Compare the pathogens discussed in the previous chapters with zoonotic pathogens.
Microbiology
FUNDAMENTALS
A Clinical Approach
Third Edition
Marjorie Kelly Cowan
&
Heidi Smith
with
Jennifer Lusk
BSN RN CCRN
©McGraw-Hill Education. All rights reserved. Authorized only for instructor use in the classroom. No reproduction or further distribution permitted without the prior written consent of McGraw-Hill Education.
Chapter 14
Disorders in Immunity
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Learning Outcomes Section 14.1
Define immunopathology, and describe the two major categories of immune dysfunction.
Identify the four major categories of hypersensitivities, or overreactions to antigens.
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Immune Response: A Two-Sided Coin(1)
The human immune system is powerful and intricate, with the potential to cause injury and disease
Defects in the immune system can range from hay fever to dermatitis
Abnormal immune functions are involved in:
Asthma
Anaphylaxis
Diabetes
Rheumatoid arthritis
Graft rejection
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Immune Response(2)
Immunopathology: the study of disease states associated with the overreactivity or underreactivity of the immune response
Hypersensitivity or overreactivity:
Allergy and autoimmunity
Tissues are attacked by immunologic functions that cannot distinguish between self and nonself
Hyposensitivity or immunodeficiency:
Immune system is incompletely developed, suppressed, or destroyed
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Disorders of the Immune System
Courtesy Baylor College of Medicine, Public Affairs (primary); ©McGraw-Hill Education/Christopher Kerrigan, photographer (secondary); ©Pixtal/age fotostock (type I); ©Roc Canals Photography/Getty Images (type II); ©Dynamic Graphics/JupiterImages (type III); ©BW Folsom/Shutterstock (type IV)
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Hypersensitivity: Four Types
Type I: “common” allergy and anaphylaxis
Type II: IgG- and IgM-mediated cell damage
Type III: immune complex
Type IV: T-cell response
Type Systems and Mechanisms Involved Examples
I Immediate hypersensitivity IgE-mediated; involves mast cells, basophils, and allergic mediators Anaphylaxis, allergies such as hay fever, asthma
II Antibody-mediated IgG, IgM antibodies act upon cells with complement and cause cell lysis; includes some autoimmune diseases Blood group incompatibility; pernicious anemia; myasthenia gravis
III Immune complex-mediated Antibody-mediated inflammation; circulating IgG complexes deposited in basement membranes of target organs; includes some autoimmune diseases Systemic lupus erythematosus; rheumatoid arthritis; serum sickness; rheumatic fever
IV T-cell-mediated Delayed hypersensitivity and cytotoxic reactions in tissues; includes some autoimmune diseases Infection reactions; contact dermatitis; graft rejection
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Concept Check (1)
Which of the following is not a result of an abnormal or undesirable immune function?
Asthma
Anaphylaxis
Contact dermatitis
Fever
Lupus
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Learning Outcomes Section 14.2
Summarize genetic and environmental factors that influence allergy development.
Identify three conditions caused by IgE-mediated allergic reactions.
Identify the two clinical forms of anaphylaxis, explaining why one is more often fatal than the other.
List the three main ways to prevent or short-circuit type I allergic reactions.
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Type I Allergic Reactions: Atopy and Anaphylaxis
Allergy: exaggerated immune response that is manifested by inflammation
Allergens: innocuous substances that induce allergy in sensitive individuals
Atopy: chronic local allergy such as hay fever or asthma
Anaphylaxis: systemic, sometimes fatal, reaction that involves airway obstruction and circulatory collapse
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Who Is Affected?(1)
In the U.S., nearly half the population is affected by airborne allergens (dust, pollen, mold)
Type I allergies:
Majority are relatively mild
Asthma and some food allergies may require hospitalization and can cause death
Some allergies last for a lifetime, some are “outgrown,” and others develop later in life
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Who Is Affected?(2)
Generalized susceptibility to allergens is inherited, not the allergy to a specific substance
Genetic basis for atopy:
Increased IgE production
Increased reactivity of mast cells
Increased susceptibility of target tissue to allergic mediators
The prospect of a child developing an atopic allergy is 25% if parents are afflicted and 50% if siblings or grandparents are also afflicted
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Hygiene Hypothesis
The industrialized world has created a hygienic environment: antimicrobial substances, well-insulated homes, etc.
Immune systems need to be “trained” by interaction with microbes as we develop
It has been shown that children who grow up on farms have lower incidences of several types of allergies
Delivery by cesarean section and maternal history of allergy elevates childhood risk of allergy by a factor of eight
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Effect of Breast Feeding
Newborns breast fed exclusively for the first 4 months have a lower risk of asthma and eczema
Cytokines and growth factors in human milk act on the baby’s gut mucosa to induce tolerance to allergens
Human Microbiome Project: 600 species of bacteria can be transferred to infants through breast milk
Important role in the development of tolerance to foreign antigens
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Nature of Allergens
As with all antigens, allergens have certain immunogenic characteristics
Proteins are more allergenic than carbohydrates, fats, or nucleic acids
Some are haptens, nonprotein substances with a molecular weight of less than 1,000 that can form complexes with carrier molecules in the body
Organic and inorganic chemicals found in industrial and household products, cosmetics, food, and drugs are haptens
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Allergen Portals of Entry(1)
Mucosa of the gut and respiratory tract:
Thin, moist surface that is normally quite penetrable
Skin:
Dry, tough keratin is generally less permeable
Access occurs through tiny breaks, glands, and hair follicles
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Allergen Portals of Entry(2)
Inhalants: airborne environmental allergens such as pollen, house dust, dander, or fungal spores
Ingestants: allergens that enter by mouth that cause food allergies
Injectants: allergies triggered by drugs, vaccines, or hymenopteran (bee) venom
Contactants: allergies that enter through the skin; many are type IV (delayed) hypersensitivities
©RubberBall/Alamy Stock Photo
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Role of Mast Cells and Basophils in Type I Allergy
Mast cells are located in all connective tissues, but in particularly high concentrations in the lungs, skin, gastrointestinal tract, and genitourinary tract
Each cell carries 30,000 to 100,000 cell receptors that bind IgE and degranulate, releasing inflammatory cytokines
Symptoms of allergy are not caused by the direct action of allergen on tissues, but the physiological effects of mast-cell-derived allergic mediators on target organs
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Cytokines, Target Organs, and Allergic Symptoms(1)
Histamine:
Most profuse and fast-acting allergic mediator
Constricts smooth muscle in the small bronchi and intestine, causing labored breathing and increased intestinal motility
Relaxes vascular smooth muscle and dilates arterioles and venules, resulting in wheal-and-flare reactions in the skin and itching
Stimulates eosinophils to release inflammatory cytokines, escalating symptoms
Bradykinin:
Prolonged smooth muscle contraction of the bronchioles
Dilation of peripheral arterioles
Increased capillary permeability
Increased mucus secretion
Serotonin:
Effects complement those of histamine and bradykinin
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Cytokines, Target Organs, and Allergic Symptoms(2)
Leukotriene:
“Slow-reacting substance of anaphylaxis”
Induces gradual contraction of smooth muscle
Prolonged bronchospasm, vascular permeability, and mucus secretion of the asthmatic individual
Stimulates polymorphonuclear leukocytes
Prostaglandins:
Regulate smooth muscle contraction; stimulate uterine contractions during delivery
Vasodilation
Increased vascular permeability
Increased sensitivity to pain
Bronchoconstriction
Nonsteroidal anti-inflammatory drugs (NSAIDs) prevent the actions of prostaglandins
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Cellular Reactions During Type I Allergic Response(1)
©Ingram Publishing (headache); ©robeo/Getty Images (hives); ©Brand X Pictures (stomachache); ©Science Photo Library (asthma); ©Ingram Publishing (blowing nose)
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Cellular Reactions During Type I Allergic Response(2)
©Ingram Publishing (headache); ©robeo/Getty Images (hives); ©Brand X Pictures (stomachache); ©Science Photo Library (asthma); ©Ingram Publishing (blowing nose)
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Hay Fever
A generic term for allergic rhinitis
Seasonal reaction to inhaled plant pollen or molds, or a chronic, year-round reaction to airborne allergens or inhalants
Targets: respiratory membranes
Symptoms: nasal congestion; sneezing; coughing; profuse mucus secretion; itchy, red, and teary eyes; mild bronchoconstriction
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Asthma
Respiratory disease characterized by episodes of impaired breathing due to severe bronchoconstriction
Airways of asthmatics are extremely sensitive to minute amounts of inhalants, ingestants, or other stimuli, such as infectious agents
Symptoms range from labored breathing to fatal suffocation
Rales: clicking, bubbling, or rattling sounds in the lungs
Lungs are overreactive to leukotrienes and serotonin
Natural killer cells are also recruited and activated
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Atopic Dermatitis/Eczema
Intensely itchy inflammatory
condition of the skin
Sensitization occurs through
ingestion, inhalation, and skin
contact with allergens
Usually begins in infancy and is
characterized by reddened,
encrusted skin lesions on the face,
scalp, neck, and inner surfaces
of limbs and trunk
Progresses to a dry, scaly, thickened skin condition in adults
Lesions are itchy, painful, and predisposed to secondary bacterial infections
©Dr. P. Marazzi/Science Source (a); ©Biophoto Associates/Science Source (b)
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Food Allergy
Most common food allergens come from peanuts, fish, cow’s milk, eggs, shellfish, and soybeans
Mode of entry is intestinal
Symptoms include vomiting, diarrhea, and abdominal pain
Other manifestations include hives, rhinitis, asthma, and occasionally anaphylaxis
Hypersensitivity involves IgE and degranulation of mast cells, but not all reactions involve this mechanism
Care should be taken vaccinating individuals with egg allergies
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Drug Allergy
Drugs are foreign compounds capable of stimulating allergic reactions
Drug allergies are one of the most common side effects of treatment, affecting 5 to 10% of hospitalized patients
Reactions range from a mild rash to fatal anaphylaxis
Compounds implicated:
Antibiotics: penicillin
Synthetic antimicrobials: sulfa drugs
Aspirin
Opiates
Contrast dye used in X rays
Allergen is not the intact drug itself, but a hapten given off when the liver processes the drug
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Anaphylaxis: An Overpowering IgE-Mediated Allergic Reaction
Anaphylaxis/anaphylactic shock: swift reaction to allergens:
Cutaneous anaphylaxis: wheal-and-flare inflammatory reaction to the local injection of allergen
Systemic anaphylaxis: characterized by sudden respiratory and circulatory disruption that can be fatal within minutes due to airway blockage
Bee stings and injection of antibiotics or serum are most commonly implicated
Result of the sudden, massive release of chemicals into the tissues and blood, which act rapidly on target organs
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Diagnosis of Allergy: In Vitro Methods
Blood testing:
Radioallergosorbent (RAST) test: measures levels of IgE to specific antigens
Tryptase test: measures tryptase, an enzyme released by mast cells that increases during an allergic response
Differential blood cell count can reveal high levels of basophils and eosinophils
Leukocyte histamine-release test: measures the amount of histamine released from the patient’s basophils when exposed to a specific allergen
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Diagnosis of Allergy: In Vivo Methods
Skin testing: in vivo method to detect precise atopic or anaphylactic sensitivities
Skin is injected, scratched, or pricked with a small amount of pure allergen extract
A wheal-and-flare result 20 minutes after antigenic challenge is indicative of histamine release
The diameter of the wheal is measured and rated on a scale from 0 (no reaction) to 4 (greater than 15 mm)
©Southern Illinois University/Science Source (a)
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Treatment and Prevention of Allergy
Take drugs that block the action of lymphocytes, mast cells, or chemical mediators
Avoid the allergen, although this may be difficult in many instances
Desensitization: controlled exposure to the antigen through ingestion, sublingual absorption, or injection to reset the allergic reaction
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Concept Check (2)
Which of the following is not an IgE- and/or mast-cell-mediated allergic condition?
Asthma
Food allergy
Systemic lupus erythematosus
Allergy to penicillin
Eczema
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Learning Outcomes Section 14.3
List the three immune components causing cell lysis in type II hypersensitivity reactions.
Explain the role of Rh factor in hemolytic disease development and how it is prevented in newborns.
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Type II Hypersensitivities: Reactions That Lyse Foreign Cells
A complex group of syndromes that involve complement-assisted destruction (lysis) of cells by antibodies (IgG and IgM) directed against those cells’ surface antigens:
Transfusion reactions
Some types of autoimmunities
Alloantigens:
Molecules that differ in the same species that are recognized by the lymphocytes of the recipient
Not an immune dysfunction; the immune system is functioning normally by reacting to foreign cells in an organ or tissue transplant
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Rh Factor and Its Clinical Importance
First discovered in experiments exploring genetic relationships among animals:
Rabbits injected with the RBCs of rhesus monkeys produced an antibody that also reacted with human RBCs
This monkey antigen (Rh for rhesus) was present in about 85% of humans and absent in about 15%
Rh+ is a dominant gene; Rh- is recessive
The only way to develop antibodies against this factor is through placental sensitization or transfusion
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Hemolytic Disease of the Newborn and Rh Incompatibility
Placental sensitization occurs when
the mother is Rh- and the unborn child is Rh+:
Fetal RBCs may leak into the mother’s circulation during childbirth
when the placenta detaches.
Mother’s immune system detects
the foreign Rh factors on fetal RBCs and is sensitized to them by producing antibodies and memory B cells
Does not usually affect the first child because the process occurs so late in pregnancy
In the next pregnancy with an Rh+ fetus:
Fetal blood cells escape into maternal circulation late in pregnancy, eliciting a memory response.
Maternal anti-Rh antibodies cross the placenta, affix to fetal RBCs, and cause complement-mediated lysis.
Outcome is potentially fatal hemolytic disease of the newborn (HDN), also called erythroblastosis fetalis, characterized by severe anemia and jaundice
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Development and Control of Rh Incompatibility
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Preventing Hemolytic Disease of the Newborn
Once sensitization has occurred, all other Rh+ fetuses will be at risk
A careful history of the Rh– pregnant woman is needed:
Rh types of children and Rh status of the father are needed
If the father is Rh-, there is no risk
If the father is Rh+, the fetus may be Rh+.
RhoGAM antiserum:
Passive immunization for an Rh- mother with an Rh+ fetus
Immunoglobulin fraction of human anti-Rh serum prepared from pooled human sera
Injected at 28 to 32 weeks and again immediately after delivery
Sequesters fetal RBCs that have escaped into maternal circulation and prevents sensitization
Must be given with each pregnancy with an Rh+ fetus
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Concept Check (3)
When is the RhoGAM shot needed?
Rh+ mother, Rh+ fetus
Rh+ mother, Rh– fetus
Rh– mother, Rh– fetus
Rh– mother, Rh+ fetus
All of the choices are correct. The mother always responds to the fetus as foreign tissue and mounts an immune response against it.
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Learning Outcomes Section 14.4
Identify commonalities and differences between type II and type III hypersensitivities.
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Type III Hypersensitivities: Immune Complex Reactions
Involves the reaction of soluble antigen with antibody, and deposition of resulting complexes in various tissues in the body:
Involves the production of IgG and IgM antibodies
Also involves the activation of complement
Unlike type II hypersensitivities, antigens are not attached to the surface of a cell
Immune complex reaction: produces free-floating complexes that are deposited into tissues
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Mechanisms of Immune Complex Disease
Large quantities of antibodies are produced in response to an exposure to a profuse amount of antigen
Upon second exposure, antigen-antibody complexes are formed:
These recruit complement and neutrophils that would normally eliminate these complexes
In immune complex disease, complexes are deposited in the basement membranes of epithelial tissues:
Neutrophils release lysosomal granules that digest tissues and cause a destructive inflammatory condition
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Stages in the Course of Infection and Disease
Arthus reaction and serum sickness are associated with certain types of passive immunization
Similar to anaphylaxis in that all require sensitization and preformed antibodies
Differences from anaphylaxis:
Depend on IgG, IgM, or IgA rather than IgE
Require large doses of antigen
Symptoms are delayed hours to days
©Koshi Johnson/Medical Images (a); Courtesy Gary P. Wiliams, M.D. (b)
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Concept Check (4)
Which of the following antibody types is not involved in serum sickness or the Arthus reaction?
IgA
IgE
IgG
IgM
All of the choices are involved.
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Learning Outcomes Section 14.5
Describe one example of a type IV delayed hypersensitivity reaction.
List four classes of grafts, and explain how host versus graft and graft versus host diseases develop.
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Type IV Hypersensitivities: Cell-Mediated (Delayed) Reactions
Involves primarily the T-cell branch of the immune system
Results when T cells respond to antigens displayed on self tissues or transplanted foreign cells
Traditionally known as delayed hypersensitivity:
Symptoms arise one to several days following the second contact with antigen
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Infectious Allergy
Tuberculin reaction:
Acute skin inflammation at the tuberculin extract injection site
Mainstay diagnostic tool for TB infections
TH1 cells release cytokines that recruit macrophages, neutrophils, and eosinophils to the site, causing a red bump
Source: CDC/Donald Kopanoff (a)
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Contact Dermatitis
Caused by exposure to resins in poison ivy and poison oak, haptens in household and personal articles, and certain drugs
Requires a sensitizing dose followed by a provocative dose
Allergen penetrates the outer skin layers:
Processed by skin dendritic cells and presented to T cells
Subsequent exposures attract lymphocytes and macrophages
Cells release enzymes and cytokines that damage the epidermis in the immediate vicinity
©carroteater/Shutterstock (b)
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T Cells and Their Role in Organ Transplantation
Transplantation or grafting of organs and tissues is a common medical procedure
Although it is life-giving, it is plagued with the natural tendency of lymphocytes to seek out and destroy foreign antigens
The bulk of the damage that occurs in graft rejections are attributed to cytotoxic T-cell action
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Genetic and Biochemical Basis for Graft Rejection
MHC or HLA classes I and II markers are extremely important for recognizing self and in regulating the immune response
Although a person can exhibit variability in the pattern of these markers, the pattern is identical in different cells in the same person
Similarity is seen in related siblings and parents, but the more distant the relationship, the less likely that the MHC genes and markers will be alike
When a donor tissue (graft) displays surface molecules of a different MHC class, the T cells of the recipient will react to it as a foreign substance
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Host Rejection of Graft
Cytotoxic T cells of a host recognize foreign class I MHC markers on the surface of grafted cells
Release IL-2 as part of general immune mobilization
Helper and cytotoxic T cells bind to the grafted tissue and secrete lymphokines that begin the rejection process within 2 weeks of transplantation
Antibodies formed against the transplanted tissue contribute to damage
The result is destruction of the vascular supply and death of the graft
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Graft Rejection of Host
Some grafted tissues (bone marrow) contain indigenous populations of passenger lymphocytes
These lymphocytes create an immune response to the host
Graft versus host disease:
Graft attacks any host tissue bearing foreign MHC markers
Effects are systemic and toxic
Papular, peeling skin rash is the most common symptom; other organs are also affected
Occurs within 100 to 300 days of the graft
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Development of Incompatible Tissue Graft Reactions
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Classes of Grafts
Autograft: tissue transplanted from one site on an individual’s body to another site
Isograft: tissue from an identical twin is used
Allograft: exchanges between genetically different individuals belonging to the same species; the most common types of grafts
Xenograft: a tissue exchange between individuals of a different species
©iStockphoto/Getty Images
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Types of Transplants
Transplantation has been performed on every major organ, but most often involves the skin, liver, heart, kidney, coronary artery, cornea, and bone marrow
Sources of organs: live donors, the recently deceased, fetal tissues
Bone marrow transplantation:
Used in individuals with immune deficiencies, aplastic anemia, leukemia, and other cancers, and radiation damage
Patient is treated with chemotherapy and whole-body irradiation to destroy their own blood cells, preventing rejection
Closely matched donor marrow is infused
GVHD can still occur, and antirejection drugs may be necessary.
After transplantation, a recipient’s blood type may change to the blood type of the donor
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Concept Check (5)
Match the class of tissue graft with its description.
Allograft
Autograft
Isograft
Xenograft
Graft between identical twins
Graft between different species
Graft within an individual
Graft between non-identical twins
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Learning Outcomes Section 14.6
List at least three autoimmune diseases and the most important immunologic features in them.
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Inappropriate Response to Self: Autoimmunity
Autoimmune diseases: individuals actually develop hypersensitivity to themselves
Autoantibodies, T cells, or both, mount an abnormal attack against self antigens
Systemic: involves several major organs
Organ specific: involves only one organ or tissue
Disease Target Type of Hypersensitivity Characteristics
Systemic lupus erythematosus (SLE) Systemic III Inflammation of many organs; antibodies against red and white blood cells, platelets, clotting factors, nucleus DNA
Rheumatoid arthritis and ankylosing spondylitis Systemic II, III, and IV Vasculitis; frequent target is joint lining; antibodies against other antibodies (rheumatoid factor), T-cell cytokine damage
Graves’ disease Thyroid III Antibodies against thyroid-stimulating hormone receptors
Myasthenia gravis Muscle III Antibodies against the acetylcholine receptors on the nerve-muscle junction alter function
Type 1 diabetes Pancreas IV T cells attack insulin-producing cells
Multiple sclerosis Myelin II and IV T cells and antibodies sensitized to myelin sheath destroy neurons
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Genetic and Gender Correlation in Autoimmune Disease
Cases cluster in families, and even unaffected members tend to develop autoantibodies for the disease
Particular genes in class I and II MHC coincide with certain autoimmune diseases:
Rheumatoid arthritis and ankylosing spondylitis are more common in persons with B-27 HLA type
Molecular mimicry:
Microbial antigens bearing molecular determinants similar to human cells induce the formation of autoantibodies
One explanation for the pathology of rheumatic fever
Psoriasis flare-ups after strep throat infections may also be due to T cells primed to react with keratin in the skin
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Examples of Autoimmune Diseases: Systemic Autoimmunities
Systemic lupus erythematosus (SLE, or lupus):
Name originated from the characteristic butterfly-shaped rash that drapes across the nose and cheeks
Manifestations vary, but all patients develop autoantibodies against organs, tissues, or intracellular materials
Viral infection and loss of normal immune response suppression are suspected as causes
Rheumatoid arthritis:
Causes progressive, debilitating damage to the joints and at times to the lungs, eyes, skin, and nervous system
Autoantibodies form immune complexes that bind to the synovial membrane of joints, activating cytokine release by macrophages
Chronic inflammation develops, leading to scar tissue and joint destruction
Cytokines trigger additional type IV delayed hypersensitivity responses
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Common Autoimmune Diseases
©ISM/CID/Medical Images (a); ©Aaron Roeth Photography (b)
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Autoimmunities of the Endocrine Glands
Graves’ disease:
Attachment of autoantibodies to receptors on thyroxin-secreting follicle cells of the thyroid gland
Abnormal stimulation of these cells causes over- production of the thyroid hormone and the symptoms of hyperthyroidism
Type I diabetes:
Molecular mimicry has been implicated in the sensitization of cytotoxic T cells to attack and lyse insulin-producing beta cells
Reduced amount of insulin underlies the symptoms of this disease
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Neuromuscular Autoimmunities(1)
Myasthenia gravis:
Autoantibodies bind to receptors for acetylcholine, a neurotransmitter required for muscle stimulation
First effects felt in the muscles of the eyes and throat, but eventually progresses to complete loss of skeletal muscle function and death
Current treatment includes immunosuppressive drugs and therapy to remove autoantibodies from circulation
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Neuromuscular Autoimmunities(2)
Multiple sclerosis:
Paralyzing neuromuscular disease associated with lesions on the myelin sheath that surrounds neurons in the white matter of the central nervous system
T cell and autoantibody-induced damage compromise the capacity of neurons to send impulses
Symptoms include muscle weakness, tremors, difficulties in speech and vision, and paralysis
Possible association between infection with human herpesvirus 6
Treatments include immunosuppressants and interferon beta to alleviate symptoms and monoclonal antibody therapy toward certain T-cell antigens
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Concept Check (6)
Autoimmunities are caused by ____.
Genetic predisposition
X-chromosome inactivation in females
Molecular mimicry
Viral infection
All of the choices are correct.
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Learning Outcomes Section 14.7
Distinguish between primary and secondary immunodeficiencies, explaining how each develops.
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Immunodeficiency Diseases: Hyposensitivity of the Immune System
Occasionally, an individual is born with or develops weakened immune responses
Predominant consequences of immunodeficiencies are recurrent, overwhelming infections with opportunistic microbes
Primary diseases: present at birth (congenital), usually stemming from genetic errors
Secondary diseases: acquired after birth and caused by natural or artificial agents
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Primary Immune Deficiencies (Genetic)
B-cell defects (low levels of B cells and antibodies):
Agammaglobulinemia (X-linked, non-sex-linked)
Hypogammaglobulinemia
Selective immunoglobulin deficiencies
T-cell defects (lack of all classes of T cells):
Thymic aplasia (DiGeorge syndrome)
Combined B-cell and T-cell defects (usually caused by lack or abnormality of lymphoid stem cell):
Severe combined immunodeficiency (SCID) disease
Adenosine deaminase (ADA) deficiency
Complement defects:
Lacking one of C components
Hereditary angioedema associated with rheumatoid diseases
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Secondary Immune Deficiencies (Acquired)
From natural causes:
Infections (AIDS) or cancers
Nutrition deficiencies
Stress
Pregnancy
Aging
From immunosuppressive agents:
Irradiation
Severe burns
Steroids (cortisones)
Immunosuppressive drugs
Removal of spleen
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Primary Immunodeficiency Diseases
Often due to an inherited abnormality
In some diseases, the lymphocytes are absent, or present at low levels
In other diseases, the lymphocytes are present, but do not function normally
An individual can lack either B or T cells, or both
Some deficiencies can affect other cell functions as well
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Stages of Development and Functions of B and T Cells
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Clinical Deficiencies in B-Cell Development or Expression(1)
Genetic deficiencies in B cells usually result in abnormal immunoglobulin (Ig) expression:
In some cases, certain Ig classes are absent
In other cases, all levels of Ig are reduced
Agammaglobulinemia: absence of gamma globulin; it is very rare for Ig to be completely absent
Hypogammaglobulinemia: abnormally low levels of gamma globulin:
Recurrent, serious bacterial infections appear about 6 months after birth
Most common infection sites: lungs, sinuses, meninges, and blood
Current treatment is passive immunotherapy with immune serum globulin and continuous antibiotic therapy
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Clinical Deficiencies in B-Cell Development or Expression(2)
Lack of a particular class of immunoglobulin is a relatively common condition:
IgA deficiency is the most prevalent form
Individuals have normal quantities of B cells and other immunoglobulins
Lack protection against local microbial invasion of mucous membranes, suffer recurrent respiratory and gastrointestinal infections
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Clinical Deficiencies in T-Cell Development or Expression
Defects in T-cell development result in a broad spectrum of diseases:
Severe opportunistic infections
Cancer
More devastating than B-cell deficiencies, because T helper cells are required to assist in most specific immune functions
Abnormal development of the thymus: DiGeorge syndrome or thymic aplasia:
Congenital absence or immaturity of the thymus gland
Makes children highly susceptible to persistent infections by fungi, protozoa, and viruses
Vaccinations using attenuated microbes pose a danger and common childhood infections can be fatal
Patients typically have reduced antibody levels
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Severe Combined Immunodeficiencies (SCIDs)(1)
Most serious form of immunodeficiency:
Involve dysfunction in both lymphocyte systems
Some SCIDs are due to the lack of lymphocyte stem cells in the bone marrow; others are due to the dysfunction of B and T cells later in development
Infants with SCID usually develop candidiasis, sepsis, pneumonia, or systemic viral infections within days after birth
Two most common forms: Swiss-type agammaglobulinemia and thymic alymphoplasia:
Genetic defects in the development of the lymphoid cell line result in extremely low numbers of all lymphocyte types and poorly developed humoral and cellular immunity
Adenosine deaminase (ADA) deficiency: lymphocytes develop but a metabolic product builds up and selectively destroys them
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Severe Combined Immunodeficiencies (SCIDs)(2)
SCID children require rigorous aseptic techniques to protect them from opportunistic infections:
David Vetter: lived his life in a sterile plastic bubble
Only serious option for longtime survival is total replacement or correction of lymphoid cells:
Infants can benefit from fetal liver or stem cell grafts
X-linked and ADA types of SCID can be treated with gene therapy; insertion of normal genes to replace the defective genes
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Secondary Immunodeficiency Diseases(1)
Caused by one of four general agents:
Infection
Noninfection metabolic disease
Chemotherapy
Radiation
Most recognized infection-induced immunodeficiency is AIDS:
T helper cells, monocytes, macrophages, and antigen-presenting cells infected by HIV
Depletion of T helper cells and impairment of immune responses account for cancers and opportunistic infections caused by AIDS
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Secondary Immunodeficiency Diseases(2)
Cancers that target the bone marrow can be responsible for malfunction of humoral and cellular immunity:
Leukemia: cancer cells outnumber normal cells, displacing them from bone marrow and blood
Plasma cell tumors: produce large amounts of nonfunctional antibodies
Thymus tumors: cause severe T-cell deficiencies
An ironic outcome of lifesaving medical procedures is the suppression of the immune system:
Drugs that prevent graft rejection can also suppress beneficial immune responses
Radiation and anticancer drugs are damaging to the bone marrow and other body cells
©McGraw-Hill Education
Concept Check (7)
The most common deficiency in immunoglobulins is _____ deficiency.
IgA
IgD
IgE
IgG
IgM
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Appendix of Image Long Descriptions
©McGraw-Hill Education
Disorders of the Immune System – Appendix
Just as the system of T cells and B cells provides necessary protection against infection and disease, the same system can cause serious and debilitating conditions by overreacting or underreacting to antigens. Hyposensitivities include primary and secondary immunodeficiencies represented by a boy living in sterile bubble due to severe combined immunodeficiency and a person with AIDS, respectively. Hypersensitivities: Type I (immediate) is represented by a boy with hay fever; Type II (antibody-mediated) is represented by someone receiving a blood transfusion; Type III (immune complex) is represented by an elderly woman with arthritis; and Type IV (cell-mediated, cytotoxic) is represented by a photo of contact dermatitis.
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Allergen Portals of Entry(2) – Appendix
(a) Common inhalants, or airborne environmental allergens, include pollen and insect parts. (b) Common ingestants, allergens that enter by mouth, include red dye, peanuts, strawberries, and shrimp. (c) Common injectants, allergens that enter via the parenteral route include bee stings and penicillin. (d) Common contactants, allergens that enter through the skin include detergent, lotion, and latex gloves.
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Cellular Reactions During Type I Allergic Response – Appendix(1)
Type I allergic response. A) Sensitization/IgE production: 1) Sensitizing dose of allergen enters. 2) Lymphatic vessel carries allergen to lymph node. 3) In lymph, B cell recognizes allergen with help of TH cell. 4) B cell proliferates into plasma cells. 5) Plasma cells synthesize IgE. B) Subsequent exposure to allergen: 6) Then, IgE binds to mast cell surface receptors. 7) Allergen is encountered again. 8) Allergen attaches to IgE on mast cells. 9) Resulting in systemic distribution of allergic mediators in bloodstream.
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Cellular Reactions During Type I Allergic Response – Appendix(2)
Type I allergic response effects on tissues are due to prostaglandin which results in dilated blood vessels, constricted bronchioles, and increased sensitivity to pain (represented here as a headache); leukotriene which results in constriction of bronchioles and airway obstruction with mucus buildup, represented by a woman using an inhaler for asthma; and histamine, serotonin, and bradykinin resulting in increased blood flow, skin manifestations (represented by dilated blood vessels and a skin test for allergens), increased peristalsis of intestine, diarrhea, and vomiting, and increased mucus secretion.
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Atopic Dermatitis/Eczema – Appendix
(a) Vesicular, weepy, encrusted lesions are typical in afflicted infants. (b) In adulthood, lesions are more likely to be dry, scaly, and thickened.
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Diagnosis of Allergy: In Vivo Methods – Appendix
The forearm is mapped and then injected with a selection of allergen extracts. The allergist must be very aware of potential anaphylaxis attacks triggered by these injections. (a) Close-up of skin wheals showing a number of positive reactions (dark lines are measurer’s marks). (b) An actual skin test record for some common environmental allergens indicated which allergens or particles the person had no reaction, slight reaction, mid reaction, moderate reaction, or severe reaction to.
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Development and Control of Rh Incompatibility – Appendix
(a) A naturally occurring blood cell incompatibility results when an Rh positive fetus develops within an Rh negative mother. Initial sensitization of the maternal immune system occurs when fetal blood passes the placental barrier. In most cases, the fetus develops normally. However, a subsequent pregnancy with an Rh positive fetus results in a severe fetal hemolysis. (b) Control of incompatibility: Anti-Rh antibody (RhoGAM) can be administered to Rh negative mothers during pregnancy to help bind, inactivate, and remove any Rh factor that may be transferred from the fetus. In some cases, RhoGAM is administered before sensitization occurs.
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Development of Incompatible Tissue Graft Reactions – Appendix
Type IV reactions. Host versus Graft: Host TC cells (and macrophages recruited by TH cells to assist) attack grafted cells with foreign MHC-I markers. Graft versus Host: Passenger lymphocytes from grafted tissue have donor MHC-I markers; attack recipient cells with different MHC-I specificity.
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Common Autoimmune Diseases – Appendix
(a) Systemic lupus erythematosus. One symptom is a prominent rash across the bridge of the nose and on the cheeks. These papules and blotches can also occur on the chest and limbs. (b) Rheumatoid arthritis commonly targets the synovial membrane of joints. Over time, chronic inflammation causes thickening of this membrane, erosion of the articular cartilage, and fusion of the joint. These effects severely limit motion and can eventually swell and distort the joints.
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Stages of Development and Functions of B and T Cells – Appendix
Some types of severe combined immunodeficiency affect lymphoid stem cells from bone marrow. (Top) In DiGeorge syndrome a breakdown occurs between Pre-T cell and Thymus. In adenosine deaminase deficiency the breakdown occurs between T cell and cell-mediated immunity, resulting in recurrent fungal, protozoan, and viral infections. (Bottom) in congenital agammaglobulinemia the breakdown occurs between Pre-B cell and bone marrow. In hypogammaglobulinemia (immunoglobulin, ADA deficiencies) the breakdown occurs resulting in a lack of B regulatory cells and recurrent bacterial infections.
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©McGraw-Hill Education
Microbiology
FUNDAMENTALS
A Clinical Approach
Third Edition
Marjorie Kelly Cowan
&
Heidi Smith
with
Jennifer Lusk
BSN RN CCRN
©McGraw-Hill Education. All rights reserved. Authorized only for instructor use in the classroom. No reproduction or further distribution permitted without the prior written consent of McGraw-Hill Education.
Chapter 14
Disorders in Immunity
©McGraw-Hill Education
Learning Outcomes Section 14.1
Define immunopathology, and describe the two major categories of immune dysfunction.
Identify the four major categories of hypersensitivities, or overreactions to antigens.
©McGraw-Hill Education
Immune Response: A Two-Sided Coin(1)
The human immune system is powerful and intricate, with the potential to cause injury and disease
Defects in the immune system can range from hay fever to dermatitis
Abnormal immune functions are involved in:
Asthma
Anaphylaxis
Diabetes
Rheumatoid arthritis
Graft rejection
©McGraw-Hill Education
Immune Response(2)
Immunopathology: the study of disease states associated with the overreactivity or underreactivity of the immune response
Hypersensitivity or overreactivity:
Allergy and autoimmunity
Tissues are attacked by immunologic functions that cannot distinguish between self and nonself
Hyposensitivity or immunodeficiency:
Immune system is incompletely developed, suppressed, or destroyed
©McGraw-Hill Education
Disorders of the Immune System
Courtesy Baylor College of Medicine, Public Affairs (primary); ©McGraw-Hill Education/Christopher Kerrigan, photographer (secondary); ©Pixtal/age fotostock (type I); ©Roc Canals Photography/Getty Images (type II); ©Dynamic Graphics/JupiterImages (type III); ©BW Folsom/Shutterstock (type IV)
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Hypersensitivity: Four Types
Type I: “common” allergy and anaphylaxis
Type II: IgG- and IgM-mediated cell damage
Type III: immune complex
Type IV: T-cell response
Type Systems and Mechanisms Involved Examples
I Immediate hypersensitivity IgE-mediated; involves mast cells, basophils, and allergic mediators Anaphylaxis, allergies such as hay fever, asthma
II Antibody-mediated IgG, IgM antibodies act upon cells with complement and cause cell lysis; includes some autoimmune diseases Blood group incompatibility; pernicious anemia; myasthenia gravis
III Immune complex-mediated Antibody-mediated inflammation; circulating IgG complexes deposited in basement membranes of target organs; includes some autoimmune diseases Systemic lupus erythematosus; rheumatoid arthritis; serum sickness; rheumatic fever
IV T-cell-mediated Delayed hypersensitivity and cytotoxic reactions in tissues; includes some autoimmune diseases Infection reactions; contact dermatitis; graft rejection
©McGraw-Hill Education
Concept Check (1)
Which of the following is not a result of an abnormal or undesirable immune function?
Asthma
Anaphylaxis
Contact dermatitis
Fever
Lupus
©McGraw-Hill Education
Learning Outcomes Section 14.2
Summarize genetic and environmental factors that influence allergy development.
Identify three conditions caused by IgE-mediated allergic reactions.
Identify the two clinical forms of anaphylaxis, explaining why one is more often fatal than the other.
List the three main ways to prevent or short-circuit type I allergic reactions.
©McGraw-Hill Education
Type I Allergic Reactions: Atopy and Anaphylaxis
Allergy: exaggerated immune response that is manifested by inflammation
Allergens: innocuous substances that induce allergy in sensitive individuals
Atopy: chronic local allergy such as hay fever or asthma
Anaphylaxis: systemic, sometimes fatal, reaction that involves airway obstruction and circulatory collapse
©McGraw-Hill Education
Who Is Affected?(1)
In the U.S., nearly half the population is affected by airborne allergens (dust, pollen, mold)
Type I allergies:
Majority are relatively mild
Asthma and some food allergies may require hospitalization and can cause death
Some allergies last for a lifetime, some are “outgrown,” and others develop later in life
©McGraw-Hill Education
Who Is Affected?(2)
Generalized susceptibility to allergens is inherited, not the allergy to a specific substance
Genetic basis for atopy:
Increased IgE production
Increased reactivity of mast cells
Increased susceptibility of target tissue to allergic mediators
The prospect of a child developing an atopic allergy is 25% if parents are afflicted and 50% if siblings or grandparents are also afflicted
©McGraw-Hill Education
Hygiene Hypothesis
The industrialized world has created a hygienic environment: antimicrobial substances, well-insulated homes, etc.
Immune systems need to be “trained” by interaction with microbes as we develop
It has been shown that children who grow up on farms have lower incidences of several types of allergies
Delivery by cesarean section and maternal history of allergy elevates childhood risk of allergy by a factor of eight
©McGraw-Hill Education
Effect of Breast Feeding
Newborns breast fed exclusively for the first 4 months have a lower risk of asthma and eczema
Cytokines and growth factors in human milk act on the baby’s gut mucosa to induce tolerance to allergens
Human Microbiome Project: 600 species of bacteria can be transferred to infants through breast milk
Important role in the development of tolerance to foreign antigens
©McGraw-Hill Education
Nature of Allergens
As with all antigens, allergens have certain immunogenic characteristics
Proteins are more allergenic than carbohydrates, fats, or nucleic acids
Some are haptens, nonprotein substances with a molecular weight of less than 1,000 that can form complexes with carrier molecules in the body
Organic and inorganic chemicals found in industrial and household products, cosmetics, food, and drugs are haptens
©McGraw-Hill Education
Allergen Portals of Entry(1)
Mucosa of the gut and respiratory tract:
Thin, moist surface that is normally quite penetrable
Skin:
Dry, tough keratin is generally less permeable
Access occurs through tiny breaks, glands, and hair follicles
©McGraw-Hill Education
Allergen Portals of Entry(2)
Inhalants: airborne environmental allergens such as pollen, house dust, dander, or fungal spores
Ingestants: allergens that enter by mouth that cause food allergies
Injectants: allergies triggered by drugs, vaccines, or hymenopteran (bee) venom
Contactants: allergies that enter through the skin; many are type IV (delayed) hypersensitivities
©RubberBall/Alamy Stock Photo
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Role of Mast Cells and Basophils in Type I Allergy
Mast cells are located in all connective tissues, but in particularly high concentrations in the lungs, skin, gastrointestinal tract, and genitourinary tract
Each cell carries 30,000 to 100,000 cell receptors that bind IgE and degranulate, releasing inflammatory cytokines
Symptoms of allergy are not caused by the direct action of allergen on tissues, but the physiological effects of mast-cell-derived allergic mediators on target organs
©McGraw-Hill Education
Cytokines, Target Organs, and Allergic Symptoms(1)
Histamine:
Most profuse and fast-acting allergic mediator
Constricts smooth muscle in the small bronchi and intestine, causing labored breathing and increased intestinal motility
Relaxes vascular smooth muscle and dilates arterioles and venules, resulting in wheal-and-flare reactions in the skin and itching
Stimulates eosinophils to release inflammatory cytokines, escalating symptoms
Bradykinin:
Prolonged smooth muscle contraction of the bronchioles
Dilation of peripheral arterioles
Increased capillary permeability
Increased mucus secretion
Serotonin:
Effects complement those of histamine and bradykinin
©McGraw-Hill Education
Cytokines, Target Organs, and Allergic Symptoms(2)
Leukotriene:
“Slow-reacting substance of anaphylaxis”
Induces gradual contraction of smooth muscle
Prolonged bronchospasm, vascular permeability, and mucus secretion of the asthmatic individual
Stimulates polymorphonuclear leukocytes
Prostaglandins:
Regulate smooth muscle contraction; stimulate uterine contractions during delivery
Vasodilation
Increased vascular permeability
Increased sensitivity to pain
Bronchoconstriction
Nonsteroidal anti-inflammatory drugs (NSAIDs) prevent the actions of prostaglandins
©McGraw-Hill Education
Cellular Reactions During Type I Allergic Response(1)
©Ingram Publishing (headache); ©robeo/Getty Images (hives); ©Brand X Pictures (stomachache); ©Science Photo Library (asthma); ©Ingram Publishing (blowing nose)
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Cellular Reactions During Type I Allergic Response(2)
©Ingram Publishing (headache); ©robeo/Getty Images (hives); ©Brand X Pictures (stomachache); ©Science Photo Library (asthma); ©Ingram Publishing (blowing nose)
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Hay Fever
A generic term for allergic rhinitis
Seasonal reaction to inhaled plant pollen or molds, or a chronic, year-round reaction to airborne allergens or inhalants
Targets: respiratory membranes
Symptoms: nasal congestion; sneezing; coughing; profuse mucus secretion; itchy, red, and teary eyes; mild bronchoconstriction
©McGraw-Hill Education
Asthma
Respiratory disease characterized by episodes of impaired breathing due to severe bronchoconstriction
Airways of asthmatics are extremely sensitive to minute amounts of inhalants, ingestants, or other stimuli, such as infectious agents
Symptoms range from labored breathing to fatal suffocation
Rales: clicking, bubbling, or rattling sounds in the lungs
Lungs are overreactive to leukotrienes and serotonin
Natural killer cells are also recruited and activated
©McGraw-Hill Education
Atopic Dermatitis/Eczema
Intensely itchy inflammatory
condition of the skin
Sensitization occurs through
ingestion, inhalation, and skin
contact with allergens
Usually begins in infancy and is
characterized by reddened,
encrusted skin lesions on the face,
scalp, neck, and inner surfaces
of limbs and trunk
Progresses to a dry, scaly, thickened skin condition in adults
Lesions are itchy, painful, and predisposed to secondary bacterial infections
©Dr. P. Marazzi/Science Source (a); ©Biophoto Associates/Science Source (b)
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Food Allergy
Most common food allergens come from peanuts, fish, cow’s milk, eggs, shellfish, and soybeans
Mode of entry is intestinal
Symptoms include vomiting, diarrhea, and abdominal pain
Other manifestations include hives, rhinitis, asthma, and occasionally anaphylaxis
Hypersensitivity involves IgE and degranulation of mast cells, but not all reactions involve this mechanism
Care should be taken vaccinating individuals with egg allergies
©McGraw-Hill Education
Drug Allergy
Drugs are foreign compounds capable of stimulating allergic reactions
Drug allergies are one of the most common side effects of treatment, affecting 5 to 10% of hospitalized patients
Reactions range from a mild rash to fatal anaphylaxis
Compounds implicated:
Antibiotics: penicillin
Synthetic antimicrobials: sulfa drugs
Aspirin
Opiates
Contrast dye used in X rays
Allergen is not the intact drug itself, but a hapten given off when the liver processes the drug
©McGraw-Hill Education
Anaphylaxis: An Overpowering IgE-Mediated Allergic Reaction
Anaphylaxis/anaphylactic shock: swift reaction to allergens:
Cutaneous anaphylaxis: wheal-and-flare inflammatory reaction to the local injection of allergen
Systemic anaphylaxis: characterized by sudden respiratory and circulatory disruption that can be fatal within minutes due to airway blockage
Bee stings and injection of antibiotics or serum are most commonly implicated
Result of the sudden, massive release of chemicals into the tissues and blood, which act rapidly on target organs
©McGraw-Hill Education
Diagnosis of Allergy: In Vitro Methods
Blood testing:
Radioallergosorbent (RAST) test: measures levels of IgE to specific antigens
Tryptase test: measures tryptase, an enzyme released by mast cells that increases during an allergic response
Differential blood cell count can reveal high levels of basophils and eosinophils
Leukocyte histamine-release test: measures the amount of histamine released from the patient’s basophils when exposed to a specific allergen
©McGraw-Hill Education
Diagnosis of Allergy: In Vivo Methods
Skin testing: in vivo method to detect precise atopic or anaphylactic sensitivities
Skin is injected, scratched, or pricked with a small amount of pure allergen extract
A wheal-and-flare result 20 minutes after antigenic challenge is indicative of histamine release
The diameter of the wheal is measured and rated on a scale from 0 (no reaction) to 4 (greater than 15 mm)
©Southern Illinois University/Science Source (a)
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Treatment and Prevention of Allergy
Take drugs that block the action of lymphocytes, mast cells, or chemical mediators
Avoid the allergen, although this may be difficult in many instances
Desensitization: controlled exposure to the antigen through ingestion, sublingual absorption, or injection to reset the allergic reaction
©McGraw-Hill Education
©McGraw-Hill Education
Concept Check (2)
Which of the following is not an IgE- and/or mast-cell-mediated allergic condition?
Asthma
Food allergy
Systemic lupus erythematosus
Allergy to penicillin
Eczema
©McGraw-Hill Education
Learning Outcomes Section 14.3
List the three immune components causing cell lysis in type II hypersensitivity reactions.
Explain the role of Rh factor in hemolytic disease development and how it is prevented in newborns.
©McGraw-Hill Education
Type II Hypersensitivities: Reactions That Lyse Foreign Cells
A complex group of syndromes that involve complement-assisted destruction (lysis) of cells by antibodies (IgG and IgM) directed against those cells’ surface antigens:
Transfusion reactions
Some types of autoimmunities
Alloantigens:
Molecules that differ in the same species that are recognized by the lymphocytes of the recipient
Not an immune dysfunction; the immune system is functioning normally by reacting to foreign cells in an organ or tissue transplant
©McGraw-Hill Education
Rh Factor and Its Clinical Importance
First discovered in experiments exploring genetic relationships among animals:
Rabbits injected with the RBCs of rhesus monkeys produced an antibody that also reacted with human RBCs
This monkey antigen (Rh for rhesus) was present in about 85% of humans and absent in about 15%
Rh+ is a dominant gene; Rh- is recessive
The only way to develop antibodies against this factor is through placental sensitization or transfusion
©McGraw-Hill Education
Hemolytic Disease of the Newborn and Rh Incompatibility
Placental sensitization occurs when
the mother is Rh- and the unborn child is Rh+:
Fetal RBCs may leak into the mother’s circulation during childbirth
when the placenta detaches.
Mother’s immune system detects
the foreign Rh factors on fetal RBCs and is sensitized to them by producing antibodies and memory B cells
Does not usually affect the first child because the process occurs so late in pregnancy
In the next pregnancy with an Rh+ fetus:
Fetal blood cells escape into maternal circulation late in pregnancy, eliciting a memory response.
Maternal anti-Rh antibodies cross the placenta, affix to fetal RBCs, and cause complement-mediated lysis.
Outcome is potentially fatal hemolytic disease of the newborn (HDN), also called erythroblastosis fetalis, characterized by severe anemia and jaundice
©McGraw-Hill Education
Development and Control of Rh Incompatibility
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Preventing Hemolytic Disease of the Newborn
Once sensitization has occurred, all other Rh+ fetuses will be at risk
A careful history of the Rh– pregnant woman is needed:
Rh types of children and Rh status of the father are needed
If the father is Rh-, there is no risk
If the father is Rh+, the fetus may be Rh+.
RhoGAM antiserum:
Passive immunization for an Rh- mother with an Rh+ fetus
Immunoglobulin fraction of human anti-Rh serum prepared from pooled human sera
Injected at 28 to 32 weeks and again immediately after delivery
Sequesters fetal RBCs that have escaped into maternal circulation and prevents sensitization
Must be given with each pregnancy with an Rh+ fetus
©McGraw-Hill Education
Concept Check (3)
When is the RhoGAM shot needed?
Rh+ mother, Rh+ fetus
Rh+ mother, Rh– fetus
Rh– mother, Rh– fetus
Rh– mother, Rh+ fetus
All of the choices are correct. The mother always responds to the fetus as foreign tissue and mounts an immune response against it.
©McGraw-Hill Education
Learning Outcomes Section 14.4
Identify commonalities and differences between type II and type III hypersensitivities.
©McGraw-Hill Education
Type III Hypersensitivities: Immune Complex Reactions
Involves the reaction of soluble antigen with antibody, and deposition of resulting complexes in various tissues in the body:
Involves the production of IgG and IgM antibodies
Also involves the activation of complement
Unlike type II hypersensitivities, antigens are not attached to the surface of a cell
Immune complex reaction: produces free-floating complexes that are deposited into tissues
©McGraw-Hill Education
Mechanisms of Immune Complex Disease
Large quantities of antibodies are produced in response to an exposure to a profuse amount of antigen
Upon second exposure, antigen-antibody complexes are formed:
These recruit complement and neutrophils that would normally eliminate these complexes
In immune complex disease, complexes are deposited in the basement membranes of epithelial tissues:
Neutrophils release lysosomal granules that digest tissues and cause a destructive inflammatory condition
©McGraw-Hill Education
Stages in the Course of Infection and Disease
Arthus reaction and serum sickness are associated with certain types of passive immunization
Similar to anaphylaxis in that all require sensitization and preformed antibodies
Differences from anaphylaxis:
Depend on IgG, IgM, or IgA rather than IgE
Require large doses of antigen
Symptoms are delayed hours to days
©Koshi Johnson/Medical Images (a); Courtesy Gary P. Wiliams, M.D. (b)
©McGraw-Hill Education
Concept Check (4)
Which of the following antibody types is not involved in serum sickness or the Arthus reaction?
IgA
IgE
IgG
IgM
All of the choices are involved.
©McGraw-Hill Education
Learning Outcomes Section 14.5
Describe one example of a type IV delayed hypersensitivity reaction.
List four classes of grafts, and explain how host versus graft and graft versus host diseases develop.
©McGraw-Hill Education
Type IV Hypersensitivities: Cell-Mediated (Delayed) Reactions
Involves primarily the T-cell branch of the immune system
Results when T cells respond to antigens displayed on self tissues or transplanted foreign cells
Traditionally known as delayed hypersensitivity:
Symptoms arise one to several days following the second contact with antigen
©McGraw-Hill Education
Infectious Allergy
Tuberculin reaction:
Acute skin inflammation at the tuberculin extract injection site
Mainstay diagnostic tool for TB infections
TH1 cells release cytokines that recruit macrophages, neutrophils, and eosinophils to the site, causing a red bump
Source: CDC/Donald Kopanoff (a)
©McGraw-Hill Education
Contact Dermatitis
Caused by exposure to resins in poison ivy and poison oak, haptens in household and personal articles, and certain drugs
Requires a sensitizing dose followed by a provocative dose
Allergen penetrates the outer skin layers:
Processed by skin dendritic cells and presented to T cells
Subsequent exposures attract lymphocytes and macrophages
Cells release enzymes and cytokines that damage the epidermis in the immediate vicinity
©carroteater/Shutterstock (b)
©McGraw-Hill Education
T Cells and Their Role in Organ Transplantation
Transplantation or grafting of organs and tissues is a common medical procedure
Although it is life-giving, it is plagued with the natural tendency of lymphocytes to seek out and destroy foreign antigens
The bulk of the damage that occurs in graft rejections are attributed to cytotoxic T-cell action
©McGraw-Hill Education
Genetic and Biochemical Basis for Graft Rejection
MHC or HLA classes I and II markers are extremely important for recognizing self and in regulating the immune response
Although a person can exhibit variability in the pattern of these markers, the pattern is identical in different cells in the same person
Similarity is seen in related siblings and parents, but the more distant the relationship, the less likely that the MHC genes and markers will be alike
When a donor tissue (graft) displays surface molecules of a different MHC class, the T cells of the recipient will react to it as a foreign substance
©McGraw-Hill Education
Host Rejection of Graft
Cytotoxic T cells of a host recognize foreign class I MHC markers on the surface of grafted cells
Release IL-2 as part of general immune mobilization
Helper and cytotoxic T cells bind to the grafted tissue and secrete lymphokines that begin the rejection process within 2 weeks of transplantation
Antibodies formed against the transplanted tissue contribute to damage
The result is destruction of the vascular supply and death of the graft
©McGraw-Hill Education
Graft Rejection of Host
Some grafted tissues (bone marrow) contain indigenous populations of passenger lymphocytes
These lymphocytes create an immune response to the host
Graft versus host disease:
Graft attacks any host tissue bearing foreign MHC markers
Effects are systemic and toxic
Papular, peeling skin rash is the most common symptom; other organs are also affected
Occurs within 100 to 300 days of the graft
©McGraw-Hill Education
Development of Incompatible Tissue Graft Reactions
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53
Classes of Grafts
Autograft: tissue transplanted from one site on an individual’s body to another site
Isograft: tissue from an identical twin is used
Allograft: exchanges between genetically different individuals belonging to the same species; the most common types of grafts
Xenograft: a tissue exchange between individuals of a different species
©iStockphoto/Getty Images
©McGraw-Hill Education
54
Types of Transplants
Transplantation has been performed on every major organ, but most often involves the skin, liver, heart, kidney, coronary artery, cornea, and bone marrow
Sources of organs: live donors, the recently deceased, fetal tissues
Bone marrow transplantation:
Used in individuals with immune deficiencies, aplastic anemia, leukemia, and other cancers, and radiation damage
Patient is treated with chemotherapy and whole-body irradiation to destroy their own blood cells, preventing rejection
Closely matched donor marrow is infused
GVHD can still occur, and antirejection drugs may be necessary.
After transplantation, a recipient’s blood type may change to the blood type of the donor
©McGraw-Hill Education
Concept Check (5)
Match the class of tissue graft with its description.
Allograft
Autograft
Isograft
Xenograft
Graft between identical twins
Graft between different species
Graft within an individual
Graft between non-identical twins
©McGraw-Hill Education
Learning Outcomes Section 14.6
List at least three autoimmune diseases and the most important immunologic features in them.
©McGraw-Hill Education
Inappropriate Response to Self: Autoimmunity
Autoimmune diseases: individuals actually develop hypersensitivity to themselves
Autoantibodies, T cells, or both, mount an abnormal attack against self antigens
Systemic: involves several major organs
Organ specific: involves only one organ or tissue
Disease Target Type of Hypersensitivity Characteristics
Systemic lupus erythematosus (SLE) Systemic III Inflammation of many organs; antibodies against red and white blood cells, platelets, clotting factors, nucleus DNA
Rheumatoid arthritis and ankylosing spondylitis Systemic II, III, and IV Vasculitis; frequent target is joint lining; antibodies against other antibodies (rheumatoid factor), T-cell cytokine damage
Graves’ disease Thyroid III Antibodies against thyroid-stimulating hormone receptors
Myasthenia gravis Muscle III Antibodies against the acetylcholine receptors on the nerve-muscle junction alter function
Type 1 diabetes Pancreas IV T cells attack insulin-producing cells
Multiple sclerosis Myelin II and IV T cells and antibodies sensitized to myelin sheath destroy neurons
©McGraw-Hill Education
Genetic and Gender Correlation in Autoimmune Disease
Cases cluster in families, and even unaffected members tend to develop autoantibodies for the disease
Particular genes in class I and II MHC coincide with certain autoimmune diseases:
Rheumatoid arthritis and ankylosing spondylitis are more common in persons with B-27 HLA type
Molecular mimicry:
Microbial antigens bearing molecular determinants similar to human cells induce the formation of autoantibodies
One explanation for the pathology of rheumatic fever
Psoriasis flare-ups after strep throat infections may also be due to T cells primed to react with keratin in the skin
©McGraw-Hill Education
Examples of Autoimmune Diseases: Systemic Autoimmunities
Systemic lupus erythematosus (SLE, or lupus):
Name originated from the characteristic butterfly-shaped rash that drapes across the nose and cheeks
Manifestations vary, but all patients develop autoantibodies against organs, tissues, or intracellular materials
Viral infection and loss of normal immune response suppression are suspected as causes
Rheumatoid arthritis:
Causes progressive, debilitating damage to the joints and at times to the lungs, eyes, skin, and nervous system
Autoantibodies form immune complexes that bind to the synovial membrane of joints, activating cytokine release by macrophages
Chronic inflammation develops, leading to scar tissue and joint destruction
Cytokines trigger additional type IV delayed hypersensitivity responses
©McGraw-Hill Education
Common Autoimmune Diseases
©ISM/CID/Medical Images (a); ©Aaron Roeth Photography (b)
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Autoimmunities of the Endocrine Glands
Graves’ disease:
Attachment of autoantibodies to receptors on thyroxin-secreting follicle cells of the thyroid gland
Abnormal stimulation of these cells causes over- production of the thyroid hormone and the symptoms of hyperthyroidism
Type I diabetes:
Molecular mimicry has been implicated in the sensitization of cytotoxic T cells to attack and lyse insulin-producing beta cells
Reduced amount of insulin underlies the symptoms of this disease
©McGraw-Hill Education
Neuromuscular Autoimmunities(1)
Myasthenia gravis:
Autoantibodies bind to receptors for acetylcholine, a neurotransmitter required for muscle stimulation
First effects felt in the muscles of the eyes and throat, but eventually progresses to complete loss of skeletal muscle function and death
Current treatment includes immunosuppressive drugs and therapy to remove autoantibodies from circulation
©McGraw-Hill Education
Neuromuscular Autoimmunities(2)
Multiple sclerosis:
Paralyzing neuromuscular disease associated with lesions on the myelin sheath that surrounds neurons in the white matter of the central nervous system
T cell and autoantibody-induced damage compromise the capacity of neurons to send impulses
Symptoms include muscle weakness, tremors, difficulties in speech and vision, and paralysis
Possible association between infection with human herpesvirus 6
Treatments include immunosuppressants and interferon beta to alleviate symptoms and monoclonal antibody therapy toward certain T-cell antigens
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Concept Check (6)
Autoimmunities are caused by ____.
Genetic predisposition
X-chromosome inactivation in females
Molecular mimicry
Viral infection
All of the choices are correct.
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Learning Outcomes Section 14.7
Distinguish between primary and secondary immunodeficiencies, explaining how each develops.
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Immunodeficiency Diseases: Hyposensitivity of the Immune System
Occasionally, an individual is born with or develops weakened immune responses
Predominant consequences of immunodeficiencies are recurrent, overwhelming infections with opportunistic microbes
Primary diseases: present at birth (congenital), usually stemming from genetic errors
Secondary diseases: acquired after birth and caused by natural or artificial agents
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Primary Immune Deficiencies (Genetic)
B-cell defects (low levels of B cells and antibodies):
Agammaglobulinemia (X-linked, non-sex-linked)
Hypogammaglobulinemia
Selective immunoglobulin deficiencies
T-cell defects (lack of all classes of T cells):
Thymic aplasia (DiGeorge syndrome)
Combined B-cell and T-cell defects (usually caused by lack or abnormality of lymphoid stem cell):
Severe combined immunodeficiency (SCID) disease
Adenosine deaminase (ADA) deficiency
Complement defects:
Lacking one of C components
Hereditary angioedema associated with rheumatoid diseases
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Secondary Immune Deficiencies (Acquired)
From natural causes:
Infections (AIDS) or cancers
Nutrition deficiencies
Stress
Pregnancy
Aging
From immunosuppressive agents:
Irradiation
Severe burns
Steroids (cortisones)
Immunosuppressive drugs
Removal of spleen
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Primary Immunodeficiency Diseases
Often due to an inherited abnormality
In some diseases, the lymphocytes are absent, or present at low levels
In other diseases, the lymphocytes are present, but do not function normally
An individual can lack either B or T cells, or both
Some deficiencies can affect other cell functions as well
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Stages of Development and Functions of B and T Cells
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Clinical Deficiencies in B-Cell Development or Expression(1)
Genetic deficiencies in B cells usually result in abnormal immunoglobulin (Ig) expression:
In some cases, certain Ig classes are absent
In other cases, all levels of Ig are reduced
Agammaglobulinemia: absence of gamma globulin; it is very rare for Ig to be completely absent
Hypogammaglobulinemia: abnormally low levels of gamma globulin:
Recurrent, serious bacterial infections appear about 6 months after birth
Most common infection sites: lungs, sinuses, meninges, and blood
Current treatment is passive immunotherapy with immune serum globulin and continuous antibiotic therapy
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Clinical Deficiencies in B-Cell Development or Expression(2)
Lack of a particular class of immunoglobulin is a relatively common condition:
IgA deficiency is the most prevalent form
Individuals have normal quantities of B cells and other immunoglobulins
Lack protection against local microbial invasion of mucous membranes, suffer recurrent respiratory and gastrointestinal infections
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Clinical Deficiencies in T-Cell Development or Expression
Defects in T-cell development result in a broad spectrum of diseases:
Severe opportunistic infections
Cancer
More devastating than B-cell deficiencies, because T helper cells are required to assist in most specific immune functions
Abnormal development of the thymus: DiGeorge syndrome or thymic aplasia:
Congenital absence or immaturity of the thymus gland
Makes children highly susceptible to persistent infections by fungi, protozoa, and viruses
Vaccinations using attenuated microbes pose a danger and common childhood infections can be fatal
Patients typically have reduced antibody levels
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Severe Combined Immunodeficiencies (SCIDs)(1)
Most serious form of immunodeficiency:
Involve dysfunction in both lymphocyte systems
Some SCIDs are due to the lack of lymphocyte stem cells in the bone marrow; others are due to the dysfunction of B and T cells later in development
Infants with SCID usually develop candidiasis, sepsis, pneumonia, or systemic viral infections within days after birth
Two most common forms: Swiss-type agammaglobulinemia and thymic alymphoplasia:
Genetic defects in the development of the lymphoid cell line result in extremely low numbers of all lymphocyte types and poorly developed humoral and cellular immunity
Adenosine deaminase (ADA) deficiency: lymphocytes develop but a metabolic product builds up and selectively destroys them
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Severe Combined Immunodeficiencies (SCIDs)(2)
SCID children require rigorous aseptic techniques to protect them from opportunistic infections:
David Vetter: lived his life in a sterile plastic bubble
Only serious option for longtime survival is total replacement or correction of lymphoid cells:
Infants can benefit from fetal liver or stem cell grafts
X-linked and ADA types of SCID can be treated with gene therapy; insertion of normal genes to replace the defective genes
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Secondary Immunodeficiency Diseases(1)
Caused by one of four general agents:
Infection
Noninfection metabolic disease
Chemotherapy
Radiation
Most recognized infection-induced immunodeficiency is AIDS:
T helper cells, monocytes, macrophages, and antigen-presenting cells infected by HIV
Depletion of T helper cells and impairment of immune responses account for cancers and opportunistic infections caused by AIDS
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Secondary Immunodeficiency Diseases(2)
Cancers that target the bone marrow can be responsible for malfunction of humoral and cellular immunity:
Leukemia: cancer cells outnumber normal cells, displacing them from bone marrow and blood
Plasma cell tumors: produce large amounts of nonfunctional antibodies
Thymus tumors: cause severe T-cell deficiencies
An ironic outcome of lifesaving medical procedures is the suppression of the immune system:
Drugs that prevent graft rejection can also suppress beneficial immune responses
Radiation and anticancer drugs are damaging to the bone marrow and other body cells
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Concept Check (7)
The most common deficiency in immunoglobulins is _____ deficiency.
IgA
IgD
IgE
IgG
IgM
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Appendix of Image Long Descriptions
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Disorders of the Immune System – Appendix
Just as the system of T cells and B cells provides necessary protection against infection and disease, the same system can cause serious and debilitating conditions by overreacting or underreacting to antigens. Hyposensitivities include primary and secondary immunodeficiencies represented by a boy living in sterile bubble due to severe combined immunodeficiency and a person with AIDS, respectively. Hypersensitivities: Type I (immediate) is represented by a boy with hay fever; Type II (antibody-mediated) is represented by someone receiving a blood transfusion; Type III (immune complex) is represented by an elderly woman with arthritis; and Type IV (cell-mediated, cytotoxic) is represented by a photo of contact dermatitis.
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Allergen Portals of Entry(2) – Appendix
(a) Common inhalants, or airborne environmental allergens, include pollen and insect parts. (b) Common ingestants, allergens that enter by mouth, include red dye, peanuts, strawberries, and shrimp. (c) Common injectants, allergens that enter via the parenteral route include bee stings and penicillin. (d) Common contactants, allergens that enter through the skin include detergent, lotion, and latex gloves.
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Cellular Reactions During Type I Allergic Response – Appendix(1)
Type I allergic response. A) Sensitization/IgE production: 1) Sensitizing dose of allergen enters. 2) Lymphatic vessel carries allergen to lymph node. 3) In lymph, B cell recognizes allergen with help of TH cell. 4) B cell proliferates into plasma cells. 5) Plasma cells synthesize IgE. B) Subsequent exposure to allergen: 6) Then, IgE binds to mast cell surface receptors. 7) Allergen is encountered again. 8) Allergen attaches to IgE on mast cells. 9) Resulting in systemic distribution of allergic mediators in bloodstream.
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Cellular Reactions During Type I Allergic Response – Appendix(2)
Type I allergic response effects on tissues are due to prostaglandin which results in dilated blood vessels, constricted bronchioles, and increased sensitivity to pain (represented here as a headache); leukotriene which results in constriction of bronchioles and airway obstruction with mucus buildup, represented by a woman using an inhaler for asthma; and histamine, serotonin, and bradykinin resulting in increased blood flow, skin manifestations (represented by dilated blood vessels and a skin test for allergens), increased peristalsis of intestine, diarrhea, and vomiting, and increased mucus secretion.
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Atopic Dermatitis/Eczema – Appendix
(a) Vesicular, weepy, encrusted lesions are typical in afflicted infants. (b) In adulthood, lesions are more likely to be dry, scaly, and thickened.
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Diagnosis of Allergy: In Vivo Methods – Appendix
The forearm is mapped and then injected with a selection of allergen extracts. The allergist must be very aware of potential anaphylaxis attacks triggered by these injections. (a) Close-up of skin wheals showing a number of positive reactions (dark lines are measurer’s marks). (b) An actual skin test record for some common environmental allergens indicated which allergens or particles the person had no reaction, slight reaction, mid reaction, moderate reaction, or severe reaction to.
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Development and Control of Rh Incompatibility – Appendix
(a) A naturally occurring blood cell incompatibility results when an Rh positive fetus develops within an Rh negative mother. Initial sensitization of the maternal immune system occurs when fetal blood passes the placental barrier. In most cases, the fetus develops normally. However, a subsequent pregnancy with an Rh positive fetus results in a severe fetal hemolysis. (b) Control of incompatibility: Anti-Rh antibody (RhoGAM) can be administered to Rh negative mothers during pregnancy to help bind, inactivate, and remove any Rh factor that may be transferred from the fetus. In some cases, RhoGAM is administered before sensitization occurs.
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Development of Incompatible Tissue Graft Reactions – Appendix
Type IV reactions. Host versus Graft: Host TC cells (and macrophages recruited by TH cells to assist) attack grafted cells with foreign MHC-I markers. Graft versus Host: Passenger lymphocytes from grafted tissue have donor MHC-I markers; attack recipient cells with different MHC-I specificity.
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Common Autoimmune Diseases – Appendix
(a) Systemic lupus erythematosus. One symptom is a prominent rash across the bridge of the nose and on the cheeks. These papules and blotches can also occur on the chest and limbs. (b) Rheumatoid arthritis commonly targets the synovial membrane of joints. Over time, chronic inflammation causes thickening of this membrane, erosion of the articular cartilage, and fusion of the joint. These effects severely limit motion and can eventually swell and distort the joints.
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Stages of Development and Functions of B and T Cells – Appendix
Some types of severe combined immunodeficiency affect lymphoid stem cells from bone marrow. (Top) In DiGeorge syndrome a breakdown occurs between Pre-T cell and Thymus. In adenosine deaminase deficiency the breakdown occurs between T cell and cell-mediated immunity, resulting in recurrent fungal, protozoan, and viral infections. (Bottom) in congenital agammaglobulinemia the breakdown occurs between Pre-B cell and bone marrow. In hypogammaglobulinemia (immunoglobulin, ADA deficiencies) the breakdown occurs resulting in a lack of B regulatory cells and recurrent bacterial infections.
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