Define immunopathology, and describe the two major categories of immune dysfunction.

Microbiology FUNDAMENTALS A Clinical Approach Third Edition

Marjorie Kelly Cowan

Heidi Smith

with

Jennifer Lusk

BSN RN CCRN

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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

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

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

Concept Check (6)

Autoimmunities are caused by ____.

Genetic predisposition

X-chromosome inactivation in females

Molecular mimicry

Viral infection

All of the choices are correct.

Learning Outcomes Section 14.7

Distinguish between primary and secondary immunodeficiencies, explaining how each develops.

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

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

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

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

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

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

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

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

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

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

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

Concept Check (7)

The most common deficiency in immunoglobulins is _____ deficiency.

IgA

IgD

IgE

IgG

IgM

Appendix of Image Long Descriptions

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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Define immunopathology, and describe the two major categories of immune dysfunction.

Compare the pathogens discussed in the previous chapters with zoonotic pathogens.

Discuss the causes and consequences of prejudice, and apply the theories and strategies of conflict resolution to a fictional situation.

Define immunopathology, and describe the two major categories of immune dysfunction.