Immunology: Chapter 13

Question 1

Mechanism #1 (Escaping immune response by alteration of antigen)

Answer 1

Using a wide variety of antigenic types
Ex: 84 varieties of Streptococcus pneumonia
Differ in their capsular polysaccharides (serotypes)
Each type is a different organism
Immunity to one confers NO protection against the others
1 variable pathogen can cause the same disease repeatedly

Question 2

Mechanism #2 (Escaping immune response by alteration of antigen)

Answer 2

Antigenic drift and antigenic shift
Ex: Influenza
Gradual development of immunity by directing neutralizing antibody against major surface proteins of hemmagglutinin

Question 3

Antigenic drift

Answer 3

Every 2-3 years, a variant arises with point muttons that allow virus to escape detection by antibodies (neutralizing antibody no longer binds)
Virus is resistant to T cells (CD8 in particular)
Epidemic that is relatively mild vlc most people have at least some cross-reactivity with the new virus

Question 4

Antigenic shift

Answer 4

Major pandemics ad fatal disease
Caused by reassortment of the segmented RNA genome
No cross-protective immunity to virus expressing a novel hemagglutinin
Major changes in hemagglutinin protein on the viral surface
Virus is recognized poorly, if at all, by antibodies and T cells from the previous variant

Question 5

Mechanism #3

Answer 5

Programed rearrangements in the DNA of the pathogen
Ex: Trypanosomes (sleeping sickness)
Glycoprotein coat (encoded by VSG genes) elicits powerful antibody response –> clears most parasites
~1,000 inactive VSG genes
Only one is expressed at a time; plead in an ‘expression site’
Active gene can be replaced by another VSG gene in the active site –> gene conversion
Immune system must start all over again
New, repeated cycles of new disease followed by antibody production and clearance
Chronic cycle leads to immune-complex damage, inflammation and neurological damage
End result: coma

Question 6

Latency

Answer 6

Some viruses persist in vivo by ceasing to replicate until immunity wanes
Some enter state of latency (virus isn’t being replicated) –> not sensitive to CD8 T cells
Causes recurring illnesses
Ex: Herpes simplex virus Type I: cause of cold sores
Infects epithelia and spreads to sensory neurons
Some viruses infect nerve cells and travel up the axon to the main body of the cells (persists in latent, non-replicating state)
Non-repicating virus particle sends out no signals and cannot be detected by the immune system
Virus can be reactivate by sunlight, bacterial infections, hormonal changes, or environmental stress
Virus travels down the neurons and infects epithelial cells –> immune respond is reactivated
Cycle can be repeated many times
Neurons contain few MHC class I molecules
Infection is cleared inn epithelial cells
Killing of infected neurons (by CD8 T cells) may not be a good idea b/c neurons regenerate slowly, it at all
Neurons are particularly prone to latent viral infections

Question 7

Myobacterium tuberculosis

Answer 7

Taken up by macrophages
Prevents fusion of the phagosome with the lysosome
Evolved to grow in macrophage vesicles

Question 8

Many viruses subvert various arms of immune system:

Answer 8

Capturing cellular genes for cytokines and cytokine receptors
Synthesizing complement-regulatory moledules
Inhibiting MHC class I synthesis or assembly
Producing decoy proteins that affect Toll-like receptor signaling

Many pathogens cause a mild or transient immunosuppression during acute infection
Makes host susceptible to secondary infection
Follows trauma, burns, and major surgery
Multi-nutrient deficiency –> immunosuppression
Immune system is 1st to suffer in protein deficiency

Question 9

Measles

Answer 9

Causes generalized immunosuppression
10% of global mortality of children under 5
8th leading cause of death worldwide
Malnourished children are main victims
Combined effects of malnourishment and measles
Cause of death is pneumonia
Lasts several months
Measles infect dendritic cells –> prevents T cell activation

Question 10

Immune responses can contribute directly to pathogenesis

Answer 10

Tuberculoid leprosy: problems are caused mostly by immune response (immunopathology)
Fever is caused by cytokines released by macrophages

Question 11

Overview HIV

Answer 11

Characterized by:
Susceptibility to infection with opportunistic pathogens
Occurrence of aggressive form of Kaposi’s sarcoma or B-cell lymphoma
HIV-1 (most common) and HIV-2
Worst is Africa, especially sub-Sahara (South Africa)
Most individuals infected with HIV progress to AIDS

Question 12

HIV… Spread by:

Answer 12

Sexual intercourse
Contaminated needles used for intravenous drug delivery
Contaminated blood or blood products
Hemophiliacs

Question 13

Transmission of HIV to children

Answer 13

In Africa, route of transmission is from infected mother to her baby at birth, or through breast milk
Virus may gain access in milk as a result of mastitis: pathogenic bacteria, such as staphylococcus aureus enter the mammary gland through the lactiferous ducts
Inflammatory response and breakdown of tight junctions between epithelial cells lining mammary glands
Allows immune factors, but also HIV to enter mammary gland
Made worse by vitamin A deficiency (independently results in disorganized epithelial colonies w/o tight junctions)
May gain access through cracked nipples at time of feeding
Can occur at birth (~25% chance): can be greatly reduced by treating pregnant HIV-positive women with zidovudine (AZT)

Question 14

Infection by HIV

Answer 14

Virusis carried mainly in infected cells that express CD4
CD4 is surface receptor for virus
Co-receptor is also required for binding:
CCR5 for “R5” viruses: main form
CXCR4 for “X4” viruses: appears late in infection cycle in some individuals
Virus os also present as free virus in blood, semen, vaginal fluid or mother’s milk

Question 15

Acute (initial) phase of HIV infection

Answer 15

CD4 T cells are obvious target of HIV, but not only target
Characterized by influenza-like illness in 80% of cases
Abundance of virus (viremia) in peripheral blood
Marked drop in number of circulating CD4 T cells
results in activation of CD8 T cells –> kill HIV-infected cells
Results in antibody production
Seroconversion: appearance of antibody in the blood as a result of infection/immunization
CD4 T levels decline rapidly, then rebound to ~800 cells/ul
“Symptomatic phase”: you know you are sick
**BEST indicator of future disease is the level of virus that persists in blood plasma once the symptoms of acute viremia have passed (2-12 year stage)
“Quiescent period” is a misnomer: virus continues to replicate at a very high rate

Question 16

Reasons for loss of CD4 T cells

Answer 16

CD4 T cells are killed by virus
Infected CD4 T cells may undergo apoptosis
Infected CD4 T cells are killed by cytotoxic CD8 T cells
Regeneration of new CD4 T cells is defective

Question 17

Not everyone infected with HIV goes on to develop AIDS

Answer 17

Exception #1: Small % of people seroconvert (make anti-HIV antibody), but have very low levels of circulating virus and do NOT seem to have progressive disease
Exception #2: seronegative people exposed to HIV and remain disease-free and virus-negative
Have specific cytokine and TH1 lymphocytes directed at infection
Anti-HIV cytotoxic CD8 T and CD4 TH1
Have either been exposed to HIV or to non-infectious HIV antigens

Question 18

HIV is a retrovirus that infects CD4 T cells, dendritic cells, and macrophages

Answer 18

Is an enveloped virus
Contains:
   2 copies fo an RNA genome
   Numerous copies of essential enzymes
Surrounded by a nucleocapsid (protein)
Whole structure is surrounded by an envelope (membrane structure with phospholipids and proteins)

Question 19

Virus enters cell

Answer 19

Via 2 non-covalently associate viral glycoproteins in the cell envelope, gp120 and gp41 (bind with high affinity to the cell surface molecule CD4)
gp120 must bind to co-receptor before virus can fuse with and enter the cell
Outer membranous envelope fuses with the cell membrane and the nucleocapsid breaks down
HIV does NOT grow in inactive T cells
CCR5: expressed on dendritic cells, macrophages and CD4 T cells
CXCR4: expressed on activated CD4 T cells

Question 20

Drugs

Answer 20

Different drugs attack different phases of the life cycle

Question 21

Non-classical (but deadly) form of HIV entry

Answer 21

HIV binds to DC-SIGN on dendrties extending onto the lumen of the intestinal epithelium
Binding of viral gp120 to dendritic cell-surface molecule DC-SIGN
Portion is taken up into (/protected by) vacuoles and remains dormant there until the dendritic cell contacts a CD4 T cell
Infects that T cell directly, OR infects via immunological synapse formed between dendritic cells and CD4 T cells

Question 22

Another non-classical form of entry

Answer 22

R5 HIV virions bind to CCR5 and glycosphingolipid galactosyl ceramide
Both are expression on apical surfaces of epithelial cells lining the rectum and endocervix
Transport R5 HIV variants (not X4) through epithelial monolayer
Allows HIV to infect submucosal CD4 T cells and dendritic cells

Question 23

What HIV infects

Answer 23

CD4 T cells
Dendritic cells (in classical way) and macrophages
These cells express small # of CD4 surface molecules + chemokine co-receptor
Does NOT seems to kill dendritic cells and macrophages
Cells may constitute long-term reservoirs of infection

Question 24

Genetic factors- in HIV

Answer 24

HLA genotype can either hasten or delay disease progression
Homozygousity for HLA class I: rapid progression
Homozygous for a 32-base pair deletion (nonfunctional allele) of CCR5 cannot be infected by R5 strains of HIV (Can be infected by X4 strains)
~16% of Caucasions are heterozygous and ~1% are homozygous
Heterozygotes are likely have slower disease progression

Question 25

Lymphoid tissue is a major reservoir for HIV infection

Answer 25

Infected T cells, monocytes, macrophages, and dendritic cells Trapped in the form of immune complexes on the surfaces of FDCs in germinal centers ~95% pf virus in blood is produced by infected CD4 T cells Memory CD4 T cells can be infected with HIV. Virus is maintained in the cells, but cannot grow in them and cannot be recognized by immune system If memory T cell is later activated (by recognition of its antigen) it will produce virus that can spread to other activated T cells Macrophages and dendritic cells can harbor replicating HIV w/o being killed Important reservoir of infection May be involved in spreading viruses to other tissues

Question 26

Elite Controllers

Answer 26

Group of people who are infected with HIV, but contain very low levels of virus and do not progress toward active disease Their central memory CD4 T cels contain a mutant receptor that either prevents or greatly hinders HIV infection (Recall: memory CD4 T cells: central and effector) HIV infection of these central memory CD4 T cells seems to be necessary to establish a persisting infection that eventually --> AIDS + death of host If central memory CD4 T cells are not infected, host is able to control the disease indefinitely (elite), even though the infected host may be unable to eliminate HI

Question 27

Host response to HIV

Answer 27

Strong CD8 T cel response is crucial (slows progression of AIDS) --> especially HIV-specific Strong CD4 T cell proliferation response is important Immune response is never strong enough and virus eventually wins Developing anti-HIV antibodies is difficult b/c: Newly released virus is heavily glycosylated and hard for antibody to recognize Antibodies are useless against established disease Virus has high mutation rate (rapid)

Question 28

New development

Answer 28

Host-cell cytidine deaminase (takes away amino group --> uracil) called APOBEC causes extensive mutation of newly formed HIV cDNA --> destroys its coding and replicative capacity APOBEC is active in resting CD4 T cells, but inactivated by the HIV virus

Question 29

HAART therapy

Answer 29

Highly active antiretroviral therapy Drugs that block HIV replication lead to rapid decrease in titer of infectious virus + increase in CD4 T cells A drug cocktail that reduced HIV to such low levels, that very few virions remain- not enough to mutate and are barely detected Ending HAART leads to rapid rebound in virus multiplication (from nay reservoirs) Therapy is accompanied by a slow, but steady increase in CD4 T cell count ~10^9 to 10^10 new visions are generated each day in an HIV-infected person Due to error-prone nature of reverse transcriptase and of RNA polymerase that makes vision RNA molecules from viral DNA Both enzymes lack proofreading mechanisms Must continually monitor effectiveness. If resistance develops, you much change to another formula.\ If mutation were 10^-3: 10^9 viruses --> 10^6 viruses would be formed in each generation 100 viruses is unlikely to give a single mutation

Question 30

HIV in the U.S.

Answer 30

~900,000 infected Americans 1/4 are unaware of their infection Number had double in the last 8 years b/c people don't die so readily (effectiveness of HAART treatment) ~40,000 new cases each year Especially a problem among African Americans (poverty, substance abuse, and increased rates of other STDs that facilitate HIV infection) AIDS is the #1 cause of death among young A. American women (acquire disease from older male sex partners)