Lecture 5: The Immune System (Part 2) PubHlth 80

B-cell

Adaptive lymphocyte that matures in the bone marrow. Each expresses a unique B-cell receptor recognizing one specific pathogen.

B-cell receptor

The specific antibody a B-cell carries on its outer surface. Immature B cells don't secrete antibodies or replicate.

Regular B-cell

Short-lived activated B-cell that secretes antibodies specific to one pathogen, into lymph or blood.

Memory B-cell

Long-lived B-cell that remembers an infection, allowing a more rapid response next time.

B-cell activation

Needs two signals: 1) specific recognition of its antigen, 2) a signal from an activated CD4 cell. Then it divides rapidly and secretes antibody.

Antibody

Protein made by B cells that mediates specific attack on pathogens. Also the B-cell receptor.

Neutralizing antibody

An antibody that binds a microbe and inactivates its infectivity by blocking it.

Antibody and phagocytosis

Antibodies binding an infectious agent increase the efficiency of phagocytosis.

Variable region (V)

Part of an antibody or T-cell receptor that determines antigen specificity.

Constant region (C)

Part of an antibody that signals to the immune system.

Combinatorial diversity

Generating a huge repertoire of receptors by random mix-and-match of a few gene segments (like LEGO: 40 parts make 10,000 figures).

Autoimmune disorder

Damage to our own body that occurs when the immune system's specificity fails and it attacks self.

Primary immune response

First response to a pathogen, with a lag time while specific cells are activated. Ends when the antigen is eliminated and active T and B cells die.

Immunological memory

The ability to respond rapidly to a previously encountered pathogen, via surviving memory B and T cells with the same receptors as the original responders.

Vaccine

Non-pathogenic antigen that triggers an immune response and memory, so a rapid response protects when the real pathogen arrives.

Killed (inactivated) vaccine

Uses the whole microorganism, killed. Cannot replicate (e.g. Salk polio vaccine).

Attenuated (weakened) vaccine

Uses the whole microorganism, weakened so it can't cause disease (e.g. Sabin polio vaccine). Can be made by serial passage in cells other than the normal host.

Variolation

1700s practice of putting thread dipped in smallpox scab pus into a recipient's wound. Worked but had a 1-2% death rate.

Vaccination (Jenner)

Term from Latin 'vacca' (cow). Jenner (1796-98) protected people against smallpox using cowpox. Led to worldwide smallpox eradication by 1977.

Salk vs Sabin polio vaccine

Salk (IPV, killed): antibodies in blood, not gut, so prevents disease but not transmission. Sabin (OPV, attenuated): replicates limitedly in gut, protects blood and gut, preventing disease and transmission.

OPV2 reversion

Just 3 mutations can revert the vaccine strain OPV2 to neurovirulence. nOPV2 is the improved, more stable strain.

Herd immunity

Once a certain percentage of the population is immune, depending on R0, the pathogen has a hard time finding susceptible hosts.

Waning protection

Some vaccines protect for life (measles, HPV), others for limited time because effectiveness wanes (tetanus, every 5-10 years) or the pathogen evolves (flu, SARS-CoV-2, annually).

Vaccine safety testing

Preclinical (animal model), IND application to FDA, Phase 1 (20-100 people, safety), Phase 2 (100-300), Phase 3 (thousands, rare side effects and effectiveness).

Sources of vaccine side effects

1) The immune system response itself. 2) Vaccine components (allergy, live attenuated vaccines).

HPV vaccine

Made of virus-like particles: not infectious, can't cause disease, and induce high antibody levels. Prevents HPV-associated cancers.

High-risk vs low-risk HPV

High risk (oncogenic, HPV 16 and 18 most common): cervical, anogenital and oropharyngeal cancers. Low risk (HPV 6 and 11): genital warts and laryngeal papillomas.

What are the two kinds of B-cells?

Regular B-cells (secrete specific antibodies, short-lived) and memory B-cells (long-lived).

Where do B cells mature?

In the bone marrow (T cells mature in the thymus).

What two signals does a B-cell need to become active?

1) Specific recognition of its antigen (binding). 2) A signal from an activated CD4 cell.

What does an active B-cell do?

Divides rapidly to make more B-cells producing the same antibody, secretes antibody into lymph or blood, and dies when the infection is cleared.

How do antibodies attack?

Neutralizing antibodies bind microbes and block their infectivity, and antibodies bound to a pathogen increase phagocytosis efficiency. Different B cells may target different parts of one viral protein.

How can ~20,000 genes create about 4 x 10^8 different B-cell receptors?

Combinatorial diversity: random mix-and-match of a few gene segments encoding the V-region.

Explain the LEGO analogy.

10 legs x 10 torsos x 10 heads x 10 hats = 10,000 figures from only 40 parts.

What do the variable and constant regions of an antibody do?

The V-region is specific for one antigen. The C-region signals to the immune system.

Why is the specificity of receptors so important?

It prevents the immune system from damaging our own body. When it fails: autoimmune disorders.

What happens at the end of a primary immune response?

The antigen is eliminated and active T and B cells die. A few survive dormant as memory cells with the same receptors.

Why is a memory response faster?

Memory cells reactivate rapidly and produce the same antibody without the lag time of the primary response.

Why do vaccines work?

Immunological memory. Antigens that can't cause disease induce a response and memory, so antibodies prevent infection from establishing in a vaccinated person.

What two things does a vaccine need, and why is it hard?

A non-pathogenic antigen and an immune response. Hard because the immune system is exceptionally good at responding only to real danger, which also prevents autoimmunity.

Name the main approaches to making a vaccine.

Use the whole microorganism (killed or weakened) or only a part of it.

Why were Jenner's cowpox vaccinations better than variolation?

Variolation used smallpox pus with a 1-2% death rate. Jenner noticed milkmaids with mild cowpox didn't get smallpox, and inoculated with cowpox, then challenged the boy with variola: no disease.

Why do some people fear vaccines, and what is the flaw in 'someone got the vaccine then died'?

Fear dates back to Gillray's 1802 cartoon. The reasoning mistakes sequence for cause: it says vaccination causes death because a death followed a shot.

Describe the stages of vaccine safety testing.

Preclinical animal work, then an IND application to the FDA, then Phase 1 (20-100 people, safety and immune response), Phase 2 (100-300) and Phase 3 (thousands, rarer side effects and effectiveness).

What causes vaccine side effects?

The immune response itself and vaccine components (allergy, live attenuated vaccines).

Compare the Salk and Sabin polio vaccines.

Salk: killed, no replication, blood antibodies, prevents disease not transmission. Sabin: attenuated, limited gut replication, blood and gut immunity, prevents disease and transmission.

Why can OPV2 cause outbreaks?

3 mutations are enough to revert the vaccine strain to neurovirulence. nOPV2 was engineered to prevent this.

What is herd immunity?

Above a certain immune percentage (depending on R0), the pathogen struggles to find susceptible hosts.

Why do some vaccines need repeating?

Protection can wane (tetanus every 5-10 years) or the pathogen evolves (flu and SARS-CoV-2 annually). Measles and HPV protect for life.

Which cancers can vaccines prevent?

Cancers caused by viruses: some liver cancers (Hepatitis B), and multiple cancers caused by HPV. HPV vaccines use non-infectious virus-like particles.

What has HPV vaccination achieved?

Started in 2006. Denmark: 70% reduction in high-grade and cancerous anal lesions in women vaccinated before 17. Scotland: complete prevention of cervical cancer if vaccinated before 14.

Summarize immunology part 2.

Adaptive immunity is specific, with two arms (antibodies and CD8 killers) coordinated by CD4 cells. Combinatorial diversity solves the antigen problem. After clearance memory cells remain, the basis of vaccines, which control infections and prevent some cancers.