Hypersensitivities, Autoimmune Diseases, and Immune Deficiencies 18 Hypersensitivities, Autoimmune Diseases, and Immune Deficiencies

Hypersensitivity Any immune response against a foreign antigen that is exaggerated beyond the norm Four types Type I (immediate) Type II (cytotoxic) Type III (immune-complex mediated) Type IV (delayed or cell-mediated)

Type I (Immediate) Hypersensitivity Localized or systemic reactions that result from the release of inflammatory molecules in response to an antigen Develop within seconds or minutes following exposure to an antigen Commonly called allergies and the antigens that stimulate them are called allergens

Sensitization Figure 18.1a

Degranulation Figure 18.1b

Mast Cells Found in sites close to body surfaces such as the skin and the walls of the intestines and airways Characteristic feature is a cytoplasm filled with large granules Granules contain a mixture of potent inflammatory chemicals

Inflammatory Molecules Released from Mast Cells Table 18.1

Basophils and Eosinophils Leukocytes that contain granules that stain with basophilic dyes Granules filled with inflammatory chemicals similar to those in the mast cells Sensitized basophils bind IgE and degranulate in the same way as mast cells

Basophils and Eosinophils Leukocytes that contain granules that stain with the dye eosin Granules contain inflammatory mediators and leukotrienes that contribute to the severity of a hypersensitivity response Mast cell degranulation stimulates the release of eosinophils that migrate to the site of mast cell degranulation where they then degranulate

Clinical Signs of Localized Allergic Reactions Type I hypersensitivity reactions are usually mild and localized Site of the reaction depends on the portal of entry Inhaled allergens may cause hay fever, an upper respiratory tract response Marked by watery nasal discharge, sneezing, itchy throat and eyes, and excessive tear production Commonly caused by mold spores, pollens, flowering plants, some trees, and dust mites

Clinical Signs of Localized Allergic Reactions Inhaled allergens that are small may reach the lungs Causes asthma Characterized by wheezing, coughing, excessive production of mucus, and constriction of the smooth muscles of the bronchi Some foods contain allergens Cause diarrhea and other gastrointestinal signs and symptoms Local dermatitis (inflammation of the skin) Produces hives, or uticaria, due to release of histamine and other mediators into nearby skin tissue and the leakage of serum from local blood vessels

Clinical Signs of Systemic Allergic Reactions Degranulation of many mast cells at once causes the release of large amounts of histamine and inflammatory mediators Acute anaphylaxis or anaphylactic shock can result Clinical signs are those of suffocation Bronchial smooth muscle contracts violently Leakage of fluid from blood vessels causes swelling of the larynx and other tissues Contraction of the smooth muscle of the intestines and bladder Must be treated promptly with epinephrine

Skin Test of Type I Hypersensitivity Figure 18.4

Treatment of Type I Hypersensitivity Administer drugs that counteract the inflammatory mediators released by degranulation Antihistamines neutralize histamine Asthma treated with an inhalant containing corticosteroid and a bronchodilator Epinephrine quickly neutralizes many of the mechanisms of anaphylaxis Relax smooth muscle and reduce vascular permeability Used in the emergency treatment of severe asthma and anaphylactic shock

Type II (Cytotoxic) Hypersensitivity Results when cells are destroyed by an immune response, often due to the combined activities of complement and antibodies Is a component of many autoimmune diseases Two significant examples Destruction of blood cells following an incompatible blood transfusion Destruction of fetal red blood cells in hemolytic disease of the newborn

ABO System and Transfusion Reactions Blood group antigens are the surface molecules of red blood cells The ABO blood group consists of two antigens designated A antigen and B antigen Each person’s red blood cells have either A antigen, B antigen, both antigens, or neither Transfusion reaction can result if individual receives blood of a different blood type Donor’s blood group antigens may stimulate the production of antibodies in the recipient that bind and eventually destroy the transfused cells

Transfusion Reactions If recipient has preexisting antibodies to foreign blood group antigens Immediate destruction of donated blood cells can occur by two mechanisms Antibody-bound cells may be phagocytized by macrophages and neutrophils Hemolysis- antibodies agglutinate cells, and complement ruptures them Can result in kidney damage, blood clotting and stress on the liver

Transfusion Reactions If recipient has no preexisting antibodies to foreign blood group antigens Transfused cells circulate and function normally for a while Eventually recipient’s immune system mounts a primary response against the foreign antigens that destroys them Happens gradually over an extended period such that severe symptoms and signs don’t occur

ABO Blood Group Characteristics and Donor/Recipient Matches Table 18.2

RH System and Hemolytic Disease of the Newborn Based on the rhesus, or Rh, antigen Antigen that is common to the red blood cells of humans and rhesus monkeys Transports anions and glucose across the cytoplasmic membrane Rh positive (Rh+) individuals have the Rh antigen on their red blood cells while Rh- individuals do not Preexisting antibodies against Rh antigen do not occur Risk of hemolytic disease of the newborn

Hemolytic Disease of the Newborn Figure 18.6a-b

Preventions of Hemolytic Disease of the Newborn Administer anti-Rh serum, called Rhogam, to Rh- pregnant women Destroys any fetal red blood cells that may have entered the body Sensitization of the mother does not occur and subsequent pregnancies are safer

Drug-Induced Cytotoxic Reactions Some drug molecules can form haptens Spontaneously bind to blood cells or platelets and stimulate the production of antibodies Can produce various diseases Immune thrombocytopenic purpura Agranulocytosis Hemolytic anemia

Purpura Figure 18.7

Type III (Immune-Complex Mediated) Hypersensitivity Due to the formation of antigen-antibody complexes, also called immune complexes Can cause systemic or localized reactions Systemic Systemic lupus erythematosus Rhematoid arthritis Localized Hypersensitivity pneumonitis Glomerulonephritis

Type III Hypersensitivity Figure 18.8

Localized Type III Hypersensitivity Reactions Hypersensitivity pneumonitis Individuals become sensitized when antigens are inhaled deep into the lungs, stimulating the production of antibodies Subsequent inhalation of the same antigen stimulates the formation of immune complexes that activate complement

Localized Type III Hypersensitivity Reactions Glomerulonephritis Immune complexes circulating in the bloodstream are deposited on the walls of glomeruli (small blood vessels in the kidney’s) Damage to the glomerular cells impedes blood filtration Result is kidney failure and ultimately death

Type IV (Delayed or Cell-Mediated) Hypersensitivity Inflammation due to contact with certain antigens occurs after 12-24 hours Result from the interactions of antigen, antigen-presenting cells, and T cells Delay in this response reflects the time it takes for macrophages and T cells to migrate to and proliferate at the site of the antigen

Type IV (Delayed or Cell-Mediated) Hypersensitivity Four examples Tuberculin response Allergic contact dermatitis Graft rejection Graft versus host disease

Tuberculin Response Skin of an individual exposed to tuberculosis or tuberculosis vaccine reacts to an injection beneath the skin of tuberculin Used to diagnose contact with antigens of M. tuberculosis No response when tuberculin injected into the skin of a never infected or vaccinated individual A red hard swelling develops when tuberculin is injected into a previously infected or immunized individual

Tuberculin Response The tuberculin response is mediated by memory T cells When first infected with M. tuberculosis, the resulting cell-mediated response generates memory T cells that persist in the body When sensitized individual is injected with tuberculin, dendritic cells migrate to the site and attract memory T cells T cells secrete cytokines that attract more T cells and macrophages to produce a slowly developing inflammatory response Macrophages ingest and destroy the tuberculin, allowing the tissue to return to normal

Allergic Contact Dermatitis A cell-mediated immune response resulting in an intensely irritating skin rash Response triggered by chemically modified skin proteins that the body regards as foreign Can happen when a hapten, such as the oil from poison ivy and related plants, binds to proteins on the skin In severe cases, TC cells destroy so many skin cells that acellular, fluid-filled blisters develop Other haptens include formaldehyde, cosmetics, and chemicals used to produce latex Can be treated with corticosteroids

Graft Rejection Rejection of tissues or organs that have been transplanted Grafts perceived as foreign by a recipient undergo rejection Graft rejection is a normal immune response against foreign major histocompatibility complex (MHC) proteins on the surface of graft cells Likelihood of graft rejection depends on the degree to which the graft is foreign to the recipient Based on the type of graft

Types of Grafts Figure 18.11

Privileged Sites Sites at which grafts are not likely to be rejected Different sites are privileged for different reasons The brain lacks lymphatic vessels, and its blood vessel walls are impermeable to lymphocytes such as T cells Cornea lacks extensive blood vessels Eyes and testes contain naturally high levels of immunosuppressive molecules Other sites either lack dendritic cells or express low levels of MHC molecules, so antigen processing does not occur

Why Fetuses are Not Rejected The fetus is not a privileged site but is not rejected Rejection is prevented by the many different immunosuppressive mechanisms Early embryos do not express MHC class I and II molecules on the placental layer that is in contact with maternal tissues Cytokines that enhance MHC expression have no effect on placental cells T cells are prevented from functioning in the placenta to reject the fetus

Graft-Versus-Host Disease Occurs when donated bone marrow cells regard the patient’s cells as foreign which produces an immune response against them If donor and recipient differ in MCH class I molecules, the grafted T cells attack all of the recipient’s tissues Produces destructive lesions in the skin and intestines If donor and recipient differ in MHC class II molecules, then the grafted T cells attack the antigen-presenting cells of the host Leads to immunosuppression Immunosuppressive drugs used to prevent graft rejection can stop graft-versus-host disease

Donor-Recipient Matching and Tissue Typing MHC compatibility between donor and recipient can be hard to achieve due to a high degree of variability among individuals The more closely the donor and recipient are related, the smaller the difference in their MHC Usually preferable that grafts are donated by a parent or sibling possessing MHC antigens similar to those of the recipient

Donor-Recipient Matching and Tissue Typing Tissue typing used to match donor and recipient as closely as possible when a closely related donors is not available Individual whose MHC proteins most closely match those of the donor is chosen to receive the graft A match of 50% or less of the MHC proteins is usually acceptable for most organs, but near absolute matches are required for successful bone marrow transplants

The Characteristics of the Four Types of Hypersensitivity Reactions Table 18.3

Immunosuppressive Drugs Valuable for successful transplants and for treating autoimmune disease Classes of immunosuppressive drugs Corticosteroids Cytotoxic drugs Immunophilins Lymphocyte-depleting therapies

The Four Classes of Immunosuppressive Drugs Table 18.4

Autoimmune Disease Due to phenomenon of autoimmunity whereby the body produces antibodies and cytotoxic T cells that target normal body cells Most autoimmune diseases appear to develop spontaneously and at random Some common features of autoimmune disease have been noted Occur more often in older individuals More common in women than men

Theories to Explain the Etiology of Autoimmunity Estrogen may stimulate the destruction of tissues by cytotoxic T cells Some maternal cells may cross the placenta, colonize the fetus (especially a female), and trigger autoimmune disease later in her life Environmental factors Some patients develop autoimmune disease following a viral infection Genetic factors Some individuals have MHC genes that in some way promote autoimmunity

Theories to Explain the Etiology of Autoimmunity T cell may encounter self-antigens that are normally “hidden” in sites where T cells rarely go Infections with a variety of microorganisms may trigger autoimmunity as a result of molecular mimcry Occurs when an infectious agent has an antigenic determinant that is similar or identical to a self-antigen The body produces antibodies that are autoantibodies which damage body tissues Failure of the normal control mechanisms of the immune system

Categories of Autoimmune Disease Two major categories Single tissue diseases Systemic diseases

Single Tissue Autoimmune Disease Can commonly affect various tissues Blood cells Endocrine glands Nervous tissue

Autoimmunity Affecting Blood Cells Production of autoantibodies to leukocytes Combating infections is difficult Production of autoantibodies to blood platelets Blood does not clot

Autoimmunity Affecting Blood Cells Production of autoantibodies to red blood cells resulting in autoimmune hemolytic anemia Autoantibodies made can be of different classes IgM-activate complement resulting in lysis of red blood cells IgG-serve as opsonins that promote phagocytosis of the red blood cells Some cases of autoimmune hemolytic anemia develop after a viral infection or treatment with certain drugs Alters the surface of red blood cells so they are recognized as foreign, triggering an immune response

Autoimmunity Affecting Endocrine Organs Production of autoantibodies or T cells can be against various endocrine organs Islets of Langerhans within the pancreas Can lead to the development of type I diabetes mellitus Results from the inability to produce insulin Some cases develop following a viral infections or in people with a genetic predisposition

Autoimmunity Affecting Endocrine Organs Thyroid gland Can cause Grave’s disease Autoantibodies bind and stimulate receptors on the cytoplasmic membranes of the cells in the anterior pituitary gland Stimulated cells produce thyroid-stimulating hormone Results in excessive production of thyroid hormone and growth of the thyroid gland

Autoimmunity Affecting Nervous Tissue Multiple sclerosis Cytotoxic T cells attack and destroy the myelin sheath that insulates the brain and spinal cord neurons and increases the speed of nerve impulses along the neurons Results in deficits in vision, speech, and neuromuscular function May be triggered by a viral infection

Systemic Autoimmune Diseases Systemic lupus erythematosus Rheumatoid arthritis

Systemic Lupus Erythematosus (SLE) Generalized immune disorder that results from a loss of control of both humoral and cell-mediated immune response Autoantibodies against DNA result in immune complex formation Deposition of complexes in the skin result in a characteristic butterfly-shaped rash for which the disease is named Complexes deposit in glomeruli and cause glomerulonephritis Complex deposition in the joints results in arthritis

Systemic Lupus Erythematosus (SLE) Autoantibodies can also occur against red blood cells, platelets, lymphocytes, and muscle cells Cause of lupus is unknown Develops in some patients due to a complement deficiency Treated with immunosuppressive drugs to reduce autoantibody formation, and with corticosteroids to reduce inflammation

Rheumatoid Arthritis Results from a type III hypersensitivity reaction B cells in the joints produce autoantibodies against collagen that covers joint surfaces The resulting immune complexes and complement bind mast cells Inflammatory chemicals released Inflammation causes damage to the tissues which in turn cause damage to joints Inflammation erodes the joint cartilage and neighboring bony structure

Rheumatoid Arthritis Joints become distorted and lose their range of motion Causes are unknown Treated with anti-inflammatory drugs to prevent further joint damage, and methotrexate to inhibit the humoral immune response

Immunodeficiency Diseases Conditions resulting from defective immune mechanisms Opportunistic infections can play an important part of these diseases

Immunodeficiency Diseases Two general types Primary Result from some genetic or developmental defect Develop in infants and young children Acquired Develop as a direct consequence of some other recognized cause Develop in later life

Primary Immunodeficiency Diseases Table 18.5

Acquired Immunodeficiency Diseases Result from a number of causes Sever stress Suppression of cell-mediated immunity results from an excess production of corticosteroids, which is toxic to T cells Malnutrition and environmental factors Inhibits production of B cells and T cells

Acquired Immunodeficiency Diseases Acquired immunodeficiency syndrome (AIDS) from infection with HIV Infects and kills helper T (CD4) cells When helper T cells reach critically low levels, infected individuals lose the ability to fight off infections