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Chapter 8
Alterations in Immunity and
Inflammation
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Hypersensitivity

Altered immunologic response to an antigen;
results in disease/damage to host
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Allergy
• Deleterious effects of hypersensitivity to environmental
(exogenous) antigens
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
Autoimmunity
• Disturbance in immunologic tolerance of self-antigens
Alloimmunity
• Immune reaction to tissues of another individual
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Hypersensitivity

Characterized by the immune mechanism

Type I
• IgE mediated
 Type II
• Tissue-specific reactions
 Type III
• Immune complex mediated
 Type IV
• Cell mediated
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Hypersensitivity
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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
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
H1 and H2 receptors
Antihistamines
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Type I
Mast Cell
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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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Clinical Symptoms of IgE Type I
Reactions
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Anaphylaxis
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Severity depends on level of sensitization
Can be very small dose (ordinary skin testing)
Within minutes after exposure:
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Itching
Hives
Skin erythema
Contraction of respiratory bronchioles
Laryngeal edema results in hoarseness
Vomiting, abdominal cramps, diarrhea
Laryngeal obstruction
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Type I Hypersensitivity
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Genetic predisposition
Tests
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Food challenges
Skin tests
Laboratory tests
Desensitization

IgG-blocking antibodies
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Type II Hypersensitivity
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Tissue specific
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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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Phagocytosis
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Neutrophil-Mediated Damage
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Antibody-Dependent Cell-Mediated
Cytotoxicity
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Induced Cell Malfunction
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Type III Hypersensitivity
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Immune complex mediated
Antigen-antibody complexes formed in the
circulation and later deposited in vessel walls
or extravascular tissues
Not organ specific
Immune complex clearance
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
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Large—macrophages
Small—renal clearance
Intermediate—deposit in tissues
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Type III Hypersensitivity
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Examples of Immune Complex–
Mediated Diseases: Type III
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Systemic lupus erythematosus
Vasculitis
Poststreptococcal glomerulonephritis
Acute glomerulonephritis
Reactive arthritis
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Type IV Hypersensitivity
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Mediated by T lymphocytes
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Destruction of the tissue usually caused by direct
killing by toxins from Tc cells
Th1 cells produce cytokines that recruit phagocytes,
especially macrophages
Examples
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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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Antigenic Targets of
Hypersensitivity Reactions
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Allergy
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Autoimmunity
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Environmental Ags
Self Ags, with damage to host tissues
Alloimmunity
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Against foreign tissue Ags
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Allergy

Environmental antigens that cause atypical
immunologic responses in genetically
predisposed individuals
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Pollens, molds, fungi, foods, animals, etc.
Allergen 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
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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
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Forbidden clone
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Ineffective peripheral tolerance
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During differentiation, lymphocytes produce
receptors that react with self-antigens
Defects in regulatory cells
Original insult
Genetic factors
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Autoimmune Examples
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Systemic lupus erythematosus (SLE)
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Chronic multisystem inflammatory disease
Autoantibodies against:
• Nucleic acids, erythrocytes, coagulation proteins,
phospholipids, lymphocytes, platelets, etc.
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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 (malar) rash, discoid rash, photosensitivity,
oral or nasopharyngeal ulcers, nonerosive
arthritis, serositis, renal disorders, neurologic
disorders, hematologic disorders, immunologic
disorders, and presence of antinuclear antibodies
(ANAs)
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Alloimmunity
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Immune system reacts with antigens on the
tissue of other genetically dissimilar members
of the same species
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Transient neonatal alloimmunity
• Fetus expresses parental antigens not found in the
mother
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Transplant rejection and transfusion reactions
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Graft Rejection
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Transplant rejection classified according to time
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Hyperacute
• Immediate and rare
• Preexisting antibody to the antigens of the graft
Acute
• Cell-mediated response against unmatched HLA antigens
Chronic
• 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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Transfusion Reactions
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Antibodies against blood group antigens
ABO system
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Two major carbohydrate antigens
• A and B (codominant)
• 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 Incompatibility:
Alloimmune Reaction
Blood
type
Ag
Ab
Incompatible with
blood type
A
A
Anti-B
B, AB
B
B
Anti-A
A, AB
AB
Universal
recipient
A+B
None
None
O
Universal
donor
None
Anti-A and Anti-B
A, B, AB
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Immunodeficiencies
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Result of impaired function of T cells, B cells,
phagocytes and/or complement
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Primary (genetic)
Secondary (acquired)
Hallmark is recurrent infections often with
opportunistic organisms
Type of infection can lead to diagnosis of type of
deficiency
• Gonorrhea suggests complement deficiency
• Viral infections suggest T cell deficiency
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Immunodeficiencies
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Clinical presentation
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Development of unusual or recurrent, severe
infections
T cell deficiencies
• Viral, fungal, yeast, and atypical microorganisms
B cell and phagocyte deficiencies
• Microorganisms requiring opsonization
Complement deficiencies
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Immunodeficiencies
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Primary (congenital) immunodeficiency
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Genetic anomaly
Secondary (acquired) immunodeficiency
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Caused by another illness
More common
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Primary Immunodeficiencies
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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
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Hypogammaglobulinemia or
agammaglobulinemia
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Bruton agammaglobulinemia
 Autosomal agammaglobulinemia
 X-linked hyper-IgM syndrome
 IgG subclass deficiency
 Selective IgA deficiency
 Common variable immunodeficiency
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T Lymphocyte Deficiencies
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DiGeorge syndrome
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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
• 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 deficiency (LAD)
C3 receptor deficiency
Chédiak-Higashi syndrome
Myeloperoxidase deficiency
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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
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Causes
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Normal physiology conditions
 Psychologic stress
 Dietary insufficiencies
 Malignancies
 Physical trauma
 Medical treatments
 Infections
 AIDS
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Graft-Versus-Host (GVH) Disease
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Immunocompromised individuals are at risk for
GVH 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
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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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