McCance 9 - M9.3 - Book

Alterations in Immunity and Inflammation

• The immune system protects against foreign antigens, particularly infectious agents.
• Problems with the immune system lead to inappropriate reactions.
• Reactions can be exaggerated against environmental antigens (allergy).
• Reactions can be misdirected against the host's own cells (autoimmunity).
• Reactions can be directed against beneficial foreign tissues (alloimmunity).
• Reactions can be insufficient to protect the host (immune deficiency).
• Most exaggerated immune responses (allergy) are the most common but usually the least life-threatening.

Hypersensitivity, Allergy, Autoimmunity, and Alloimmunity

• Hypersensitivity is an altered immunologic response to an antigen that results in disease or damage to the host.
• Reactions are classified by the source of the antigen the immune system attacks: allergy, autoimmunity, alloimmunity.
• Reactions are classified by the mechanism that causes disease: types I, II, III, and IV.
• Allergy's meaning has shifted from immunity and hypersensitivity as facets of the same immune response.
• Allergy now means hypersensitivity to environmental antigens.
• Immunity now means protective responses to antigens expressed by disease-causing agents.
• Autoimmunity results from a disturbance in the immunologic tolerance of self-antigens.
• Normally, the immune system does not strongly recognize the individual's own antigens.
• Healthy individuals might produce low quantities of antibodies against their own antigens (autoantibodies).
• Autoimmune diseases occur when the immune system damages the person's own tissues through self-antigen attacks.
• Many clinical disorders are associated with autoimmunity and referred to collectively as autoimmune diseases.
• Alloimmunity occurs when the immune system of one individual reacts against tissues of another.
• Alloimmunity is observed during reactions against transfusions, transplanted tissue, or the fetus during pregnancy.
• The mechanism initiating hypersensitivity, whether allergy, autoimmunity, or alloimmunity, remains incompletely understood.
• Genetic, infectious, and possibly environmental factors contribute to hypersensitivity.
• Diseases develop from interactions of three variables.
• Original insult: alters immunologic homeostasis.
• Genetic makeup determines the degree of the resultant immune response from effects of the insult.
• Immunologic process causes the symptoms of the disease.

Mechanisms of Hypersensitivity

• Diseases are characterized by the immune mechanism that results in the disease:
  • Type I: immunoglobulin E (IgE)-mediated.
  • Type II: tissue-specific.
  • Type III: immune complex-mediated.
  • Type IV: cell-mediated.
• This classification can be artificial since a particular disease is seldom associated with only a single mechanism.
• Several mechanisms can be at work simultaneously or sequentially.
• Some mechanisms are secondary to disease and not directly involved in the pathologic process, while others are the primary cause of destruction.
• Hypersensitivity reactions require sensitization against a particular antigen, resulting in primary and secondary immune responses.
• Sensitization occurs when enough antibodies or T cells are available to cause a noticeable reaction upon re-exposure to the antigen.
• Time between re-exposure to the antigen and the onset of clinical symptoms determine if reactions are immediate or delayed.
• Reactions occurring within minutes to a few hours are immediate.
• Delayed reactions may take several hours to appear and maximum severity in days after re-exposure to the antigen.
• Anaphylaxis, the most rapid and severe immediate hypersensitivity reaction, occurs within minutes of re-exposure to the antigen.
• Anaphylaxis can be systemic (generalized) or cutaneous (localized).
• Symptoms of systemic anaphylaxis include itching, erythema, headaches, vomiting, abdominal cramps, diarrhea, and breathing difficulties.
• Severe reactions may include contraction of bronchial smooth muscle, laryngeal edema, and vascular collapse, leading to shock and death.
• Examples of systemic anaphylaxis are allergic reactions to bee stings, peanuts, eggs, and shellfish.
• Cutaneous anaphylaxis results in local symptoms such as pain, swelling, and redness at the site of exposure.
• Type I (IgE-mediated) reactions are mediated by antigen-specific IgE and mast cells.
• Most common allergies (pollen allergies) are type I reactions, most against environmental antigens and are allergic, however, IgE can contribute to autoimmune and alloimmune diseases.
• Exposure to an environmental antigen causes primarily IgE production, and repeated exposure is required for sufficient IgE for "sensitization".
• IgE has a short life span in blood because it rapidly binds to Fc receptors on mast cells.
• IgG4, a subclass, also has specific receptors on the mast cell and may contribute to the type I mechanism.
• Antibody binding to mast cells is termed cytotropic antibody or reagin (skin-sensitizing antibody).
• Fc receptors on phagocytes bind IgG that has reacted with antigen, while Fc receptors on mast cells bind IgE that has not interacted with antigen.
• In sensitized individuals, further antigen exposure leads to the simultaneous binding to two IgE-Fc receptor complexes on the mast cell (cross-link).
• Cross-linking activates intracellular signaling pathways and mast cell degranulation with signals requiring two antigenic determinants on the same molecule.
• IgE-mediated response can be beneficial against parasites (described in Chapter 8).
• Mast cell degranulation products modulate aspects of acute inflammatory response (effects illustrated in Fig. 7.11).
• Histamine is a potent mediator affecting several key target cells and contracts bronchial smooth muscles through H1 receptors.
• Histamine increases vascular permeability, causing edema, and vasodilation, increasing blood flow and interaction with H2 receptors.
• Histamine results in increased gastric acid secretion and basophil/mast cell histamine decrease.
• H2 receptors suggest a negative-feedback mechanism stopping degranulation where released histamine inhibits further histamine release by interacting with mast cells.
• Through H2 receptors on the immune system, histamine may affect immune response control.
• Enhances chemotactic activity of factors like eosinophil chemotactic factor of anaphylaxis (ECF-A), drawing eosinophils into allergic reactions and preventing migration out.
• Antihistamines control some type I responses by blocking histamine receptors.
• Mast cells initiate synthesis of lipid-derived mediators, such as leukotrienes, platelet-activating factor (PAF), and prostaglandins.
• Released more slowly than histamine, they prolong clinical symptoms, like recruiting inflammatory cells, promoting vascular permeability and edema, or inducing bronchoconstriction, or rhinitis.
• Therapy use competitive inhibitors of receptors for lipid mediators to treat patient.
• Type II (tissue-specific) reactions are characterized by a specific cell or tissue as the target of an immune response.
• Most cells have antigens beyond major histocompatibility locus antigens (HLAs), some are tissue-specific antigens expressed on plasma membranes of certain cells in specific tissues.
• Platelets, for instance, have unique antigens.
• Type II disease symptoms are determined by affected tissue/organ expressing antigen.
• Environmental antigens may bind to plasma membranes of specific cells and function as type II reaction targets.

Type II Hypersensitivity Reactions

• The five general mechanisms by which these reactions can affect cells are shown in Fig. 9.2.
  • Mechanism: Antibody binds to tissue-specific antigens/antigens attached to particular tissues.
  • Cell destruction can be triggered by antibody (IgG/IgM) and complement cascade activation through classical pathway
  • Opsonins (IgG/C3b) can cause cell destruction via phagocytosis of macrophages through binding to receptors.
  • Neutrophils may be attracted through antibody and complement if antigen expressed normally on vessel walls.
  • Antibody-dependent cell-mediated cytotoxicity (ADCC): subpopulation of cytotoxic cells/natural killer (NK) cells releases toxic substances.
  • Target cell malfunction: antibody directed against specific cell surface receptor antigenic determinants.
• The antibody reacts with receptors, modulating or preventing function of the receptor to prevent interaction with ligands.

Type III: Immune Complex-Mediated Hypersensitivity Reactions

• Most are caused by antigen-antibody (immune) complexes that are formed in the circulation and deposited in vessel walls/extravascular tissues.
• Key difference: Type II hypersensitivity involves binding of antibody to antigen on the cell surface, while type III involves binding to soluble antigen released into blood/body fluids with complex depositing in tissues.
• Not organ specific; symptoms have little to do with the particular antigenic target of the antibody.
• Harmful effects are from complement activation, particularly through generation of chemotactic factors for neutrophils.
• Neutrophils bind to antibody and C3b in the complexes and attempt to ingest them, but the complexes are often bound to large tissue areas.
• Large quantities of lysosomal enzymes are released in inflammatory site instead of phagolysosomes and cause tissue damage.
• Depending on relative amounts of antigen and antibody immune complexes can be various sizes.
• Rapidly cleared: large complexes are cleared from the circulation by tissue macrophages.
• Filtered by kidneys: very small complexes eventually filtered from blood without any pathologic consequences.
• Pathologic consequences: intermediate-sized complexes have severe effects ( inflammation in the kidneys (glomerulonephritis). _ Vessels (vasculitis), or joints (arthritis or degenerative joint disease)._
• Immune Complex Disease: The nature of the immune complexes may change and change progression during the disease, and severity of symptoms from formation of immune complexes is dynamic.
• Formation varies with the ratio of antigen to antibody, antibody subclass, and circulating antigen quantity and quality.
• Tremendous heterogeneity of immune complexes: it is not surprising that immune complex diseases characterized by a variety of symptoms and periods of remission or exacerbation of symptoms.
• Complement blood levels may decrease effectively during active disease in active complex activation. Complicating conditions could be: _ Hypocomplementemic: Blood contains below normal amounts of complement activity._ _ During type I, II, or IV hypersensitivity reactions, complement levels unaffected, or some components may even increase._

Hypersensitivity

• Modeled by serum sickness: systemic type III hypersensitivities.
• Modeled by Arthus reaction: localized or cutaneous reactions.
• Serum Sickness: Systemic prototype of immune complex-mediated disease is called serum sickness because it was caused by administration of foreign serum such as horse serum with tetanus antibody.
• The foreign serum no longer can be given, however, serum sickness reactions cause from repeated intravenous administration of other antigens. Characteristics of serum sickness observed in systemic Type III is autoimmune diseases.
• Typically includes affected blood vessels, joints, and kidneys. Additional symptoms including enlarged lymph nodes, rash, and pain at sites of inflammation.
• One form is Raynaud phenomenon is a condition caused by the temperature dependent deposition of immune complexes in the capillary beds of the peripheral circulation. Precipitates block the circulation and cause localized pallor and numbness.
• An Arthus Reaction is the prototypic example of a localized immune complex-mediated inflammatory response, due to repeated local exposure to an antigen that reacts with preformed antibody forms immune complexes in the local blood vessels.

Type IV Reactions

• Differs from others as it is affected by antibody. reactions are mediated by T lymphocytes not involved antibody (Fig. 9.4). Type
• This leads to mechanisms through either Cytotoxic T Lymphocytes (Tc cells), Th1 And Th17 cells producing lymphokine.
• Tissue destruction usually caused by direct killing by toxins from Tc cells or by the release of soluble factors.
• The clinical examples can be graft rejection and allergic reactions due to contact with poison ivy and metals. The type IV component present can be in many auotoimmune diseases.

Antigenic Targets of Hypersensitivity Reactions

• Allergy is a hypersensitivity response against an environmental antigen (allergen), most common.

Common Allergies

• Type I hypersensitivities however other three mechanisms can cause depending on the particular allergen.
• Allergens include pollens, foods, animals, cigarette smoke, and house dust.
• Allergens with type IV elicit plant resins, metals, chemicals in rubber,cosmetics, detergents, and topical antibiotics.
• Rare can be antibiotics and soluble antigens produced by infectious agents like hepatitis B in type II and type III
• In Multiple Exposures Sensitization multiple exposures elicit a hypersensitivity response
• Genetic Predisposition has certain individuals that predisposed to develop allergies are called atopic, affecting up to 80% depending on parents.
  • Individuals has increased productions for IgE with more Fc receptos in mast cells in both their airways and skin being more receptive to stimuli.

Clinical Symptoms of Type I Allergies

• Clinical manifestations are attributable to biologic effects of histamine. Tissues in common contain tissues that contain large numbers of mast cells and sensitive to the effects of histamine from its effects.
• For the Allergens on the Mucosa Include Mucous of eyes, nose,& respiratory tract cause continuous adverse affects.
• Urticaria, or hives, has dermal (skin) manifestation of type I is allergic reactions caused the localized release of histamine and increased Vascular permeability Resulting in limited areas of edema that's white and fluid filled surrounded by Redness.
• Gastro Intestinal The allergies are caused Food or med entering through the mouth-Usually with Food or Medicines: which may have symptoms that cause vomiting abdominal pain in minutes with Malabsorption issues, or other life threatening reactions.

Type IV Allergic Hypersensitivities

• Have mostly haptens that are reacted with normal self-proteins in the skin ,that are recognized by PRRs on antigen-presenting cells that induce cell-mediated response resulting in a allergic contact.
• Type I results in Skin Reactions that are characterized by widely distributed lesions.
• Type (II) and (III) is hypersensitivities are allergies from haptens binding to the surface of cells (eliciting an IgG or IgM response.)
• A similar action is the Allergic reactions occur when the Membrane attacks allergens for the Cell Destroying those specific cells with what's been mentioned.

Autoimmunity

• Results from the coincidence of a individual at an initiating event in the development of a autoimmune mechanism that affects the specific Issues.
• Autoimmune diseases can be familial and be attributed with susptibility genes that can result in similar hypersensitivity such AS (Ankylosing spondylitis) is considered for developing for development if that auotoimmune inflammatory's issue is not found.
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