1. Hypersensitivities, Autoimmune Diseases, and Immune Deficiencies18
Hypersensitivities, Autoimmune Diseases, and Immune Deficiencies

2. 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)

3. 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

4. Sensitization
Figure 18.1a

5. Degranulation
Figure 18.1b

6. 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

7. Inflammatory Molecules Released from Mast Cells
Table 18.1

8. 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

9. 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

10. 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

11. 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

12. 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

13. Skin Test of Type I Hypersensitivity
Figure 18.4

14. 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

15. 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

16. 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

17. 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

18. 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

19. ABO Blood Group Characteristics and Donor/Recipient Matches
Table 18.2

20. 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

21. Hemolytic Disease of the Newborn
Figure 18.6a-b

22. 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

23. 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

24. Purpura
Figure 18.7

25. 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

26. Type III Hypersensitivity
Figure 18.8

27. 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

28. 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

29. Type IV (Delayed or Cell-Mediated) Hypersensitivity
Inflammation due to contact with certain antigens occurs after 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

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

31. 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

32. 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

33. 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

34. 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

35. Types of Grafts
Figure 18.11

36. 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

37. 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

38. 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

39. 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

40. 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

41. The Characteristics of the Four Types of Hypersensitivity Reactions
Table 18.3

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

43. The Four Classes of Immunosuppressive Drugs
Table 18.4

44. 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

45. 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

46. 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

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

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

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

50. 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

51. 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

52. 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

53. 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

54. Systemic Autoimmune Diseases
Systemic lupus erythematosus
Rheumatoid arthritis

55. 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

56. 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

57. 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

58. 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

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

60. 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

61. Primary Immunodeficiency Diseases
Table 18.5

62. 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

63. 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