mechanism because the excess tears dilute and wash away the irritating substance or microorganisms before infection can occur. **How does the lacrimal apparatus protect the eyes against infections?**

early stages of inflammation

microbial structures, such as flagellin, lipopolysaccharides (LPS), and bacterial DNA stimulate the Toll-like receptors of macrophages to produce cytokines, such as tumor necrosis factor alpha (TNF-α). In response to TNF-α in the blood, the liver synthesizes a group of proteins called acute-phase proteins

four types of adaptive immunity

naturally acquired active immunity naturally acquired passive immunity artificially acquired active immunity artificially acquired passive immunity

commensalism

one organism uses the body of a larger organism as its physical environment and may make use of the body to obtain nutrients. Thus in commensalism, one organism benefits while the other is unaffected. Most microbes that are part of the commensal microbiota are found on the skin and in the gastrointestinal tract. The majority of such microbes are bacteria that have highly specialized attachment mechanisms and precise environmental requirements for survival. Normally, such microbes are harmless, but they may cause disease if their environmental conditions change. These opportunistic pathogens include E. coli, S. aureus, S. epidermidis, Enterococcus faecalis, Pseudomonas aeruginosa, and oral streptococci.

tumor necrosis factor alpha (TNF-a)

originally earned its name because tumor cells were observed to be one of its targets. These important cytokines are a strong factor in inflammatory reactions of autoimmune diseases such as rheumatoid arthritis (page 537). Monoclonal antibodies (see pages 508-510) that block the action of TNFs are an available therapy for some of these conditions.

C3: inflammatory response(pg. 460-462)

protective biological response triggered by inflammatory mediators released by host cells in response to tissue damage or infection helps contain site of damage, localized response, eliminate invader, and restore tissue function results in pain, swelling, redness, heat, sometimes loss of function acute v.s. chronic inflammation

acute-phase protein

other acute-phase proteins are present in the blood in an inactive form and are converted to an active form during inflammation. Acute-phase proteins induce both local and systemic responses and include proteins such as C-reactive protein, mannose-binding lectin (page 465), and several specialized proteins such as fibrinogen for blood clotting and kinins for vasodilation. All of the cells involved in inflammation have receptors for TNF-α and are activated by it to produce more of their own TNF-α. This amplifies the inflammatory response. Unfortunately, excessive production of TNF-α may lead to disorders such as rheumatoid arthritis and Crohn's disease. Monoclonal antibodies are used therapeutically to treat such inflammatory disorders (see Chapter 18, pages 508-509). For purposes of our discussion, we will divide the process of inflammation into three stages: vasodilation and increased permeability of blood vessels, phagocyte migration and phagocytosis, and tissue repair.

immune system response chart

pathogen(virus, bacteria,fungi)- enter body first line defense(part 1): -skin -mucous membranes -antimicrobial -substances -normal microbiota/flora blood cells and cells of the immune system(part 2): -granulocytes -arganulocytes -cell communication: cytokins -detection systems:PRRs second line defense(part 3): -the complete system -phagocytosis -inflammatory response fever

Detection by pattern recognition receptors(PRRs)

pathogen-associated molecular patterns(PAMPs): microbial components that remind unchanged over the course of evolution -cell wall components(LPS, PG) -bacterial peptides(flagellin) -bacterial and viral DNA or RNA PAMPs can be detected as "non-self" by PRRs * sentinel cells of the innate immune system, triggering a response against pathogen.

lymphatic capillaries

permit interstitial fluid derived from blood plasma to flow into them, but not out. Within the lymphatic capillaries, the fluid is called lymph. Lymphatic capillaries converge to form larger lymphatic vessels

increased permeability

permits defensive substances normally retained in the blood to pass through the walls of the blood vessels and enter the injured area. The increase in permeability, which permits fluid to move from the blood into tissue spaces, is responsible for the edema (accumulation of fluid) of inflammation. The pain of inflammation can be caused by nerve damage, irritation by toxins, or the pressure of edema.

vagina secretions

play a role in antibacterial activity in two ways. Glycogen produced by vaginal epithelial cells is broken down into lactic acid by Lactobacillus spp. This creates an acidic pH (3-5) that inhibits microbes. Cervical mucus also has some antimicrobial activity.

Cytotoxic T Lymphocytes (CD8+ T Cells)

precursor T cytotoxic cells (CTLp) can differentiate into an effector cell called a cytotoxic T lymphocyte. Cytotoxic T lymphocytes, or CTLs, are not capable of attacking any target cell as they emerge from the thymus as CTLp cells. However, they quickly attain this capability. This differentiation requires sequential—and complex—activation of the CTLp by an antigen processed by an antigen-presenting cell and interaction with a T helper cell and costimulatory signals. The resulting CTL is an effector cell that has the ability to recognize and kill target cells that are considered nonself (see Figure 17.13). Primarily, these target cells are self-cells that have been altered by infection with a pathogen, especially viruses. On the infected cell's surface, they carry fragments of endogenous antigens that are generally synthesized within the cell and are mostly of viral or parasitic origin. Other important target cells are tumor cells (see Figure 19.12, page 542) and transplanted foreign tissue. Rather than reacting with antigenic fragments presented by an APC in complex with MHC class II molecules, the CTL recognizes endogenous antigens on the target cell's surface that are in combination with an MHC class I molecule. MHC class I molecules are found on nucleated cells; therefore, a CTL can attack almost any cell of the host that has been altered. In its attack, a CTL attaches to the target cell and releases a pore-forming protein, perforin. Pore formation contributes to the subsequent death of the cell and is similar to the action of the complement membrane attack complex described in Chapter 16 (see Figure 16.12a, page 466). Granzymes, proteases that induce apoptosis, are then able to enter through the pore. Apoptosis (a-pah-TO-sis; from the Greek for falling away like leaves) is also called programmed cell death. This is a necessary process in multicellular organisms.* Tracking the death of cells and determining whether the demise is natural or due to trauma or disease are important. If the cell's death is due to trauma or disease, then the body's defense and repair mechanisms mobilize. Programmed cell death is also an infection-fighting mechanism of last resort: if a cell cannot clear a pathogen any other way, it will die. This helps prevent spread of pathogens, particularly viruses, to nearby healthy cells. Cells that die from apoptosis first cut their genome into fragments, and the external membranes bulge outward in a manner called blebbing Signals are displayed on the cell's surface that attract circulating phagocytes to digest the remains before any significant leakage of contents occurs.

saliva

produced by the salivary glands helps dilute the numbers of microorganisms and wash them from the surface of the teeth and the mucous membrane of the mouth. This helps prevent colonization by microbes.

prostaglandins

substances released by damaged cells, intensify the effects of histamine and kinins and help phagocytes move through capillary walls. Despite their positive role in the inflammatory process, prostaglandins are also associated with the pain related to inflammation.

perspiration

sweat glands of the skin produce helps maintain body temperature, eliminates certain wastes, and flushes microorganisms from the surface of the skin. Perspiration also contains lysozyme, an enzyme capable of breaking down cell walls of gram-positive bacteria and, to a lesser extent, gram-negative bacteria Specifically, lysozyme breaks chemical bonds on peptidoglycan, which destroys the cell walls. Lysozyme is also found in tears, saliva, nasal secretions, tissue fluids, and urine, where it exhibits its antimicrobial activity. Alexander Fleming was studying lysozyme in 1928 when he accidentally discovered the antimicrobial effects of penicillin

adherence

the attachment of the phagocyte's plasma membrane to the surface of the microorganism or other foreign material. Adherence is facilitated by the attachment of pathogen-associated molecular patterns (PAMPs) of microbes to receptors, such as Toll-like receptors (TLRs), on the surface of phagocytes. The binding of PAMPs to TLRs not only initiates phagocytosis, but also induces the phagocyte to release specific cytokines that recruit additional phagocytes. adherence occurs easily, and the microorganism is readily phagocytized. Microorganisms can be more readily phagocytized if they are first coated with certain serum proteins that promote attachment of the microorganisms to the phagocyte. This coating process is called opsonization. The proteins that act as opsonins include some components of the complement system and antibody molecules

outcomes of complement activation

the classical, alternative, and lectin pathways result in complement cascades that activate C3. Activation of C3, in turn, can lead to cytolysis, opsonization, and inflammation.

opsonization

the coating of antigens with antibodies or complement proteins. This enhances ingestion and lysis by phagocytic cells. Antibody-dependent cell-mediated cytotoxicity resembles opsonization in that the target organism becomes coated with antibodies; **however, in this case the target cell is not engulfed but remains external to the phagocytic cell attacking it

Second line defense

the complement system- consists of a group of serum proteins can detect pathogenic components, and activate a cascade of events leading to immune response - phagocytosis: the ingestion of microbes by phagocytes -inflammation: the body's response to tissue damage and/or infection to help contain site of damage, localize response, eliminate invader, and restore tissue function -fever: an abnormally high body temp in response to infection, caused by pyrogens

C4: fever

the hypothalamus, temp-regulation center, is normally set at 37* C but raises during infection response to Pyrogens: - endogenous pyrogens such as cytokines, C5a -exogenous pyrogens such as LPS of Gram negative bacteria Moderate temperature rise increase rates of enzymes, enhances inflammatory response, phagocytic killing, multiplication of lymphocytes, production of interferons and antibodies, and release of leukocytes from bone marrow high temperature rise may compromise older people with medical conditions, can cause dehydration, seizure in children, delirium and coma. death occurs when the body reaches 45*C

lectin pathway

the most recently discovered mechanism for complement activation. When macrophages ingest bacteria, viruses, and other foreign matter by phagocytosis, they release cytokines that stimulate the liver to produce lectins, proteins that bind to carbohydrates,

epidermis

the outer, thinner portion, is in direct contact with the external environment. The epidermis consists of many layers of continuous sheets of tightly packed epithelial cells with little or no material between the cells.

3 categories

transportation regulation(homeostasis) protection

serial monitoring of white blood cells counts

used to monitor treatment for infants battling the bacterial infection pertussis. Rapidly rising high white blood cell counts have been shown to be associated with higher mortality among infants.