Chapter 12 Failure of Host Defense Mechanisms

1. Part V: The Immune System in Health and Disease Chapter 12 Failure of Host Defense Mechanisms 1. Pathogen avoids the immune system [Pathogens avoid the immune system long enough to infect another person. Killing the host (or killing him too soon) is usually disadvantageous to the pathogen.] Pathogen and host co-evolve, neither eradicating the other (usually) Host invents defenses pathogen invents strategies to avoid the defenses • 2. Immunodeficiency • Inherited • acquired (e.g., HIV/AIDS)

2. Antigenic Variation (three types) ~84 Streptococcus pneumoniae serotypes 1. A variety of serotypes (antigenic types) simultaneously in the environment Therefore, each infection with a different serotype is like a new disease Similar for the virus that causes common cold Explains why a vaccine for these diseases is difficult. (A 23-valent capsular S. pneumoniae polysaccharide vaccine is available.) Explains why younger people get more colds than older people. Figure 12.1 7th ed

3. Antigenic Variation (three types) 2. Changes by mutation or gene exchange: antigenic drift and antigenic shift 2. Changes by mutation or gene exchange: (a) antigenic drift and (b) antigenic shift The problem for the influenza virus is that it rapidly infects many people. Since immunity protects from reinfection, virus will quickly run out of hosts to infect. The solution is to mutate such that new antigens are presented each year. Antigenic drift leaves some epitopes from previous strain. Thus, previous exposure (immunity) to related stains may ease the severity of the disease and the symptoms but still lets the virus replicate and spread.

4. Antigenic Variation (three types) Bird influenza virus Human influenza virus 2. Changes by mutation or gene exchange: antigenic drift and antigenic shift Antigenic shift can create viruses that do not share epitopes with previous strains (no cross-reaction). Therefore, there is no partial protection from previous infections and the disease is much more severe than in years where there is only antigenic drift. The flu pandemic of 1918-19 killed >40,000,000. Was the worst pandemic of the last century. Also, antigenic shifts in 1957 and 1968

5. Antigenic Variation (three types) 3. Changes by gene rearrangements (gene conversion) African trypanosomes (protozoan) cause African sleeping sickness. In the terminal stages of the disease there is severe neurological damage, coma and death VSG=variant-specific glycoprotein Figure 12-3 Similar mechanisms used by salmonella and gonorrhea

6. Some viruses become latent. When latent, there is no viral replication, there are no viral proteins made and thus, no immune response. Herpes virus (simplex, zoster) becomes latent Herpes simplex I becomes latent in nerves because nerves are low in MHC class I*. When immunity is low, virus can emerge from the nerves, infect epithelia, reproduce and spread. ~90% of the population have latent herpes simplex I (causes cold sores/fever blisters) but only about 15% of the population gets symptoms. *Why would nerves be low in MHC class I?

7. Mechanisms of subversion of host defenses by viruses

8. Superantigen can activate T cells and B cells This T cell does not bind this B cell because the B cell is presenting no peptide or a peptide that is not recognized by this T cell (e.g. the B cell binds e. coli flagellum and the T cell binds polio virus capsid) This is the same T cell and B cell from above; however, now, the B cell is infected with MMTV* and is making a superantigen (ORF) *Mouse mammary tumor virus Not in book The superantigen binds to MHC class II and to TCRs that use a particular v gene segment. Thus, in the presence of the superantigen, any T cell that uses that particular v gene segment to make its TCR, regardless of its antigen-specificity, will bind to MHC class II and deliver signals as if it had bound antigen.

9. Mouse mammary tumor virus (MMTV) uses superantigen to aid in its replication Not in book Some mice make their own superantigens. This causes all T cells that use a particular v gene to be deleted in the thymus. Thus, they are protected from the MMTV (but sacrifice a significant proportion of their T cell repertoire). MMTV is a retrovirus

10. Symptoms of leprosy range from somewhat mild to severe. It appears that the severity of the disease is related to whether the immune system responds to the infecting bacteria with a TH1 or TH2 response

11. Inherited Immunedeficiencies Lots of them because the immune system has lots of components. The most severe deficiencies will be rare because they will be lethal. In fact, the the first immunoeficiencies were not describe until 1952 because death from infectious diseases was so common that the underlying causes of death from infection were not explored. What happened around 1952 that helped reveal the immunodeficiences that lead to bacterial infections? Answer: Antibiotics

12. X-linked agammaglobulinemia (XLA)

13. Infants go through a period of low Ig levels at around 3-12 months of age (immunodeficiency?)

14. Defects in the complement system can be serious

15. Defects in phagocytic cells Prevents adhesion and migration Respiratory burst defect, chronic TH1 stimulation Respiratory burst defect Respiratory burst defect Vesicle fusion defect

16. Severe combined immunodeficiency syndromes Adenosine deaminase deficiency

17. Bone marrow transplants can correct most immune defects [however, the procedure is only done in the most severe cases because there are significant risks (including death) from the procedure]. Also a cure for certain leukemias Irradiated the recipient to remove existing malfunctioning immune system (or leukemia) and mature T cells Allele or Haplotype?? MHCA is yellowMHCB is blue Thymic epithelium (positive selection for MHC-restriction specificity) Bone marrow-derived APC (negative selection against anti self specificity) Must remove mature T cells from both the recipient and the donor tissue (see next slide for the consequence if mature T cells are not removed) Recall: semi-allogeneic bone marrow transplants work but fully-allogeneic bone marrow transplants do not work (see figure 7.28 and Chapter 7 slides 23-28)

18. Mature T cells from the donor must not be present if a semi-allogeneic graft to an immunoincompetent individual is to be successful because these T cell will kill the host (GVHD). (immunoincompetence from genetic defect or irradiation). Mature T cell in the host must not be present if a semi-allogeneic graft is to be successful because these T cells will reject the grafted tissue Bone Marrow Transplants Yellow is graft Blue is recipient If the graft is not successful the recipient is left with no immune system (from irradiation) and may not survive Figure 12.16

19. Human immunodeficiency virus (HIV) cause acquired immune deficiency syndrome (AIDS) More than 25 million people have died of AIDS since 1981. Africa has 12 million AIDS orphans. At the end of 2006, women accounted for 48% of all adults living with HIV worldwide, and for 59% in sub-Saharan Africa. Young people (15-24 years old) account for half of all new HIV infections worldwide - around 6,000 become infected with HIV every day. In developing and transitional countries, 6.8 million people are in immediate need of life-saving AIDS drugs; of these, only 1.65 million are receiving the drugs.

20. The latest statistics of the global HIV and AIDS were published by UNAIDS in November 2009, and refer to the end of 2008. More than 25 million people have died of AIDS since 1981. Africa has over 14 million AIDS orphans. At the end of 2008, women accounted for 50% of all adults living with HIV worldwide In developing and transitional countries, 9.5 million people are in immediate need of life-saving AIDS drugs; of these, only 4 million (42%) are receiving the drugs.

21. Human immunodeficiency virus (HIV) cause acquired immune deficiency syndrome (AIDS) HIV infects CD4+ cells and macrophages [CD4 is a receptor for the virus; CCR5 (a chemokine receptor) is a co-receptor] CD4+ cells in HIV infected individuals For us, AIDS is defined as fewer than 200 CD4+ cells per ml of blood

22. The HIV Genome

23. Opportunistic Infections and Cancers That Kill AIDS Patients