Download hypersensitivities ppt

Hypersensitivities, Infection, and Immune
Deficiencies
Chapter 7
Hypersensitivity
• Altered immunologic response to an antigen that
results in disease or damage to the host
Hypersensitivity
• Allergy
• Deleterious effects of hypersensitivity to
environmental (exogenous) antigens
• Autoimmunity
• Disturbance in the immunologic tolerance of
self-antigens
• Alloimmunity
• Immune reaction to tissues of another
individual
Hypersensitivity
• Characterized by the immune mechanism
• Type I
• IgE mediated
• Type II
• Tissue-specific reactions
• Type III
• Immune complex mediated
• Type IV
• Cell mediated
Hypersensitivity
• Immediate hypersensitivity reactions
• Anaphylaxis
• Delayed hypersensitivity reactions
Type I Hypersensitivity
• 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
Type I Hypersensitivity
• Manifestations
• Itching
• Urticaria
• Conjunctivitis
• Rhinitis
• Hypotension
• Bronchospasm
• Dysrhythmias
• GI cramps and malabsorption
Type I Hypersensitivity
• Genetic predisposition
• Tests
• Food challenges
• Skin tests
• Laboratory tests
• Desensitization
• IgG-blocking antibodies
Type I Hypersensitivity
Type II Hypersensitivity
• Tissue specific
• Specific cell or tissue (tissue-specific antigens)
is the target of an immune response
Type II Hypersensitivity
• Five mechanisms
• 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
Type III Hypersensitivity
• Immune complex mediated
• Antigen-antibody complexes are formed in the
circulation and are later deposited in vessel walls
or extravascular tissues
• Not organ specific
Type III Hypersensitivity
• Immune complex clearance
• Large—macrophages
• Small—renal clearance
• Intermediate—deposit in tissues
Type III Hypersensitivity
• Immune complex disease
• Serum sickness
• Arthus reaction
Type IV Hypersensitivity
• Does not involve antibody
• Cytotoxic T-lymphocytes or lymphokine producing
Th1 cells
• 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
Allergy
• Environmental antigens that cause atypical
immunologic responses in genetically
predisposed individuals
• 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
Autoimmunity
• Breakdown of tolerance
• Body recognizes self-antigens as foreign
• Sequestered antigen
• Self-antigens not normally seen by the immune
system
• Infectious disease
• Molecular mimicry
• Neoantigen
• Haptens become immunogenic when they bind
to host proteins
Autoimmunity
• Forbidden clone
• During differentiation, lymphocytes produce
receptor that react with self-antigens
• Ineffective peripheral tolerance
• Defects in regulatory cells
• Original insult
• Genetic factors
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
Autoimmune Examples
• Systemic lupus erythematosus (SLE)
• Chronic multisystem inflammatory disease
• Autoantibodies against:
• Nucleic acids, erythrocytes, coagulation
proteins, phospholipids, lymphocytes,
platelets, etc.
Autoimmune Examples
• Systemic lupus erythematosus (SLE)
• Deposition of circulating immune complexes
containing antibody against host DNA
• More common in females
Systemic Lupus Erythematosus
• Clinical manifestations
• Arthralgias or arthritis (90% of individuals)
• Vasculitis and rash (70%-80%)
• Renal disease (40%-50%)
• Hematologic changes (50%)
• Cardiovascular disease (30%-50%)
Systemic Lupus Erythematosus
• Eleven common findings
• Serial or simultaneous presence of at least four
indicates SLE
• 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)
Graft Rejection
• Transplant rejection is classified according to time
• Hyperacute
• Immediate and rare
• Preexisting antibody to the antigens of the
graft
• Acute
• Cell-mediated immune response against
unmatched HLA antigens
Graft Rejection
• Transplant rejection is classified according to time
• Chronic
• Months or years
• Inflammatory damage to endothelial cells of
vessels as a result of a weak cell-mediated
reaction against minor HLA antigens
Microorganism and
Human Relationship
• Mutual relationship
• Normal flora
• Relationship can be breached by injury
• Leave their normal sites and cause infection
elsewhere
• Opportunistic microorganisms
Stages of Infection
•
•
•
•
Colonization
Invasion
Multiplication
Spread
Factors for Infection
•
•
•
•
•
•
Mechanism of action
Infectivity
Pathogenicity
Virulence
Immunogenicity
Toxigenicity
Classes of Infectious
Microorganisms
•
•
•
•
•
•
•
•
Virus
Chlamydia
Rickettsia
Mycoplasma
Bacteria
Fungi
Protozoa
Helminths
Pathogen Defense Mechanisms
• Surface coats
• Inhibit phagocytosis, surface receptors to bind
host cells, and toxins
• Antigenic variation
• Mutation
• Antigenic drift
• Recombination
• Antigenic shifts
• Gene switching
Bacterial Virulence and Infectivity
• Bacteria must have iron to multiply
• Siderophores (iron receptors)
• Presence of polysaccharide capsules
• Suppression of complement activation
• Bacterial proliferation rates can surpass protective
response
Bacterial Virulence and Infectivity
• Toxin production
• Exotoxins
• Enzymes released during growth, causing
specific responses
• Immunogenic
• Antitoxin production
• Endotoxins
• Lipopolysaccharides contained in the cell
walls of gram-negative organisms
• Pyrogenic effects
Bacterial Virulence and Infectivity
• Bacteremia or septicemia
• Presence of bacteria in the blood as a result of
a failure of the body’s defense mechanisms
• Usually caused by gram-negative bacteria
• Toxins released in the blood cause the release
of vasoactive peptides and cytokines that
produce widespread vasodilation
Viral Infection and Injury
• Obligate intracellular parasites
• Dependent on host cells
• No metabolism or incapable of independent
reproduction
• Permissive host cell
• Virion binds to receptors on the plasma
membrane
• Usually a self-limiting infection
• Spreads cell to cell
Viral Replication
•
•
•
•
•
•
DNA or RNA
Single or double stranded
Protein receptor-binding site
Virus uncoats
Most RNA viruses directly produce mRNA
DNA “provirus” enters nucleus and is transcribed
into mRNA
Viral Replication
• Translation of mRNA results in the production of
viral proteins
• New virions are released through budding
• Viral DNA that is integrated in host cell DNA is
transmitted to daughter cells by mitosis
Cellular Effects of Viruses
• Inhibition of host cell DNA, RNA, or protein
synthesis
• Disruption of lysosomal membranes
• Promotion of apoptosis
• Fusion of infected, adjacent host cells
• Alteration of antigenic properties
Cellular Effects of Viruses
• Transformation of host cells into cancerous cells
• Promotion of secondary bacterial infections
Fungal Infection and Injury
• Large microorganisms with thick cell walls
• Eukaryotes
• Exist as single-celled yeasts, multi-celled molds, or
both
Fungal Infection and Injury
• Pathogenicity
• Adapt to host environment
• Wide temperature variations, digest keratin,
low oxygen
• Suppress the immune defenses
Fungal Infection and Injury
• Diseases caused by fungi are called mycoses
• Superficial, deep, or opportunistic
• Fungi that invade the skin, hair, or nails are
known as dermatophytes
• The diseases they produce are called tineas
(ringworm)
• Tinea capitis, tinea pedis, and tinea cruris
Fungal Infection and Injury
• Deep fungal infections are life threatening and are
commonly opportunistic
Clinical Manifestations of
Infectious Disease
• Variable depending on the pathogen
• Directly caused by the pathogen or indirectly
caused by its products
• Fever
• Resetting the hypothalamus
• Exogenous pyrogens
• Endogenous pyrogens
Countermeasures
• Vaccines
• Induction of long-lasting protective immune
responses that will not result in disease in a
healthy recipient
• Attenuated organism
• Killed organisms
• Recombinant viral protein
• Bacterial antigens
• Toxins
Countermeasures
• Antimicrobials
• Inhibit synthesis of cell wall
• Damage cytoplasmic membrane
• Alter metabolism of nucleic acid
• Inhibit protein synthesis
• Modify energy metabolism
Pathogenic Adaptations
• Suppression of immune response
• Antigenic changes
• Development of resistance
Immune Deficiencies
• Failure of immune mechanisms of self-defense
• Primary (congenital) immunodeficiency
• Genetic anomaly
• Secondary (acquired) immunodeficiency
• Caused by another illness
• More common
Immune Deficiencies
• Clinical presentation
• 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
Primary Immune Deficiencies
• Most are the result of a single gene defect
• Five groups
• B-lymphocyte deficiencies
• T-lymphocyte deficiencies
• Combined T and B cell deficiencies
• Complement defects
• Phagocyte defects
B Lymphocyte Deficiencies
• Hypogammaglobulinemia or agammaglobulinemia
• Bruton agammaglobulinemia
• Autosomal agammaglobulinemia
• X-linked hyper-IgM syndrome
• IgG subclass deficiency
• Selective IgA deficiency
• Common variable immune deficiency
T-Lymphocyte Deficiencies
• DiGeorge syndrome
• Partial or complete absence of T cell immunity
• Chronic mucocutaneous candidiasis
Combined T and B Cell
Deficiencies
• Severe combined immunodeficiency (SCID)
• Reticular dysgenesis (most severe form)
• Adenosine deaminase (ADA) deficiency
• X-linked SCID
• JAK3 deficiency
• IL-7 receptor deficiency
• Purine nucleoside phosphorylase deficiency
Combined T and B Cell
Deficiencies
•
•
•
•
•
RAG-1 or RAG-2 deficiency
Bare lymphocyte deficiency
MHC class I and II deficiency
Wiskott-Aldrich syndrome
Ataxia-telangiectasia (AT)
Complement Deficiencies
•
•
•
•
•
C3 deficiency
Mannose-binding lectin (MBL) deficiency
Properdin deficiency
Factor I and factor H deficiency
C9 deficiency
Phagocytic Deficiencies
• Severe congenital neutropenia
• Cyclic neutropenia
• Leukocyte adhesion deficiencies (LAD)
• C3 receptor deficiency
• Chédiak-Higashi syndrome
• Myeloperoxidase deficiency
• Chronic granulomatous disease
Secondary Deficiencies
• Also referred to as acquired deficiencies
• Far more common than primary deficiencies
Secondary Deficiencies
• Causes
• Normal physiology conditions
• Psychologic stress
• Dietary insufficiencies
• Malignancies
• Physical trauma
• Medical treatments
• Infections
• Acquired immunodeficiency syndrome (AIDS)
Acquired Immunodeficiency
Syndrome (AIDS)
• Syndrome caused by a viral disease
• Human immunodeficiency virus (HIV)
• Depletes the body’s Th cells
• Incidence
• Worldwide
• 5 million per year
• United States
• About 31,000 cases per year
Acquired Immunodeficiency
Syndrome (AIDS)
• Effective antiviral therapies have made AIDS a
chronic disease
• Epidemiology
• Blood-borne pathogen
• Increasing faster in women than men
Acquired Immunodeficiency
Syndrome (AIDS)
• Pathogenesis
• Retrovirus
• Genetic information is in the form of RNA
• Contains reverse transcriptase to convert
RNA into double-stranded DNA
• Integrase
Human Immunodeficiency Virus
(HIV)
Human Immunodeficiency Virus
(HIV)
• Structure
• gp120 protein binds to the CD4 molecule found
primarily on the surface of helper T cells
• CD4+ Th cells
• Typically 800 to 1000 cells/mm3
• Reverses CD4/CD8 ratio
Human Immunodeficiency Virus
(HIV)
• Structure
• Co-receptors
• CXCR4 and CCR5
• Strains can be selective for these
receptors; influences the tropism of the
target cells
Human Immunodeficiency Virus
(HIV)
• Clinical manifestations
• 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
Human Immunodeficiency Virus
(HIV)
• Treatment and prevention
• Highly active antiretroviral therapy (HAART)
• Reverse transcriptase inhibitors
• Protease inhibitors
• New drugs
• Entrance inhibitors
• Integrase inhibitors
• Vaccine development
Graft-Versus-Host Disease
(GVHD)
• Immunocompromised individuals are at risk for
CVHD
• T cells in the graft are mature and capable of
cell-mediated destruction tissues within the
recipient
• Not a problem if patient is immunocompetent
Evaluation of Immunity
• Complete blood count (CBC) with a differential
• Subpopulations of lymphocytes
• Quantitative determination of immunoglobulins
• Subpopulations of immunoglobulins
• Assay for total complement
• Skin tests
Treatment for Immunodeficiencies
•
•
•
•
Gamma globulin therapy
Transplantation or transfusion
Treatment with soluble immune mediators
Gene therapy