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Hypersensitivities, Infection, and Immune Deficiencies
Chapter 7
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Hypersensitivity Altered immunologic response to an antigen that results in disease or damage to the host
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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
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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 Immediate hypersensitivity reactions Anaphylaxis
Delayed hypersensitivity reactions
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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
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Type I Hypersensitivity
Manifestations Itching Urticaria Conjunctivitis Rhinitis Hypotension Bronchospasm Dysrhythmias GI cramps and malabsorption
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Type I Hypersensitivity
Genetic predisposition Tests Food challenges Skin tests Laboratory tests Desensitization 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
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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
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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
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Type III Hypersensitivity
Immune complex clearance Large—macrophages Small—renal clearance Intermediate—deposit in tissues
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Type III Hypersensitivity
Immune complex disease Serum sickness Arthus reaction
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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
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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
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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
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Autoimmunity Forbidden clone
During differentiation, lymphocytes produce receptor that react with self-antigens Ineffective peripheral tolerance Defects in regulatory cells Original insult Genetic factors
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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)
Chronic multisystem inflammatory disease Autoantibodies against: Nucleic acids, erythrocytes, coagulation proteins, phospholipids, lymphocytes, platelets, etc.
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Autoimmune Examples Systemic lupus erythematosus (SLE)
Deposition of circulating immune complexes containing antibody against host DNA More common in females
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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%)
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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)
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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
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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
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Microorganism and Human Relationship
Mutual relationship Normal flora Relationship can be breached by injury Leave their normal sites and cause infection elsewhere Opportunistic microorganisms
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Stages of Infection Colonization Invasion Multiplication Spread
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Factors for Infection Mechanism of action Infectivity Pathogenicity
Virulence Immunogenicity Toxigenicity
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Classes of Infectious Microorganisms
Virus Chlamydia Rickettsia Mycoplasma Bacteria Fungi Protozoa Helminths
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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
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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
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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
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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
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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
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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
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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
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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
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Cellular Effects of Viruses
Transformation of host cells into cancerous cells Promotion of secondary bacterial infections
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Fungal Infection and Injury
Large microorganisms with thick cell walls Eukaryotes Exist as single-celled yeasts, multi-celled molds, or both
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Fungal Infection and Injury
Pathogenicity Adapt to host environment Wide temperature variations, digest keratin, low oxygen Suppress the immune defenses
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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
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Fungal Infection and Injury
Deep fungal infections are life threatening and are commonly opportunistic
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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
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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
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Countermeasures Antimicrobials Inhibit synthesis of cell wall
Damage cytoplasmic membrane Alter metabolism of nucleic acid Inhibit protein synthesis Modify energy metabolism
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Pathogenic Adaptations
Suppression of immune response Antigenic changes Development of resistance
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Immune Deficiencies Failure of immune mechanisms of self-defense
Primary (congenital) immunodeficiency Genetic anomaly Secondary (acquired) immunodeficiency Caused by another illness More common
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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
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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
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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
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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
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
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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)
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Complement Deficiencies
C3 deficiency Mannose-binding lectin (MBL) deficiency Properdin deficiency Factor I and factor H deficiency C9 deficiency
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Phagocytic Deficiencies
Severe congenital neutropenia Cyclic neutropenia Leukocyte adhesion deficiencies (LAD) C3 receptor deficiency Chédiak-Higashi syndrome Myeloperoxidase deficiency Chronic granulomatous disease
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Secondary Deficiencies
Also referred to as acquired deficiencies Far more common than primary deficiencies
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Secondary Deficiencies
Causes Normal physiology conditions Psychologic 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 Human immunodeficiency virus (HIV) Depletes the body’s Th cells Incidence Worldwide 5 million per year United States About 31,000 cases per year
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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 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 Typically 800 to 1000 cells/mm3 Reverses CD4/CD8 ratio
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Human Immunodeficiency Virus (HIV)
Structure 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)
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
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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
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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
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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
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Treatment for Immunodeficiencies
Gamma globulin therapy Transplantation or transfusion Treatment with soluble immune mediators Gene therapy
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