Pathology: study of disease
Etiology: cause of a disease
Pathogenesis: the manner in which a disease progresses
Infection: invasion or colonization of the body by microorganisms
Disease: any change from a state of health
Normal Flora (normal microbiota): microbes that are resident in a region of the body, but do not usually cause disease
- transient flora: appear briefly in a body region, then disappear
- microbial antagonism: normal flora help the host by preventing growth of other harmful microorganisms
o normal bacterial flora of the vagina maintain a low pH (3.5 - 4.5) that prevents growth of the yeast Candida albicans
o Streptococci in the mouth release compounds that inhibit growth of most gram-positive & gram-negative bacteria
o E. coli in the large intestine produces bacteriocins – proteins that inhibit growth of similar species (pathogenic Salmonella, Shigella)
o Normal flora of the large intestine prevent growth of Clostridium difficile (responsible for most GI tract infections following antibiotics)
- antibiotic therapy can diminish numbers of normal flora, increasing the probability of infection
Symbiosis: relationship between 2 organisms of different species
- mutualism: both organisms benefit
o E. coli in the large intestine synthesizes vitamin K & some B vitamins
- commensalisms: one organism benefits, the other is unaffected
o many of the normal microbiota are commensals (corynebacteria on the eye surface & saprophytic mycobacteria in the ear)
- parasitism: one organism benefits, the other is harmed
Opportunistic pathogens: do not ordinarily cause disease in their normal habitat, but may do so if conditions change
- example: infection of wound; infections in AIDS patients (Pneumocystis pneumonia caused by Pneumocystis carinii) due to immunosuppressed state
Robert Koch: helped establish the link between microorganisms & disease (germ theory of disease)
- showed that the bacterium Bacillus anthracis was always in the blood of anthrax patients, but not in the blood of healthy individuals
- developed a sequence of experimental steps to help determine the specific organism that causes a disease (Koch¹s postulates)
Koch¹s postulates: determine etiology of disease
- same pathogen must be present in all disease cases
- pathogen must be isolated from host & grown in culture
- pure pathogen isolated from culture must cause disease in healthy animal
- pathogen isolated from diseased animal must be original pathogen
- exceptions to Koch¹s postulates:
o some pathogens cannot be easily cultured (Treponema pallidum, which causes syphilis and Mycobacterium leprae, which causes leprosy)
§ also, ricketssias & viral pathogens require a host cell population
o some pathogens can cause several different disease states
§ Streptococcus pyogenes causes sore throat, scarlet fever, skin infections (erysipelas) and osteomyelitis
o some diseases can be caused by several different pathogens
§ nephritis, meningitis & pneumonia can each be caused by several different microorganisms
Classifying Infectious Diseases:
- symptoms: changes in body function that may accompany a disease; not easily observed (e.g.: pain & malaise)
- signs: objective, observable changes in a patient (e.g.: swelling, lesions)
- syndrome: a specific group of symptoms or signs that always accompany a given disease
- communicable disease: a disease that can be passed from one host to another
- contagious disease: a disease that can be easily passed from one host to another
- noncommunicable disease: cannot be spread from one host to another
- The occurrence of a disease:
o Incidence: the number of people in a population that develop a disease in a given period of time
o Prevalence: the number of people in a population that are affected by a disease in a given period of time (takes into account both old & new cases)
o sporadic disease: only occurs occasionally (e.g.: typhoid fever in US)
o endemic disease: disease constantly present in a population (e.g.: common cold)
o epidemic disease: disease acquired by many people in a population in a short time (e.g.: influenza)
o pandemic disease: worldwide epidemic disease (e.g.: influenza, perhaps AIDS)
- The severity or duration of a disease
o acute disease: develops rapidly but lasts a short time (e.g.: flu)
o chronic disease: develops slowly, lasts for a long period, & may be recurrent (e.g.: tuberculosis, mononucleosis, hepatitis B)
o subacute disease: intermediate between acute & chronic (e.g.: subacute sclerosing panencephalitis)
o latent disease: causative agent of disease remains dormant for long periods but become active to produce symptoms of disease (e.g.: shingles is caused by reactivation of a latent varicella-zoster virus - the same pathogen that causes chicken pox)
- The extent of host involvement
o local infection: limited to small area of body (e.g.: boils & abscesses)
o systemic infection: infection spread throughout body by blood or lymph (e.g.: measles)
o focal infection: migration of local infection to other site(s) (e.g.: oral cavity infections can migrate through blood to other tissues)
o bacteremia: bacteria in blood
o septicemia: multiplying bacteria in blood
o toxemia: toxins in blood (e.g.: tetanus toxins)
o viremia: viruses in blood
o primary infection: acute infection that causes initial illness
o secondary infection: caused by opportunistic pathogen following primary infection (Pneumocystis pneumonia as a consequence of AIDS/HIV infection)
o subclinical infection: infection that produces no noticeable illness (e.g.: infection by poliovirus & hepatitis A virus may not result in illness)
Patterns of disease:
- predisposing factor: makes the body more susceptible to disease
- development of disease:
o incubation period: time between initial infection & appearance of signs/symptoms
o prodromal period: development of mild symptoms immediately following incubation period
o period of illness: acute disease period, with overt signs/symptoms; if disease is not overcome, patient may die
o period of decline: signs & symptoms subside
o period of convalescence: body recovers; return to nondiseased state
Reservoir of infection: organism or object that provides a pathogen with adequate conditions for survival, multiplication & transmission
- human reservoirs (carriers): can transmit disease with or without being affected by disease (carriers important in transmission of AIDS, diphtheria, hepatitis, gonorrhea..)
- animal reservoirs (can cause zoonoses – primarily animal diseases that can be transmitted to humans)
o about 150 known zoonoses (e.g.: rabies, malaria, anthrax, parasitic worm infections...)
- nonliving reservoirs (soil & water)
o Clostridium species (C. botulinum, C. tetani) deposited by animal waste in soil
o water contaminated by human waste can carry organisms that cause GI tract diseases (e.g.: Salmonella typhi, Vibrio cholerae)
Transmission of disease:
- contact transmission:
o direct (person-to-person) (e.g.: influenza, hepatitis A, STDs)
o indirect (from nonliving object or fomite)
§ fomites include tissues, towels, bedding, eating utensils, toys, thermometers...
§ contaminated syringes serve as fomites in transmission of AIDS, hepatitis B
o droplet (mucus droplets or droplet nuclei from sneezing, etc.)
§ influenza, pneumonia, pertussis, etc. spread by droplets
- vehicle transmission: by medium (air, water, food)
- vectors: arthropods can carry pathogens
o biological transmission: from insect bite
o mechanical transmission: from contact with insect
- portals of exit: generally respiratory (mucus droplets) & GI tracts (feces, saliva); also urogenital tract (urine, secretions) & skin (wounds)
Nosocomial Infections: hospital-acquired infections
- about 5-15% of all hospitalized patients acquire nosocomial infections
- caused by opportunistic pathogens in compromised host (resistance to infection impaired by disease, therapy or burns)
- microorganisms in the hospital
o opportunistic drug-resistant gram-negative bacteria (Pseudomonas aeruginosa) are a frequent cause of nosocomial infections
o at one time, Staphylococcus aureus was primary cause of nosocomial infections
o gram-negative rods (E. coli, P. aeruginosa) later emerged as most common
o recently, antibiotic-resistant gram-positive bacteria (MRSA: methicillin-resistant S. aureus) have become more common causes of nosocomial infections
- normal microbiota can cause infection when introduced through surgery or catheterization
o urinary tract infections (UTIs), particularily catheter-associated UTIs, are among the most common nosocomial infections
§ common causes are E.coli, P. aeruginosa, C. albicans
o invasive procedures carry a great risk of infection
- hospital personnel major source of opportunistic pathogens, as well as other patients
- control: hand washing, sterile instruments, supplies, proper aseptic technique
Epidemiology: the study of when & where diseases occur & how they are transmitted in populations
- Descriptive Epidemiology: collect all data relevant to occurrence of disease under study (i.e.: information about individuals, time & place)
o Retrospective study: looks backward to cause & source of disease
o Prospective study: looks at development of disease in normal populations
- Analytical Epidemiology: analyzes a particular disease to determine its cause
o Case control method: compare normal individuals with individuals with the disease under study
o Cohort method: compares individuals that have had contact with the agent causing the disease with those who have not
- Case reporting provides data on incidence & prevalence to local, state & national health officials
- notifiable diseases: diseases physicians are required by law to report
- CDC (Centers for Disease Control & Prevention) issues the Morbidity & Mortality Weekly Report (MMWR) that contains information on morbidity & mortality for notifiable diseases
- morbidity: incidence of specific notifiable diseases
- mortality: the number of deaths from specific notifiable diseases
- morbidity rate: number of people affected by a disease in a given time period in relation to total population
- mortality rate: number of deaths resulting from a disease in a population in a given time period in relation to total population
Portals of entry (routes by which pathogens gain entry to the human body):
- mucous membranes: many pathogens penetrate mucous membranes of GI and respiratory tracts (also, genitourinary tract & conjunctiva)
o inhalation of pathogens through respiratory tract or ingestion of contaminated foods into GI tract most common
- skin: openings in skin (hair follicles, sweat gland ducts); some pathogens can grow on skin (fungi) or bore through skin (larvae of hookworm)
- parenteral route: microbes deposited directly into tissues beneath skin or mucous membranes when these barriers disrupted
o punctures, injections, bites, cuts, surgery can all establish parenteral routes
- preferred portal of entry: entry route required by some pathogens to cause disease
Numbers of invading microbes:
- LD50: lethal dose for 50% of hosts
- ID50: infectious dose for 50% of hosts
- the likelihood of disease increases as number of pathogens increases
- environmental conditions (pH, nutrients) can affect ID50
Adherence: adhesins or ligands on pathogen surface bind to receptors on host cell/tissue surface
- adhesins are glycoproteins or lipoproteins that may be located on glycocalyx or other structures (fimbriae) of pathogen
Bacterial pathogens:
- virulence: capacity of a microorganism to cause disease
- bacterial pathogens penetrate host defenses by:
o capsule: impairs phagocytosis (phagocytic cell can¹t adhere)
§ strains of Streptococcus pneumoniae with a capsule are virulent (those without a capsule are not due to phagocytosis)
§ some pathogens that produce capsules: Klebsiella pneumoniae, Haemophilus influenzae, Bacillus anthracis, Yersinia pestis
o cell wall components: M protein of cell wall of Streptococcus pyogenes resists phagocytosis
§ also, waxes of cell wall of Mycobacterium tuberculosis resist phagocytosis (M. tuberculosis can multiply inside phagocytes)
o enzymes:
§ leukocidins: destroy white blood cells (e.g.: staphylococci & streptococci)
§ hemolysins: lyse red blood cells (e.g.: staphylococci, streptococci & Clostridium perfringens)
· streptococci produce streptolysins (streptolysin-O and –S) that lyse red blood cells as well as white blood cells & other cells
§ coagulases: clot fibrinogen (some members of genus Staphylococcus)
§ kinases: break down fibrin & dissolve clots
· streptococci produce fibrinolysin, staphylococci produce staphylokinase
§ hyaluronidase: breaks down extracellular matrix (e.g.: some Clostridium)
§ collagenase: breaks down collagen (e.g.: some Clostridium)
o penetration into host cell cytoskeleton: Salmonella produce invasins that rearrange actin of cytoskeleton to allow entry into cell
- damage host cells by:
o direct damage: bacteria pathogen metabolism & multiplication damages/kills host cell; penetration of cell (by motility or enzymes) can damage cell
o toxins: poisonous substances; major source of damage to host cell
§ toxigenicity: capacity of microorganisms to produce toxins
§ toxemia: presence of toxins in the blood
§ exotoxins: proteins (often enzymes) produced inside bacteria (usually gram-positive) by growth & metabolism & released outside cell
· exotoxin genes are carried on plasmids or phages
· exotoxins destroy host cell structures or inhibit metabolism
· cytotoxins kill host cell or affect its functions (diphtheria toxin inhibits translation; erythrogenic toxins from S. pyogenes damage capillaries)
· neurotoxins interfere with transmission of nerve impulse (botulinum toxin causes paralysis & tetanus toxin causes convulsions of lockjaw)
· enterotoxins induce fluid of electrolyte loss from cells lining GI tract (cholera toxin, staphylococcal enterotoxin and heat-labile toxin from E. coli bind to cells, causes release of fluids & ions; leads to fluid & electrolyte loss)
· antitoxins: antibodies produced to exotoxins
§ endotoxins: lipopolysaccharides (lipid A of gram-negative outer membrane)
· released by bacterial cell death (antibiotics & antibodies)
· cause fever due to IL-1 interaction with ³thermostat² in hypothalamus, & septic shock by TNF induced reduction of blood pressure
· allow bacteria to cross blood-brain barrier
o plasmids carrying genes for antibiotic resistance, toxins, capsules or fimbriae
o lysogenic conversion of bacteria – bacteria may pick up virulence factors (toxins or capsules) from other bacteria through bacteriophage
Pathogenic properties of viruses:
- viruses avoid the host immune response: grow inside cells; interfere with cellular immunity (antigen processing)
o HIV hides its attachment sites from immune response & infects only CD4 T cells (primarily helper T cells)
- attachment sites for receptors on host cell
- cytopathic effects (CPE): visible signs of viral infection (cell division arrest, lysis, inclusion bodies, cell fusion, chromosomal or antigenic changes, & transformation (of host cell to cancer cell))
Pathogenic properties of fungi:
- some fungi have toxic metabolic products; chronic fungal infections can trigger an allergic response
- ergotism caused by a fungal toxin (ergot; similar to LSD)
- aflotoxin (produced by Aspergillus) has carcinogenic properties
- neurotoxins called mycotoxins produced by some mushrooms (Amanita)
Pathogenic properties of protozoans:
- several protozoans attach to & enter host cells (Plasmodium, Toxoplasma & Giardia)
- some protozoans (Plasmodium) can switch surface antigens (specific identifying plasma membrane proteins) to escape immune response
Pathogenic properties of helminths:
- can use host tissues for their own growth or produce large parasitic masses
o the roundworm Wuchereria bancrofti (causes elephantiasis) blocks lymphatic circulation
Pathogenic properties of algae:
- a few species of algae produce neurotoxins (dinoflagellates produce a neurotoxin called saxitoxin; people who feed on infected shellfish develop paralytic shellfish poisoning)
o red tides indicate dinoflagellate-infected waters
Chapter 16: Nonspecific Defenses of the Host
Nonspecific resistance: protect against any pathogen
Specific resistance: protect against particular pathogens
Skin & Mucous Membranes: first line of defense against microbes
- Mechanical factors: layering of skin (dermis & epidermis), closely packed cells of intact skin & waterproof keratin in outer epidermis provide a barrier to microbial entry
o Langerhans¹ cells: in epidermis; stimulate proliferation of immune cells
o mucous membranes: still layered, but less efficient protection
o perspiration washes microbes from skin surface
o lacrimal apparatus in eyes produce tears & salivary glands in mouth produce saliva that dilute & wash away irritating substances or microbes
o mucus of respiratory tract & GI tract trap microbes; in lower respiratory tract, mucus is propelled away from lungs by ciliated cells
o urine moves microbes away from urinary tract & vaginal secretions move microbes out of vagina
- Chemical factors:
o sebum produced by sebaceous glands contains unsaturated fatty acids (low pH) that inhibit growth of certain pathogens
o lysozyme - an enzyme that breaks down bacterial cell walls – is found in perspiration, tears, saliva, nasal secretions & tissue fluids
o gastric juice in stomach has low pH (1.2-3.0) that destroys most bacteria & their toxins (some bacteria can neutralize stomach acid)
o vaginal secretions also slightly acidic
o blood carries transferrins: inhibit bacterial growth by reducing amounts of available iron
Normal Microbiota: can prevent the growth of pathogens by competition for resources, production of toxic materials & altering conditions (pH, oxygen availability)
- normal microbiota in the vagina alter pH to prevent growth of the yeast Candida albicans
- E. coli in the large intestine produce bacteriocins to prevent growth of Salmonella & Shigella
- commensal microbiota in the skin & GI tract can be opportunistic pathogens if environmental conditions change (e.g.: E. coli & S. aureus)
Blood: consists of plasma (fluid) & formed elements (red blood cells, white blood cells & platelets)
- leukocytes or white blood cells divided into granulocytes (neutrophils, basophils & eosinophils) & agranulocytes (lymphocytes & monocytes)
- infection can result in leukocytosis (increase in leukocyte numbers) or leucopenia (decrease in leukocyte numbers)
Phagocytes:
- activated by bacterial components (lipid A) or cytokines
- wandering macrophages: derived from monocytes in blood
- fixed macrophages (histiocytes): located in specific tissues
- during bacterial infection, neutrophils are initially dominant phagocytes, then are replaced by scavenging macrophages
Phagocytosis: ingestion of microbes (bacteria) or particulate matter by a phagocytic cell (phagocytes)
- chemotaxis: phagocytes attracted to microbes
- adherence: phagocyte adheres to microbesŠ facilitated by opsonization (microbe coated with serum proteins)
- ingestion: pseudopods of phagocytes engulf microbe & enclose it in phagocytic vesicle (phagosome)
- digestion: phagosome fuses with lysosome & microbe is killed by enzymatic digestion & oxidation
- some microbes survive phagocytosis & may multiply within phagocyte (Coxiella burnetii)
- some pathohgens (HIV, Chlamydia, Mycobacterium, Leishmania) evade immune system by entering phagocytes, preventing formation of phagolysosome, multiply & lyse phagocytes
Inflammation: the response of the body to cell damage
- includes redness, pain, heat, swelling & may include loss of function
- inflammation destroys the injurious agent & removes it or walls it off, and then speeds repair of damaged tissues
- vasodilation: increase in diameter of blood vessels – increases blood flow to damaged area, & results in redness & heat
- increased permeability of blood vessels: allows defensive molecules to enter damaged site & results in swelling (edema)
- vasodilation & increased vascular permeability caused by chemicals released by damaged cells (histamine, kinins) & enhanced by prostaglandins
- blood clots forming around an abscess & prevent spread of infection
- phagocytes can stick to blood vessels (margination) & move through blood vessels (emigration or diapedesis)
- pus: accumulation of damaged tissue & dead microbes & leukocytes
- tissue repair: stroma (supporting tissue) or parenchyma (functioning tissue) produce new cells to replace damaged cells
o stromal repair by fibroblasts produces scar tissue
Fever: abnormally high body temperature in response to bacterial or viral infection
- can be induced by bacterial endotoxins & interleukin-1
- chill: indication of rising body temperature
- crisis or sweating: indicates a fall in body temperature
Antimicrobial substances:
- the complement system: a group of serum proteins that activate one another to destroy invading microbes
o complement activation: complement system activated byŠ
§ classical pathway: antigen-antibody interaction
§ alternative pathway: direct interaction of polysaccharides on the cell surface (of bacteria, fungi, red blood cells) with complement protein factors B, D & P (properidin)
o C1 binds to antibody-antigen complexes to activate C3
o C3 along with factor B, factor D & factor P bind to cell wall polysaccharides to activate C3b
o cytolysis: C3 activation can produce cell lysis (using membrane attack complex C5-C9), inflammation & opsonization
o complement is inactivated by regulatory proteins in host¹s blood
o deficiencies in complement proteins can lead to disorders & increased susceptibility of infection
§ deficiencies in C1, C2 or C4 cause collagen vascular disorders & hypersensitivity; deficiencies in C5-C9 result in increased susceptibility to Neisseria meningitides & N. gonorrhoeae infections
- interferons: a class of antiviral proteins produced by certain animal cells following infection that interfere with viral multiplication
- host-cell specific but not virus-specific
- 3 types of human interferons (IFNs): a-interferon, b-interferon, & g-interferon
o a-IFN & b-IFN induce uninfected cells to produce antiviral proteins (AVPs) to inhibit viral multiplication
o g-IFN activates neutrophils to kill bacteria
Immunity: a specific defensive response to invasion by foreign organisms or other substances
- antigens: provoke immune response
- immunity results from production of specialized lymphocytes & antibodies
Acquired Immunity: specific resistance to infection developed during the life of the individual
- Naturally acquired immunity: immunity resulting from infection (naturally acquired active immunity) or transfer of antibodies from mother to fetus or newborn (naturally acquired passive immunity)
- Artificially acquired immunity: immunity resulting from vaccination (artificially acquired active immunity) or injection of humoral antibodies (artificially acquired passive immunity)
o antiserum: serum containing antibodies
o antibodies found in gamma fraction of serum (from electrophoresis) called gamma globulin
Antigens (Immunogens): a chemical substance that causes the body to produce specific antibodies or sensitized T cells
- usually foreign substances (organic molecules from invading microbes)
- formed against specific regions on antigen called antigenic determinants
- hapten: low molecular weight substance that requires carrier to induce antibody formation
Antibodies (Immunoglobulins): proteins produced by B cells in response to an antigen & capable of specifically combining with that antigen
- antibody structure: most antibodies consist of 4 polypeptide chains (2 heavy chains & 2 light chains)
o each chain has a variable (V( region that binds antigen & a constant © region
o the Fc (crystallizable fragment) region of the constant region can attach to a host cell or complement
- 5 immunoglobulin (antibody) classes:
· IgD: B cell antigen receptor
· IgM: monomer & pentamer forms
o monomer – B cell antigen receptor
o pentamer – circulates in blood plasma; first Ig class secreted; potent agglutinating agent
· IgG: most abundant circulating antibody; protects against bacteria, viruses & toxins; fixes complement; primary antibody of primary & secondary responses; confers naturally acquired passive immunity
· IgA: monomer & dimer forms
o monomer: small amounts in plasma
o dimer: found in secretions (mucus, saliva, sweat intestinal juice, milk), helps to prevent pathogens from entering body
· IgE: normally rarely in plasma (levels rise during allergic reaction), secreted by plasma cells in skin, mucosae of digestive & respiratory tracts, & tonsils; when activated by antigen, binds to mast cells & basophils & causes release of histamine & other mediators of inflammation
B Cells & Humoral Immunity:
- B cells develop from stem cells in red bone marrow, & migrate to lymphoid organs such as the spleen & lymph nodes
- B cells exposed to free antigen become activated & differentiate into plasma cells that produce antibodies against the antigen
- B cells that bind antigen to their antigen receptors undergo clonal selection – form a clone of many cells that recognize the same antigen
o self-tolerance: B cell clones that recognize self-antigen undergo clonal deletion during fetal decvelopment
- Apoptosis: programmed cell death – rids the body of unneeded cells
o B cells that do not encounter antigen soon undergo apoptosis
- antibodies produced by plasma cells bind antigen at the antigen binding site – tags foreign cells & molecules for destruction by phagocytes & complement
o agglutination, opsonization, neutralization, antibody-dependent cell-mediated cytotoxicity & complement-mediated cell lysis
- antibody titer: amount of antibody in serum
o primary response: upon first exposure to antigen, antibody titer gradually rises then declines
o memory response: memory B cells allow a quick rise in antibody titer following reexposure to the antigen
- monoclonal antibodies: recognize 1 specific epitope (antigenic determinant) – synthesized using hybridoma (B cell from mouse spleen fused to a cancerous B cell)
T Cells & Cell-Mediated Immunity:
- cytokines: regulate immune cells – interleukins trigger differentiation & clonal selection of lymphocytes
- T cells develop from stem cells in the bone marrow & migrate tot the thymus where they mature
- Like B cells, T cells undergo clonal selection following binding antigen
o T cells bind antigen to their T cell receptor
o Some cells become memory T cells to facilitate rapid secondary response
- CD4 cells: have CD4 cell surface receptor; primarily helper T cells
- CD8 cells: have CD8 cell surface receptor; cytotoxic T cells & suppressor T cells
- T cell receptors interact with antigen bound to (presented by) HLA (human MHC) molecules expressed on the cell surface of antigen-presenting cells (APCs)
o APCs: include many cell types; primarily macrophages & dendritic cells
o the antigens bound to HLA molecules are usually peptide fragments from proteins (foreign or self) broken down within APCs
- Helper T cells: using cytokine signals, they induce cytotoxic T cell formation, activate macrophages, & induce antibody production by B cells
- Cytotoxic T cells: bind HLA-antigen complex on APCs with T cell receptor & destroy (lyse) the APC using perforin (protein that tears a hole in the plasma membrane)
Natural Killer (NK) Cells: destroy virus-infected and tumor cells nonspecifically
o important against helminthic parasites
Vaccines: a suspension of organisms or fractions of organisms that induce immunity
- attenuated whole-agent vaccines: use living, attenuated (weakened) microbes
- inactivated whole-agent vaccines: use killed (usually by formalin or phenol) microbes
- toxoids: inactivated toxins; vaccine directed at a pathogen¹s toxin
- subunit vaccines: use specific antigens of paqthogen that are most immunogenic (capable of generating an immune response)
- conjugated vaccines: capsular polysaccharides of pathogen are combined with proteins to increase immunogenicity
- nucleic acid vaccines (DNA vaccines): uses plasmid carrying gene from pathogen
- adjuvants: chemicals (e.g.: alum) added to vaccine to improve inmmunogenicity of antigen
Diagnostic Immunology: antibodies used to diagnose disease
- precipitation reactions: reaction of soluble antigen with IgG or IgM antibodies to form large aggregates called lattices
o immunodiffusion tests: precipitation tests carried out in agar
o immunoelectrophoresis: used to identify proteins precipitated with antibody (Western blot)
- agglutination reactions: antigens linked together by antibodies to form visible aggregates
o direct agglutination tests: use antibodies directed against large cellular antigens (surface receptors on red blood cells, bacteria & fungi)
§ hemagglutination: detects clumping of red blood cells
o indirect (passive) agglutination tests: use antibodies directed against soluble antigens adsorbed onto particles (latex spheres)
- neutralization reactions: detects neutralization – an antigen-antibody reaction in which the harmful effects of a bacterial exotoxin or a virus are inhibited by specific antibodies
- complement fixation reactions: used for antibodies that do not produce a visible reaction by other methods – detects amount of complement that is fixed (used up) following antigen-antibody interaction
- fluorescent antibody (FA) techniques: can be used to identify microbes in clinical specimens & detect a specific antibody in serum
o fluorescent dyes (e.g.: FITC) are combined with antibodies & fluoresce when exposed to UV light
o can detect cell surface antigens bound to FA using fluorescence-activated cell sorter (FACS)
o can detect soluble or cell surface antigen bound to FA using confocal microscope
- enzyme-linked immunosorbent assay (ELISA): detects antigen (direct) or antibody (indirect)
o secondary antibody is linked to enzyme that produces color or light reaction when exposed to substrate
Chapter 19: Disorders Associated with the Immune System
Hypersensitivity: an antigenic response beyond what is considered normal (allergy)
- anaphlaxis: reactions that occur following antigens combining with IgE
- Type I (anaphylactic) reactions: occurs within 30 minutes of reexposure to an allergen to which a person has been sensitized
o IgE binds mast cells or basophils & causes degranulation (release of granules) – histamine causes inflammation, & leukotrienes & prostaglandins cause smooth muscle contraction (spasms) & increased mucus secretion
o Systemic anaphlaxis: caused by sensitization to an allergen
§ anaphylactic shock from drug injections & snake venom
o Localized anaphylaxis: associated with ingested antigens (food or pollen)
§ asthma: allergic reaction that affects mainly the lower respiratory system
- Type II (cytotoxic) reactions: occurs 5-12 hours after reexposure to antigen
o antigen causes formation of IgM & IgG that bind to & destroy target cell using complement pathway
o most common in transfusion reactions against incompatible blood group antigens & Rh incompatibility
- Type III (immune complex) reactions: occurs 3-8 hours after reexposure to antigen
o antigen-antibody complexes form that cause damaging inflammation e.g.: glomerulonephritis)
- Type IV (cell-mediated) reactions: occurs 24-48 hours after reexposure to antigen
o antigens stimulate cytotoxic T cell formation that kill target cells
o examples are rejection of transplanted tissues, contact dermatitis (poison ivy; allergy to cosmetics, latex)
Autoimmunity: the immune system attacks self-antigens & causes damage to one¹s own organs
- result from loss of self-tolerance (normally T cells that target host cells are eliminated or inactivated during thymic development)
- antibodies or sensitized T cells react against a person¹s own tissue antigens
- Type I Autoimmunity: antibodies that attack self
o may be antibodies made against a foreign antigen (protein from invading virus) that resembles a self antigen
- Type II (Cytotoxic) Autoimmune Reactions: antibodies react with cell-surface antigens (receptors) without destruction of cells
o Graves disease: antibodies attach to thyroid-stimulating hormone (TSH) receptors on thyroid gland cells, resulting in increased thyroid hormone production
o Myasthenia gravis: antibodies bind acetylcholine (Ach) receptors at neuromuscular junctions, resulting in faulty muscle responses
- Type III (Immune Complex) Autoimmune Reactions: antibodies react with various self tissues, resulting in deposits of antigen-antibody complexes
o Systemic Lupus Erythematosus: antibodies appear to react with cellular DNA, resulting in various immune complexes (some in kidney glomeruli)
o Rhematoid arthritis): immune complexes of IgG, IgM & complement deposit in joints
- Type IV (Cell-Mediated) Autoimmune Reactions: T cells attack self cells
o Hashimoto¹s thyroiditis: thyroid gland destroyed
o Insulin-dependent diabetes mellitus: destruction of insulin-secreting cells of pancreas
Reactions related to Human Leukocyte Antigen (HLA)
- self antigens: antigens that are not immunogenic to an individual but strongly immunogenic to others
o MHC (major histocompatibility complex) proteins: self antigens involved in cellular immunity
· In humans, called HLA (human leukocyte antigen) molecules
· Class I MHC proteins: on surface of nearly all cells
· Class II MHC proteins: only on surface of professional antigen-presenting cells (APCs)
Reactions to Transplants & Prevention of Rejection: cytotoxic T cells will normally target & kill foreign tissue
- both ABO blood group antigens & MHC antigens are typed to match (slight mismatches in MHC antigens are often tolerable)
- immunosuppressive therapy kills activated & circulating immune cells (as well as other rapidly dividing cells)
- privileged site: sites where antibodies do not normally circulate (cornea of eye), and so are unlikely to reject a graft
- privileged tissue: tissue that will normally not be rejected (replacement of heart valve with pig heart valve)
Grafts:
- autograft: one¹s own tissue is grafted to another part of the body
- isograft: graft of tissue from a genetically identical individual (identical twin)
- allograft: grafts between people who are not identical twins
- xenograft: transplanted tissue or organs from animals
o hyperacute rejection: rejection due to antibodies developed during infancy to all distantly-related animals
Bone Marrow Transplants: replacement of bone marrow cells for immunodeficient or immunocompromised, or those with leukemia
- can result in graft-versus-host (GVH) disease (transplanted bone marrow attacks host cells)
- umbilical cord blood may be better approach – fewer immunocompetent cells
Immune Deficiencies: absence of a sufficient immune response
- congenital immune deficiencies: individuals born with a defective immune system (lack of B cells or thymus/T cells due to inheritance of a recessive trait)
o severe combined immunodeficiency syndrome (SCID): condition resulting from deficits in both T and B cells
§ can be caused by nonfunctional interleukin receptors, defective adenosine deaminase (toxic to T cells)
- acquired immune deficiency: caused by a variety of drugs, cancers or infective agents (viruses)
o acquired immunodeficiency syndrome (AIDS): infection with human immunodeficiency virus (HIV) destroys helper T cells
§ viral surface proteins target/bind to CD4 protein on helper T cells
§ if untreated, over time helper T cell populations diminish & the condition can be fatal due to any type of infection
§ treatments are available that inhibit viral replication/synthesis, but must be continuous as the virus is not eliminated by the treatment
§ since these treatments only prevent new viral production, new research is aimed at treatments to prevent viral binding to/entry into helper T cells & specific removal of infected T cells
The Immune System & Cancer:
- cancer cells are normal cells that have undergone ³transformation²Š they divide uncontrollably & produce tumor-associated antigens
- cytotoxic T cells can lyse & kill cancer cells that they recognize
- cancer cells may escape immune detection, suppress T cells or grow faster than the immune system can respond
Immunotherapy: the treatment of cancer by immunological means
- cytokines like tumor necrosis factor (TNF) are being tested as cancer treatments (TNF interferes with the blood supply to cancer cells)
- immunotoxins are toxic chemicals linked to antibodies that bind to cancer cell antigens
- cytotoxic T cells may also be developed to target specific cancer cell types
- tumor antigen vaccines may also be useful for some cancers
Acquired Immunodeficiency Syndrome (AIDS):
- AIDS is the final stage of HIV infection (takes about 10 years to progress from HIV infection to AIDS)
- HIV is a retrovirus with single-stranded RNA (multiple strands), the enzyme reverse transcriptase & a phospholipids envelope with spikes
- HIV spikes bind to CD4 & coreceptors on host cells (helper T cells, macrophages & dendritic cells)
- Viral RNA is reverse transcribed to DNA, which integrates into the host cell chromosome (can direct new viral synthesis or remain latent there)
- HIV evades the immune system in latency, in vacuoles, by using cell-cell fusion & by antigenic change
- Stages of HIV infection: categorized by symptoms (Category A (asymptomatic), Category B (select symptoms), Category C (AIDS indicator conditions))
- Additionally, a CD4 T cell count < 200 cells/mm3 is reported as AIDS
- Diagnoses: HIV antibodies used in ELISA & western blots
- HIV transmission: sexual contact, breast milk, contaminated needles, transplacental infection, artificial insemination & blood transfusion
- AIDS prevention: minimize transmission through use of condoms & sterile needles
- AIDS treatment: nucleotide analogs (AZT, ddI & ddC) inhibit reverse transcriptase; protease inhibitors block reverse transcriptase
o vaccine development difficult due to lack of nonhuman host
History of Chemotherapy:
- antimicrobial drug: chemical that destroys pathogens with minimal damage to host
- chemotherapeutic agents: chemicals that combat disease
o Paul Ehrlich developed concept of chemotherapy to treat microbial disease
- antibiotic: substance produced by a microorganism that in small amounts inhibits growth of another microorganism
o penicillin: first antibiotic; discovered by Alexander Fleming in 1929; first trials testing penicillin in 1940
The spectrum of Antimicrobial activity:
- narrow-spectrum drugs: affect only a select group of microbes (e.g.: only gram-positive bacteria)
- broad-spectrum drugs: affect a large number of microbes
- antimicrobial agents should not cause excessive harm to normal flora
- superinfections: pathogen develops resistance to drug or normally resistant microbiota multiply excessively
The action of antimicrobial drugs:
- bactericidal drugs: kill microorganisms
- bacteriostatic drugs: inhibit or slow growth of bacteria
Antibacterial antibiotics:
Inhibitors of cell wall synthesis:
- penicillins: antibiotics with a ß-lactam ring
- penicillinases (ß-lactamases): bacterial enzymes that destroy natural penicillins
- natural penicillins: produced by Penicillium
o effective against gram-positive cocci & spirochetes
- semisynthetic penicillins: made in lab by adding different side chains onto ß-lactam ring
o resistant to penicillinases & have a broader spectrum of activity
- synthetic penicillins: monobactams have only a single ring (instead of the ß-lactam double ring)
o monobactams only affect gram-negative bacteria
- cephalosporins: used against penicillin-resistant strains
- carbapenams: broad-spectrum ß-lactam combination
o primaxin® appears to be very effective; very broad spectrum
- bacitracin: affects primarily gram-positive bacteria (staphylococci & streptococci)
o polypeptide used topically to treat superficial infections
- vancomycin: may be used to kill penicillinase-producing staphylococci
o glycopeptide antibiotic; used to treat penicillin-resistant Staphylococcus aureus infections
o relatively toxic with narrow activity range
o streptogramins: inhibit protein synthesis; may be used to kill vancomycin-resistant bacteria (expensive & high incidence of side effects)
- isoniazid (INH): inhibits mycolic acid synthesis in mycobacteria
o administered with rifampin & ethambutol to treat tuberculosis (TB)
Inhibitors of protein synthesis: react with 50S or 70S ribosome
- aminoglycosides (e.g.: streptomycin, neomycin, gentamicin): broad-spectrum, bacteriocidal
o used as an alternative treatment for TB
o can affect hearing by damaging auditory nerve; may damage kidneys
- tetracyclines: broad-spectrum for gram-positive & gram-negative bacteria, & rickettsias & chlamydias
o semisynthetic tetracyclines: doxycycline & minocycline; retained longer in body
o used to treat urinary tract infections, mycoplasmal pneumonia & chlamydial & rickettsial infections
o also used as alternative treatment for syphilis & gonorrhea
o can lead to GI tract upsets & fungal superinfections by suppressing normal flora
o not advised for children (causes teeth discoloration) & pregnant women (may cause liver damage)
- chloramphenicol: broad-spectrum bacteriostatic
o usually prepared synthetically
o suppresses bone marrow activity, affecting blood cell formation (may lead to aplastic anemia)
- macrolides (e.g.: erythromycin): possess macrocyclic lactone ring
o narrow-spectrum (gram-positive bacteria); often alternative to penicillin for streptococcal & staphylococcal infections in children (flavored preparation)
o erythromycin drug of choice for legionellosis, mycoplasmal pneumonia & several other infections
Injury to plasma membrane:
- polymixin B: effective against gram-negative bacteria; bactericidal
o used with bacitracin & neomycin in non-prescription topical preparations
Inhibitors of nucleic acid (DNA/RNA) synthesis:
- rifamycins: rifampin inhibits mRNA synthesis
o used to treat TB & leprosy
o can result in appearance or orange-red urine, feces saliva, sweat & tears
- quinolones & fluoroquinolones: inhibit DNA gyrase
o used to treat urinary tract infections
o may adversely affect cartilage development
Competitive inhibitors of synthesis of essential metabolites:
- sulfonamides: competitively inhibit folic acid synthesis
o TMP-SMZ: combination of trimethoprim & sulfamethoxazole
§ broad-spectrum (ineffective against pseudomonads)
§ competitively inhibits dihydrofolic acid synthesis (necessary for synthesis of proteins & nucleic acids in cells)
Antifungal Drugs:
- Polyenes: fungicidal; combine with plasma membrane sterols
o nystatin & amphotericin B
o used to treat systemic mycoses (histoplasmosis, coccidioidomycosis)
o administered in liposomes to limit kidney toxicity
- Azoles: interfere with sterol synthesis
o used to treat cutaneous & systemic mycoses
o ketoconazole used to treat dermatomyycoses
- Griseofulvin: interferes with eukaryotic cell division
o used to treat superficial fungal skin infections (hair & nails)
- Flucytosine: antimetabolite of cytosine; interferes with nucleic acid synthesis
o kidney & bone marrow toxicity
Antiviral Drugs:
- Nucleoside & nucleotide analogs: inhibit nucleic acid synthesis
o Acyclovir used to treat herpesvirus infections
o AZT, ddI & ddC used to treat HIV infections
- Protease inhibitors: block retroviral reverse transcriptase
o indinavir, saquinavir
- Alpha-interferons: inhibit spread of viral infections to new cells
Antiprotozoan drugs:
- Chloroquine & mefloquine used to treat malaria
- Quinacrine used to treat giardiasis
- Diiodohydroxyquin (iodoquinol) used to treat intestinal amoebic diseases
o optic nerve damage possible at high doses
- Metronidazole (Flagyl®): widely used to treat parasitic protozoa & obligately anaerobic bacteria
Antihelminthic drugs:
- Niclosamide & praziquantel used to treat tapeworm infections
o praziquantel used to treat several fluke-caused diseases (schistosomiasis)
- Mebendazole: disrupts microtubules; reduces worm motility
o
used to treat several of the most common intestinal helminthic
infections (ascariasis (roundworms), pinworms & whipworms)
Tests to guide Chemotherapy:
- Diffusion methods (Kirby-Bauer sensitivity test): filter paper disks impregnated with chemotherapeutic agents are overlaid on bacterial culture
o absence of microbial growth (zone of inhibition) indicates effectiveness of agent against that bacterium
- Broth Dilution tests: microorganism grown in liquid media with different concentrations of chemotherapeutic agent
o Minimun concentration of agent that kills bacteria is called minimum bactericidal concentration (MBC)