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Alterations in Immunity and
Inflammation (Including
Hypersensitivities)
Chapter 8
1
Hypersensitivity

Altered immunologic response to an antigen
that results in disease or damage to the host

Allergy
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
Autoimmunity


Deleterious effects of hypersensitivity to
environmental (exogenous) antigens
Disturbance in the immunologic tolerance of selfantigens
Alloimmunity

Immune reaction to tissues of another individual
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Hypersensitivity

Characterized by the immune mechanism
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Type I
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Type II
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Tissue-specific reactions
Type III
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IgE mediated
Immune complex mediated
Type IV

Cell mediated
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Hypersensitivity
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
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Immediate hypersensitivity reactions
Anaphylaxis
Delayed hypersensitivity reactions
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Type I Hypersensitivity

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IgE mediated
Against environmental antigens (allergens)
IgE binds to Fc receptors on surface of mast
cells (cytotropic antibody)
Histamine release


H1 and H2 receptors
Antihistamines
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Type I Hypersensitivity
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Manifestations
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Itching
Urticaria
Conjunctivitis
Rhinitis
Hypotension
Bronchospasm
Dysrhythmias
GI cramps and malabsorption
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Type I Hypersensitivity


Genetic predisposition
Tests
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Food challenges
Skin tests
Laboratory tests
Desensitization
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IgG-blocking antibodies
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Type I Hypersensitivity
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Type II Hypersensitivity

Tissue specific


Specific cell or tissue (tissue-specific antigens) is the
target of an immune response
Five mechanisms
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Cell is destroyed by antibodies and complement
Cell destruction through phagocytosis
Soluble antigen may enter the circulation and deposit on
tissues
Antibody-dependent cell-mediated cytotoxicity
Causes target cell malfunction
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Type II Hypersensitivity
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Type III Hypersensitivity

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Immune complex mediated
Antigen-antibody complexes are formed in the
circulation and are later deposited in vessel walls or
extravascular tissues
Not organ specific
Immune complex clearance


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Large—macrophages
Small—renal clearance
Intermediate—deposit in tissues
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Type III Hypersensitivity

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Immune complex disease
Serum sickness
Arthus reaction
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Type III Hypersensitivity
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Type IV Hypersensitivity


Does not involve antibody
Cytotoxic T lymphocytes or lymphokine
producing Th1 cells
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
Direct killing by Tc or recruitment of phagocytic
cells by Th1 cells
Examples

Acute graft rejection, skin test for TB, contact
allergic reactions, and some autoimmune diseases
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Type IV Hypersensitivity
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Type IV Hypersensitivity
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Allergy

Environmental antigens that cause atypical
immunologic responses in genetically
predisposed individuals
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Pollens, molds and fungi, foods, animals, etc.
Allergen is contained within a particle too
large to be phagocytosed or is protected by a
nonallergenic coat
Original insult is apparent
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Autoimmunity

Breakdown of tolerance
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Sequestered antigen
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Self-antigens not normally seen by the immune
system
Infectious disease
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Body recognizes self-antigens as foreign
Molecular mimicry
Neoantigen
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Haptens become immunogenic when they bind to
host proteins
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Autoimmunity

Forbidden clone
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Ineffective peripheral tolerance
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During differentiation, lymphocytes produce
receptor that react with self-antigens
Defects in regulatory cells
Original insult
Genetic factors
19
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Alloimmunity

Immune system reacts with antigens on the
tissue of other genetically dissimilar members
of the same species

Transient neonatal alloimmunity


Fetus expresses parental antigens not found in the
mother
Transplant rejection and transfusion reactions
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Autoimmune Examples

Systemic lupus erythematosus (SLE)
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Chronic multisystem inflammatory disease
Autoantibodies against:
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Nucleic acids, erythrocytes, coagulation proteins,
phospholipids, lymphocytes, platelets, etc.
Deposition of circulating immune complexes
containing antibody against host DNA
More common in females
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Systemic Lupus Erythematosus
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Clinical manifestations
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Arthralgias or arthritis (90% of individuals)
Vasculitis and rash (70%-80%)
Renal disease (40%-50%)
Hematologic changes (50%)
Cardiovascular disease (30%-50%)
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Systemic Lupus Erythematosus
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
Eleven common findings
Serial or simultaneous presence of at least
four indicates SLE
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Facial rash (malar rash), discoid rash,
photosensitivity, oral or nasopharyngeal ulcers,
nonerosive arthritis, serositis, renal disorder,
neurologic disorder, hematologic disorders,
immunologic disorders, and presence of
antinuclear antibodies (ANA)
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Graft Rejection

Transplant rejection is classified according to time

Hyperacute
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Acute
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Immediate and rare
Preexisting antibody to the antigens of the graft
Cell-mediated immune response against unmatched HLA
antigens
Chronic

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Months or years
Inflammatory damage to endothelial cells of vessels due to a
weak cell-mediated reaction against minor HLA antigens
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Graft Rejection
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Transfusion Reactions
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Antibodies against blood group antigens
ABO system
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Two major carbohydrate antigens
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A and B (co-dominant)
Individuals have naturally occurring antibodies to the A and B
antigens they lack
Anti-A and anti-B antibody production is induced by similar
antigens on naturally occurring bacteria in the intestinal tract
Antibodies are usually of the IgM class
O blood type (universal donor)
AB blood type (universal recipient)
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ABO System
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Immune Deficiencies


Failure of immune mechanisms of selfdefense
Primary (congenital) immunodeficiency
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Genetic anomaly
Secondary (acquired) immunodeficiency


Caused by another illness
More common
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Immune Deficiencies

Clinical presentation

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Development of unusual or recurrent, severe
infections
T cell deficiencies
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B cell and phagocyte deficiencies
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
Viral, fungal, yeast, and atypical microorganisms
Microorganisms requiring opsonization
Complement deficiencies
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Primary Immune Deficiencies
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Most are the result of a single gene defect
Five groups
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B lymphocyte deficiencies
T lymphocyte deficiencies
Combined T and B cell deficiencies
Complement defects
Phagocyte defects
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B Lymphocyte Deficiencies

Hypogammaglobulinemia or
agammaglobulinemia
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Bruton agammaglobulinemia
Autosomal agammaglobulinemia
X-linked hyper-IgM syndrome
IgG subclass deficiency
Selective IgA deficiency
Common variable immune deficiency
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T Lymphocyte Deficiencies

DiGeorge syndrome


Partial or complete absence of T cell immunity
Chronic mucocutaneous candidiasis
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Combined T and B Cell
Deficiencies
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Severe combined immunodeficiency (SCID)
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Reticular dysgenesis
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Most severe form
Adenosine deaminase (ADA) deficiency
X-linked SCID
JAK3 deficiency
IL-7 receptor deficiency
Purine nucleoside phosphorylase deficiency
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Combined T and B Cell
Deficiencies
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RAG-1 or RAG-2 deficiency
Bare lymphocyte deficiency
MHC class I and II deficiency
Wiskott-Aldrich syndrome
Ataxia-telangiectasia (AT)
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Complement Deficiencies
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C3 deficiency
Mannose-binding lectin (MBL) deficiency
Properdin deficiency
Factor I and factor H deficiency
C9 deficiency
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Complement Deficiencies
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Phagocytic Deficiencies
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Severe congenital neutropenia
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Cyclic neutropenia
Leukocyte adhesion deficiencies (LAD)
C3 receptor deficiency
Chédiak-Higashi syndrome
Myeloperoxidase deficiency

Chronic granulomatous disease
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Secondary Deficiencies
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
Also referred to as acquired deficiencies
Far more common than primary deficiencies
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Secondary Deficiencies

Causes
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Normal physiology conditions
Psychological stress
Dietary insufficiencies
Malignancies
Physical trauma
Medical treatments
Infections
Acquired immunodeficiency syndrome (AIDS)
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Acquired Immunodeficiency
Syndrome (AIDS)

Syndrome caused by a viral disease

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Human immunodeficiency virus (HIV)
Depletes the body’s Th cells
Incidence

Worldwide


5 million per year
United States
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About 31,000 cases per year
400,000 currently living with AIDS
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Acquired Immunodeficiency
Syndrome (AIDS)


Effective antiviral therapies have made AIDS
a chronic disease
Epidemiology


Blood-borne pathogen
Increasing faster in women than men
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Acquired Immunodeficiency
Syndrome (AIDS)

Pathogenesis

Retrovirus
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Genetic information is in the form of RNA
Contains reverse transcriptase to convert RNA into
double-stranded DNA
Integrase
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Human Immunodeficiency Virus
(HIV)
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Human Immunodeficiency Virus
(HIV)

Structure

gp120 protein binds to the CD4 molecule found
primarily on the surface of helper T cells

CD4+ Th cells
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Typically 800 to 1000 cells/mm3
Reverses CD4/CD8 ratio
Co-receptors

CXCR4 and CCR5

Strains can be selective for these receptors; influences the
tropism of the target cells
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Human Immunodeficiency Virus
(HIV)
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Human Immunodeficiency Virus
(HIV)
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Human Immunodeficiency Virus
(HIV)

Clinical manifestations

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Serologically negative, serologically positive but
asymptomatic, early stages of HIV, or AIDS
Window period
Th cells <200 cells/mm3
Diagnosis of AIDS is made in association with
various clinical conditions

Atypical or opportunistic infections, and cancer
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Human Immunodeficiency Virus
(HIV)
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Human Immunodeficiency Virus
(HIV)

Treatment and prevention

Highly active antiretroviral therapy (HAART)
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New drugs

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Reverse transcriptase inhibitors
Protease inhibitors
Entrance inhibitors
Integrase inhibitors
Vaccine development
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Graft-vs.-Host Disease (GVHD)

Immunocompromised individuals are at risk
for graft-vs.-host disease

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T cells in the graft are mature and capable of cellmediated destruction tissues within the recipient
Not a problem if patient is immunocompetent
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Evaluation of Immunity

Complete blood count (CBC) with a
differential
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Quantitative determination of
immunoglobulins
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Subpopulations of lymphocytes
Subpopulations of immunoglobulins
Assay for total complement
Skin tests
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Treatment for Immunodeficiencies

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Gamma-globulin therapy
Transplantation or transfusion
Treatment with soluble immune mediators
Gene therapy
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