Immunological Responses and Vaccine Principles of Vaccination

Functional Types of T Cells

• T cells originate in the thymus.
• There are three main functional types of T cells:
  • Helper T cells: These cells activate macrophages, assist in B cell processes, and help activate cytotoxic T cells.
  • Regulatory T cells: These cells control the T cell response. They act by creating anti-inflammatory cytokines or by preventing proliferation to ensure the response remains regulated.
  • Cytotoxic T cells: These lead to the direct destruction of infected host cells and foreign cells.

B Cell Origins and Antigen Response

• B cells originate and mature in the bone marrow.
• When a B cell is activated by an antigen, it divides and gives rise to plasma cells.
• Plasma Cells: Each plasma cell has the same reactive profile. They release antibodies into the tissue and blood.
• Antibodies: These attach to specific antigens for which they are designed, marking those antigens for destruction or neutralization.

Lymphocyte Development and Circulation

• T Cell Circulation: T cells constantly circulate between the lymphatic system and the general circulatory system. They migrate to specific T cell areas within the spleen and lymph nodes. It is estimated that approximately $1,000,000,000$ T cells pass between these systems every single day.
• B Cell Development: Hundreds of millions of B cells develop through gene modification and selection within the bone marrow.
• Maturation Pathways:
  • Stem cells in the bone marrow become granulocytes, monocytes, or lymphocytes.
  • Lymphocytes that stay in the bone marrow become B cells.
  • Lymphocytes that migrate to the thymus become T cells.
• Antigen Receptors: Each naive lymphocyte builds a unique antigen receptor. By the time they reach secondary lymphoid tissues, each cell is equipped to respond to a single, unique antigen.
• Comparison of B and T Cells:
  • MHC Requirement: T cells require antigens to be presented with MHC (Major Histocompatibility Complex); B cells do not.
  • Concentration in Blood: T cells have a high concentration in the blood, whereas B cells have a low concentration.

Stromal Cells and Tissue Structure

• Definition: Stromal cells make up the physical structure of every organ in the body.
• Immune Function: When a foreign presence or inflammation is detected, stromal cells alert T cells and B cells, acting as instruments to bring immune cells to the target area.

Immune Tolerance and Autoimmune Disorders

• Immune Tolerance: This is the removal of potentially harmful clones through a process called clonal deletion to ensure tolerance to the self.
• Autoimmune Disease: This occurs when the immune system fails to distinguish self from non-self and attacks the body's own tissues.
  • Examples: Lupus and Hashimoto’s (which affects the endocrine system).
  • Progression: Individuals with one autoimmune disease are at a higher risk of developing a second one, often within a five-year window.

Antigens and Immunogens

• Antigen: A substance that provokes an immune response in specific lymphocytes.
• Immunogen: An antigen that has already been responded to by the immune system. In many clinical contexts, these terms are used interchangeably.
• Efficiency: Antigens that provoke strong responses are considered "good" antigens. Factors affecting this include:
  • Chemical Composition.
  • Cytokine Content.
  • Size: In general, large antigens are better than small antigens, though large size alone is not always sufficient to provoke a response.

Alloantigens, Blood Groups, and Incompatibility

• Alloantigen: Proteins or other molecules found in one person that are antigenic to another person of the same species. They are the basis for individual blood group and MHC profiles.
• Transfusion Incompatibility: If a person with Type A blood receives Type B blood, the B antigens cause an immune reaction.
• Agglutination: This is the clumping of blood cells that occurs during an incompatible transfusion.
• Organ Grafting: Alloantigens are responsible for the incompatibilities observed in organ transplants and blood transfusions.

Super Antigens and Cytokine storm

• Definition: Bacterial toxins that act as potent stimuli for T cells.
• Potency: They activate T cells at a rate of approximately $100$ times greater than ordinary antigens.
• Risks: This mass activation can lead to an overwhelming release of cytokines, known as a cytokine storm, resulting in cell death and organ failure.
• Associated Conditions: Toxic Shock Syndrome and certain autoimmune diseases.
• Toxic Shock Syndrome History: In the $1980s$, a product called Rely tampons was associated with a high incidence of Toxic Shock Syndrome.

Routes of Antigen Entry

• Respiratory Mucosa.
• Gastrointestinal Mucus Membranes.
• Thin Skin.
• Across the Placenta: Contrary to old beliefs that the placenta protected the fetus from all external factors, it is now known that substances like alcohol, drugs, and smoke cross the placenta.
• Intravenous: Antigens introduced this way travel through the bloodstream and end up in the liver, spleen, bone marrow, kidneys, and lungs.
• Other Routes: Antigens are carried in lymphatic fluid and concentrated by the lymph nodes.

Cell-Mediated Killing Mechanisms

• Perforins: Proteins that punch holes in the membranes of target cells, causing ions to leak out.
• Granzymes: Enzymes that enter through the holes created by perforins to attack the proteins of target cells.
• Apoptosis: This is the process of programmed cell death or "cell suicide" that the targeted cell undergoes after the attack.

Specialized Lymphocytes: NK and Gamma Delta T Cells

• Gamma Delta T Cells: These cells have T cell receptors rearranged to recognize a wide range of antigens; they respond quickly and produce memory cells.
• Natural Killer (NK) Cells: These are lymphocytes related to T cells but they lack specificity for antigens.
  • Location: They circulate through the spleen, blood, and lungs.
  • Function: They are the first killer cells to attack cancer cells and virus-infected cells.
  • Identification: They identify target cells not by receptors, but by physical abnormalities (e.g., atypical shapes of cancer cells) and clustering patterns.
  • Clinical Sensation: Because NK cells work efficiently in the early stages of cancer, a patient may remain asymptomatic until the disease reaches Stage $3$ or Stage $4$.

Serology and Immune Response Timing

• Titer: A measurement of the concentration of antibodies in serum over time to determine the immune system's reaction to an antigen.
• Primary Response: Occurs upon the first exposure to an antigen.
  • Latent Period: A stage marked by a lack of antibody production while the antigen is being concentrated in lymphoid tissue.
  • Plateau: Serum titer increases to a plateau before tapering off over weeks or months.

Categories of Acquired Immunity

• Active Immunity:
  • Develops when an individual receives an immune stimulus (antigen).
  • Creates a memory for quick action upon re-exposure.
  • Requires several days to develop.
  • Lasts a long time, sometimes for life.
  • Can be natural or artificial.
• Passive Immunity:
  • Occurs when an individual receives antibodies produced by another human or animal donor (e.g., mother to fetus).
  • Is characterized by a lack of memory for the original antigen.
  • Provides short-term effectiveness because the body eventually disposes of the foreign antibodies.
• Natural Immunity: Acquired during normal biological experiences, not through medical intervention.
• Artificial Immunity: Induced by medical intervention, such as vaccines or immune serum.
  • Gamma Globulin: Also called intravenous immune globulin, this is extracted from the pooled blood of donors and usually injected intramuscularly, providing protection for $2$ to $3$ months.

Principles of Vaccination

• Vaccination Definition: Exposing a person to material that is antigenic but not pathogenic.
• Purpose: To stimulate a primary immune response that primes the system for future exposure. In a secondary response, the immune action will be immediate, powerful, and sustained.
• Considerations: Factors include antigen selection, effectiveness, ease of administration, safety, and cost.
• Requirements for Effectiveness:
  • Low level of adverse side effects or toxicity.
  • Protection against natural "wild" forms of the pathogen.
  • Stimulation of both B cell (antibody) and T cell (cell-mediated) responses.
  • Production of lasting memory.
  • Minimal doses or boosters required (though not always possible).
  • Inexpensive/free and a long shelf life.

Vaccine Types and Technologies

• Live/Attenuated: Pathogens that can replicate in the recipient to stimulate strong immunity (e.g., MMR vaccine).
• Whole Killed/Inactivated: Viruses containing a wide range of surface markers, but unable to replicate (e.g., Flu vaccine).
• Subunit/Genetic: Harmless viruses or nanoparticles carrying RNA or DNA for surface components (e.g., COVID-19 vaccine).
• Booster Shot: An additional dose administered to shore up long-term effectiveness.
• New Horizons:
  • CRISPR: Gene editing techniques for vaccine development.
  • Nanoparticles: Vaccines made of surface proteins that do not require human cells to translate mRNA.
  • Engineered B Cells: Research into designing B cells that express specific antibodies.

Vaccine Safety and Misinformation

• Side Effects:
  • Local reactions: Redness, soreness, and swelling at the injection site.
  • General: Short-term flu-like symptoms caused by interferon release.
  • Anaphylaxis: The most serious side effect; a severe allergic reaction that prevents breathing. For the COVID-19 vaccine, the rate was approximately $5$ cases out of every $1,000,000$.
• Misconceptions:
  • Getting the flu from the flu vaccine: This is false; symptoms are caused by the immune response, not the flu itself.
  • Mercury and Autism: The measles vaccine has never contained mercury and has been proven not to cause autism.
• Vaccine Hesitancy: Named by the WHO in $2019$ as one of the top $10$ threats to global health.

Questions & Discussion

• Question: How would you describe antigens to someone who knows nothing about them?
• Answer: Antigens act like security markers. They identify the "bad guys" that need to be "shot down" or destroyed.
• Question: Where do B cells originate from?
• Answer: The bone marrow.
• Question: What do we call a swollen lymph node?
• Answer: Adenitis.
• Question: If NK cells attack cancer, why is cancer still a problem?
• Answer: Cancer cells are dysregulated; they undergo mitosis at an uncontrolled rate. While NK cells are efficient, the cancer may replicate too fast for the immune system to keep up.
• Question: What percentage of the time are cells normally in mitosis?
• Answer: Approximately $10\%$. The rest of the time ($90\%$) is spent in Interphase.
• Question: What is meiosis?
• Answer: The process that produces sex cells (gametes).
• Question: Why do they make you wait after getting a vaccine?
• Answer: To monitor for a potential anaphylactic reaction so medical intervention can be provided if the patient cannot breathe.