1. Disorders Associated with the Immune System
Chapter 19
Disorders Associated with the Immune System

2. Introduction
Hay fever/allergies, autoimmune disease, and transplant rejection are examples of harmful immune reactions
Infection and immunosuppression are failures of the immune system to function properly.
Superantigens cause indiscriminate activation of many T cell receptors at once to release excessive quantity of cytokines that cause adverse host responses

3. Hypersensitivity
An antigenic response leading to damage instead of protection (immunity)
Allergy = hypersensitivity
Occurs in a person who has been sensitized by previous exposure to an Ag (allergen)
Re-exposure with the same allergen cause the immune system to react in a damaging manner

4. Type I (Anaphylactic) Reactions
Reactions occur within 2 to 30 minutes after re-exposure in a sensitized person Ag + IgE Ab + mast cells or basophils
Localized: hay fever, hives or asthma from contact, inhaled or ingested antigens
Systemic: shock and breathing difficulties from injected Ag (sometimes ingested Ag for food); can be fatal
Figure 19.1a

5. Type I (Anaphylactic) Reactions
Skin testing may be helpful in diagnosing allergens inflammation = allergen
Not reliable for food-related allergies
Avoid contact
Desensitization
inject a series of dosages of the Ag beneath the skin to cause the production
of IgG instead of
IgE Abs
Figure 19.3

6. Type II (Cytotoxic) Reactions
Involve Ags located on cell or tissue surfaces, IgG or IgM antibodies, and complement
Complement activation causes cell lysis or damage by macrophages & other cells that attack Ab-coated cells (delayed for hr)
E.g. Transfusion reactions (ABO/Rh Ags on the red blood cells, RBCs)
Incompatible ABO blood type formation of Ag-Ab complex (in vitro = agglutination; in vivo = complement-mediated lysis of the donor RBCs)

7. Type II (Cytotoxic) Reactions
Rh incompatibility induce Abs production against donor’s Rh+ Ag in Rh- recipient (sensitization) when Rh+ blood is transfused into the same Rh- recipient again agglutination (in vitro) or complement-mediated hemolysis (in vivo)
E.g. Hemolytic Disease of the Newborn (HDNB) = Rh incompatibility during pregnancy (if mother is Rh- & father is Rh+)
Passive immunization of mother with anti-Rh Abs after the birth of first Rh+ baby to prevent HDNB

8. ABO blood group system
Table 19.2

9. Hemolytic disease of the newborn
Figure 19.4

10. Drug-induced thrombocytopenic purpura
Destruction of platelet by drug-induced cytotoxic reactions
Results in hemorrhages & purple spots (purpura) on the skin
Similar phenomena exist for drug-induced cytotoxic reactions of white blood cells or RBCs (hemolytic anemia)
Figure 19.5

11. Type III (Immune Complex Reactions)
Involves Abs (usually IgG) against soluble Ags circulating in the serum
Small Ag-Ab complexes formed (escape phagocytosis) are deposited in the basement membrane beneath the cells or organs to cause inflammatory damage (mediated by complement)
E.g. glumerulonephritis cause inflammatory damage to the kidney glomeruli (sites of blood filtration)

12. Type III (Immune Complex) Reactions
IgG antibodies and antigens form complexes that lodge in basement membranes.
Figure 19.6

13. Type IV (Cell-Mediated) Reactions
Delayed-type hypersensitivities due to TD cells (TB skin test)
Upon re-exposure to the same foreign Ags, memory T cells secrete cytokines to attract macrophages and initiate tissue damage (by TC cells)
Figure 19.8

14. Type IV (Cell-Mediated) Reactions
E.g. Allergic contact dermatitis (poison ivy, cosmetics, and the metals in jewelry)
Caused by haptens that combine with proteins in the skin of some people
Hypersensitivity to latex (reaction against chemicals used in manufacturing of latex) may cause anaphylactic shock (leading to death)
Patch test used to determine environmental factor inducing dermatitis look for inflammation in 48 hr

16. Autoimmune Diseases
Clonal deletion during fetal development ensures self-tolerance
Autoimmunity is loss of self-tolerance
Autoimmune disease: damage to one’s own organs due to action of the immune system (production of Abs or by sensitized T cells against one’s own tissue Ags)
Relatively rare; affect about 5% of population in the developed world; about 75% of the cases selectively affect women

17. Autoimmune Diseases
Autoimmune reaction can be cytotoxic, immune complex, or cell-mediated in nature
Type I Due to antibodies against pathogens which end up attacking self cells (due to similarity between Ags)
Type II Antibodies react with cell-surface antigens, but no cytotoxic destruction of the cells; e.g. Graves’ disease & myasthenia gravis

18. Autoimmune Diseases
Type III (Immune Complex) immune complexes (formed by Ag + IgM, IgG + complement) deposited in tissues; e.g. Systemic lupus erythematosus (mainly in women; deposit in the kidney glomeruli), & rheumatoid arthritis (deposit in the joints)
Type IV mediated by T cells to attack or destroy self components; e.g. Multiple sclerosis (myelin sheath of nerves), & insulin-dependent diabetes mellitus (insulin-secreting cells of the pancreas)

19. Reactions Related to the Human Leukocyte Antigen (HLA) Complex
Histocompatibility antigens: self antigens on cell surfaces (inherited genetic differences among individuals)
Major histocompatibility complex (MHC): genes encoding histocompatibility antigens
Human leukocyte antigen (HLA) complex: MHC genes in humans
Most Ags stimulate immune response only if they are associated with an MHC molecule

20. HLA Typing Used to identify and compare HLAs
Can identify susceptibility to diseases

21. HLA Typing
Used to match donor & recipient of transplantation (tissue typing) to avoid rejection
Also need to match ABO blood type
PCR can be used in HLA typing
Figure 19.9

22. Reactions to Transplantation
Transplants may be attacked by T cells (direct lysis of grafted cells/tissues), macrophages, and complement-fixing antibodies if recognized as nonself.
Transplants to privileged sites (cornea & brain) do not cause an immune response.
Stem cells may allow therapeutic cloning to avoid rejection.
Stem cells can give rise to more stem cells & generate different cell types (nerves, blood, or liver cells)

23. Grafts Autograft: use of one's own tissue
Isograft: use of identical twin's tissue
Allograft: use of tissue from another person
Xenotransplantation product: use of non-human tissue (need to overcome hyperacute rejection)
Graft-versus-host disease can result from transplanted bone marrow that contains immunocompetent cells
Cell-mediated immune response by transplanted bone marrow against host’s tissue

24. Immunosuppression
Immunosuppression prevents an immune response to transplanted tissues
Generally suppress cell-mediated immunity using immunosuppressant drugs
Cyclosporine suppresses IL-2
Mycophenolate mofetil inhibits T cell and B cell proliferation
Sirolimus blocks IL-2 & inhibit both cell-mediated & humoral immunity
Ideal solution = induce tolerance (see transplants as self)

25. Immune Deficiencies Absence of a sufficient immune response
Congenital: due to defective or missing genes
Selective IgA immunodeficiency
Severe combined immunodeficiency
Nude mouse (lack thymus = no T cells); DiGeorge syndrome in human (lack a thymus gland)
Acquired: develop during an individual's life, due to drugs, cancers, or infections
Artificial: Immunosuppression drugs
Natural: HIV infections

26. The Immune System and Cancer
Immunological surveillance: body’s immune response to cancer
Cancer cells arise by mutation or virus-induced changes by escaping the immunological surveillance and becomes resistant to immune rejection
Immune system (esp. cell-mediated immunity) constantly patrols and eliminates mutated cells before they become established tumors
Cancer cells possess tumor-specific Ags

27. The Immune System and Cancer
TC cells recognize and lyse cancer cells
Cancer cells may lack tumor antigens; kill TC cells; grow faster to outpace the immune response
Figure 19.11

28. Immunotherapy Treatment of cancer using immunologic methods
Tumor necrosis factor, IL-2, and interferons may kill cancer cells
Immunotoxins link poisons with an monoclonal antibody (Mab) directed at a tumor antigen Mab selectively locates the cancer cell and destroy only the cancer cell
Vaccines containing tumor-specific antigens has been effective for a type of cancer in poultry

29. Acquired Immunodeficiency Syndrome (AIDS)
1981 In U.S., cluster of Pneumocystis and Kaposi's sarcoma in young homosexual men discovered. The men showed loss of immune function.
1983 Discovery of virus (HIV) causing loss of immune function that selectively infects T helper cells

30. The Origin of AIDS AIDS is the final stage of HIV infection
Crossed the species barrier into humans in Africa in the 1930s
Patient who died in 1959 in Congo is the oldest known case
Spread in Africa as a result of urbanization
Spread in world through modern transportation and unsafe sexual practices
Norwegian sailor who died in 1976 is the first known case in Western world

31. Structure of HIV (human immunodeficiency virus)
Retrovirus (genus Lentivirus) with 2 identical strands of RNA
Figure 19.12a

32. Multiplication of Retroviridae
Reverse transcriptase
Capsid
DNA
Virus
Two identical + stands of RNA 1
Retrovirus penetrates host cell.
Host cell
DNA of one of the host cell’s chromosomes 5
Mature retrovirus leaves host cell, acquiring an envelope as it buds out.
Reverse transcriptase
Viral DNA 2
Viral RNA
Virion penetrates cell and its DNA is uncoated; reverse transcriptase produce double-stranded DNA from viral RNA
Identical strands of RNA 4
Transcription of the provirus may also occur, producing RNA for new retrovirus genomes and RNA that codes for the retrovirus capsid and envelope proteins.
Viral proteins
RNA 3
The new viral DNA is transported into the host cell’s nucleus and integrated as a provirus. The provirus may divide indefinitely with the host cell DNA.
Provirus
Figure 13.19

33. HIV Infection
Spikes (gp120) enable the virus to attach to the CD4 receptor in association with coreceptor (CXCR4) on the T helper cells, macrophages, and dendritic cells
Figure 19.12b

34. HIV Infection
Following attachment, HIV penetrate the host cell (uncoating of virion) & viral RNA is transcribed into double-stranded DNA by viral reverse transcriptase
Viral DNA gets incorporated into the host chromosomal DNA (provirus)
Provirus evades host immune system
Proviral DNA can cause active HIV infection or latent infection

35. HIV Infection (T cells)
Active infection: proviral DNA directs synthesis of new viruses; new virus bud from the host cell
Latent infection: proviral DNA stays dormant; no viral genes nor new viruses are made
Figure 19.13

36. HIV Infection (macrophages)
Figure 19.14

37. HIV Infection
HIV evades the immune system by staying as provirus (latency), latent virions in vacuoles, cell-cell fusion (to move to adjacent uninfected cell), and rapid antigenic changes (no proofreading mechanism for reverse transcriptase)
Clades: subtypes (of HIV)
HIV-1 is the most common. It has 11 clades:
90% of U.S. infections caused by clade B
Clade C predominates in sub-Saharan African
Clades B, C, & E are in south and southeast Asia
HIV-2 is seen in western Africa

38. The Stages of HIV Infection
(Persistent infection by Candida albicans)
(Clinical AIDS;
CMV, TB, Pneumocystis, toxoplasmosis, & kaposi’s sarcoma)
Figure 19.15

39. Some Common Diseases Associated with AIDS
Table 19.5

40. Diagnostic Methods Seroconversion (Ab testing) takes up to 3 months
HIV antibodies detected by ELISA
HIV antigens detected by Western blotting
Plasma viral load tests (detect and quantify HIV circulating in the blood) is determined by PCR or nucleic acid hybridization
PCR testing narrow the window of nondetection to about 12 days

41. HIV Transmission HIV survives 6 hours outside a cell
HIV survives >1.5 days inside a cell
Infected body fluids transmit HIV via:
Sexual contact
Breast milk
Transplacental infection of fetus
Blood-contaminated needles
Organ transplants
Artificial insemination
Blood transfusion

42. Modes of HIV Transmission
Figure 19.17

43. AIDS Worldwide
Global pandemic – rapid & continuing spread of new infections
Three basic epidemiological patterns
U.S., Canada, western Europe, Australia, northern Africa, South America
Injecting drug use, male-to-male sexual contact
Sub-Saharan Africa
Heterosexual contact
Eastern Europe, Middles East, Asia
Injecting drug use, heterosexual contact

44. AIDS Worldwide
Figure 19.16

45. Prevention of AIDS Use of condoms and sterile needles
Health-case workers use universal precautions
Wear gloves, gowns, masks, goggles
Do not recap needles
Risk of infection from infected needlestick injury is 0.3%
HIV vaccines
Rapid mutation rate of HIV  difficult to develop a vaccine effective for all forms of HIV

46. Prevention and Treatment of AIDS
Current vaccine development
Whole-cell Salmonella with gp120 gene
Subunit vaccine using gp120 expressed in Saccharomyces
Canarypox virus with HIV capsid protein genes
Naked DNA consisting of tat (transcription factor) or gag (capsid protein) genes
Available drugs only delay the progress of the infection; do not cure HIV infection
Treat opportunistic infections & to inhibit HIV multiplication

47. Treatment of AIDS (Chemotherapy)
Nucleotide Reverse Transcriptase Inhibitors
Non- Nucleoside Reverse Transcriptase Inhibitors
Protease Inhibitors
Virus decoys
Highly Active Antiretroviral Therapy (HAART): combinations of nucleoside reverse transcriptase inhibitors + Non-nucleoside reverse transcriptase inhibitor or protease inhibitor

48. Chapter Review
Know how hypersensitivity occurs and the four classes of hypersensitivity.
An antigenic response leading to damage instead of protection (immunity)
Allergy = hypersensitivity
Occurs in a person who has been sensitized by previous exposure to an Ag (allergen)
Re-exposure with the same allergen cause the immune system to react in a damaging manner (IgE + mast cells or basophils)

50. Chapter Review
2. Know how autoimmune diseases occur and four types of autoimmune diseases.
Autoimmunity is loss of self-tolerance; reaction can be cytotoxic, immune complex, or cell-mediated in nature
Autoimmune disease: damage to one’s own organs due to action of the immune system (production of Abs or by sensitized T cells against one’s own tissue Ags)

51. Chapter Review
Type I: due to antibodies against pathogens which end up attacking self cells (due to similarity between Ags)
Type II: antibodies react with cell-surface antigens, but no cytotoxic destruction of the cells; e.g. Graves’ disease & myasthenia gravis
Type III (Immune Complex): immune complexes (formed by Ag + IgM, IgG + complement) deposited in tissues; e.g. Systemic lupus erythematosus (mainly in women; deposit in the kidney glomeruli), & rheumatoid arthritis (deposit in the joints)

52. Chapter Review
Type IV: mediated by T cells to attack or destroy self components; e.g. Multiple sclerosis (myelin sheath of nerves), & insulin-dependent diabetes mellitus (insulin-secreting cells of the pancreas)
3. Know what HLA typing is used for, different types of grafts & how transplantation is rejected.
Used to identify and compare HLAs (self MHC)
Can identify susceptibility to diseases
Used to match donor & recipient of transplantation (tissue typing) to avoid rejection

53. Chapter Review
Transplants may be attacked by T cells (direct lysis of grafted cells/tissues), macrophages, and complement-fixing antibodies if recognized as nonself.
Autograft: use of one's own tissue
Isograft: use of identical twin's tissue
Allograft: use of tissue from another person
Xenotransplantation product: use of non-human tissue (need to overcome hyperacute rejection)

54. Chapter Review
4. Know what immunosuppression is and what immune deficiency is.
Immunosuppression prevents an immune response to transplanted tissues
Generally suppress cell-mediated immunity using immunosuppressant drugs
Immune deficiency: absence of a sufficient immune response
Congenital: due to defective or missing genes
Acquired: develop during an individual's life, due to drugs, cancers, or infections

55. Chapter Review 5. Know how cancer develops
Artificial: Immunosuppression drugs
Natural: HIV infections
5. Know how cancer develops
Immunological surveillance: body’s immune response to cancer
Cancer cells arise by mutation or virus-induced changes by escaping the immunological surveillance and becomes resistant to immune rejection

56. Chapter Review Cancer cells possess tumor-specific Ags
Immune system (esp. cell-mediated immunity) constantly patrols and eliminates mutated cells before they become established tumors
Cancer cells possess tumor-specific Ags
TC cells recognize and lyse cancer cells
Cancer cells evade immune surveillance by: may lack tumor antigens; kill TC cells; grow faster to outpace the immune response

57. Chapter Review
6. Know why HIV infection is classified as acquired immunodeficiency; how HIV infection occurs and how it evades the host immune system
HIV infection results in absence of a sufficient immune response because it destroys certain component of the immune system (by infecting T helper cells, and APCs such as macrophages and dendritic cells)

58. Chapter Review
Spikes (gp 120) allows HIV to attach to a host CD4 receptor and coreceptor. Virus enters the host cell (uncoating of viral RNA). Viral RNA transcribed into double-stranded DNA by viral reverse transcriptase. Viral DNA gets incorporated into the host chromosomal DNA and can cause an active infection (host may or may not die) or become a latent infection.

59. Chapter Review
HIV evades the immune system by staying as provirus (latency), latent virions in vacuoles, cell-cell fusion (to move to adjacent uninfected cell), and rapid antigenic changes (no proofreading mechanism for reverse transcriptase).