20. Blood and Immune System Intro

Introduction to Blood and Immune System

Learning Objectives

  • Understand the key differences between the innate and adaptive immune systems.

  • Recognize immunological terms and start building a glossary.

  • Appreciate how scientists use antibodies in their research.

Blood Components

  • Blood consists of plasma (55%) and cells (45%).

  • Plasma: water and dissolved substances.

    • Secretes IgG antibody

  • Cells: red blood cells, white blood cells, and platelets.

Cellular Components of Blood

  • Red Blood Cells: Carry oxygen.

  • White Blood Cells: Fight infection (includes neutrophils, lymphocytes, and monocytes).

  • Platelets: Aid in blood clotting.

Immunology and the Immune System

  • Immunology: The study of the immune system.

  • Immune System Functions:

    • Differentiates between self and non-self.

    • Seeks and destroys non-self entities.

Adaptive immunity and immune memory

  1. A system that changes with time to respond faster and more effectively to a pathogen. Immune memory can provide life-long protection (e.g. measles).

  2. A massive repertoire of billions of naive B and T cells is formed randomly before birth. Each lymphocyte has a different antigen specificity.

  3. The affinity of a B/T cell antigen receptor (BCR and TCR) towards its antigen, increases over time and the persistence of antigen.

  4. Diversity is caused by random gene rearrangement and recombination in the genetic loci that code for the B and T cell antigen receptors.

  5. BCR and TCR are the only genetic region in your entire genome that can rearrange in this fashion because the small segments that make up your Ig and TcR loci all have the essential RS sequences at their ends.


Genetic Recombination

  • produces millions of different VH and VL domains.


Immune Repertoire

  • Your immune doesn’t have a complete idea of what pathogens you might face in your lifetime.

  • Therefore, it makes as may receptor combinations as possible.

  • The pathogen then selects and expands just the right clone thru a process of cell clonal selection and affinity maturation.




Useful Definitions

  • Pathology: The study of diseases and their progression.

  • Pathogen: Something that causes a disease (e.g., bacteria, virus).

  • Immune System: A defense system to stop invading pathogens.

  • Immunogenic: Something that induces an immune response (antibody and/or cell-mediated).

  • Antigen: A molecule that induces an immune response via a lymphocyte.

  • Antibody: A molecular component of the immune system that recognizes and binds to antigens.

Innate vs. Adaptive Immunity

  • Innate Immunity (Always Deployed):

    • First line of defense.

    • External innate defenses: skin, secretions, mucous membranes.

    • Internal innate defenses: phagocytic cells, natural killer cells, defensive proteins, inflammatory response.

  • Adaptive Immunity (Activated by Exposure to Specific Pathogens):

    • Third line of defense.

    • Internal adaptive defenses: lymphocytes (B cells and T cells), antibodies.

  • Lymphatic System: Involved in internal innate immunity and adaptive immunity.

External Innate Defenses

  • Barrier defenses act as a wall to stop pathogens.

    • Skin.

    • Mucous and mucous membranes.

    • Bodily secretions.

  • Pathogens must bypass these barriers to access the body.

Internal Innate Defenses: Phagocytosis and Inflammation

  • Vasodilation and increased permeability of blood vessels.

  • Blood cells leave blood vessels and enter the injury site (redness, heat, swelling).

  • Phagocytosis of pathogens.

  • Natural killer cell recognition and killing of virus-infected cells.

  • Cleanup and repair via phagocytosis.

Inflammation Process

  1. Tissue Injury: Release of chemical signals like histamine.

  2. Dilation and Increased Leakiness: Local blood vessels dilate, and phagocytic cells migrate to the area.

  3. Phagocytosis: Phagocytic cells engulf bacteria and cell debris; tissue heals.

Phagocytosis

  • Performed by phagocytes (e.g., neutrophils, monocytes/macrophages).

  • Involves engulfing and digesting pathogens.

Events in Inflammation

  • Tissue cells are damaged by the wound.

  • Damaged cells release chemicals (histamine).

  • Histamine makes blood vessels leaky, causing fluid entry into tissues (swelling).

  • Fluid includes factors for healing and clotting.

  • Phagocytic cells are activated to recognize and engulf bacteria.

Internal Adaptive Defenses: B and T Cells

  • Adaptive immune response generated in the lymphatic system.

  • B Cells: Develop and specialize in the bone marrow; produce antibodies.

  • T Cells: Develop in the bone marrow and mature in the thymus.

  • Both B and T cells require activation to be functional.

  • Both B and T cells require activation to be functional. B cells use specific shapes of receptors to detect pathogens, recognize the antigen, and help clone themselves to produce antibodies and memory B cells, while T cells recognize the antigen and help B cells.

Specificity and Activation of B and T Cells

  • B and T cells are activated by exposure to specific pathogens.

  • Specific shapes of receptors detect specific pathogens.

  • A massive repertoire of B and T lymphocytes is present at birth.

  • Each lymphocyte recognizes a different antigen.

  • Specificity is randomly produced by rearrangement of the genes coding for the B cell and T cell antigen receptors.


Antibodies

  • Formed from repeated protein unit: Ig domain

  • Ig domain - Immuno

Antigens and Antigen Receptors

  • Antigens

    • Immunogenicity: the ability to provoke an immune response by stimulating the production of antibodies or T-cells.

    • Reactivity: the ability of the antigen to react specifically with the antibodies or cells it provoked.

  • Most antigens have several epitopes that are recognized by antibodies or T-cells

  • Antigen recognition activates lymphocytes to undergo clonal expansion that mediate adaptive immunity

Memory Cells

  • Memory B cells (and T cells) can live for decades in lymph nodes.

  • Activated upon second exposure to the same pathogen.

  • The secondary response is faster, stronger, and lasts longer than the first.

  • Provides the basis for infection-induced immunity and vaccination.

Scenarios After Initial Immune Response

  • Scenarios after the immediate response:

    • If the immediate response didn’t eliminate all bacteria.

    • Even if phagocytes ingested some bacteria.

  • Bacteria grow rapidly (20-minute doubling time) leading to infection spread.

  • T cells recognize the antigen and help B cells.

  • B cells clone themselves and produce antibodies and memory B cells.

Using Antibodies to Understand the SARS-COV-2 Pandemic

  • Antibodies are induced promptly after SARS-CoV-2 infection.

  • Antibodies are important markers of previous infection and immunity.

  • Immunodominant Antigens: Nucleocapsid and Spike/RBD are commonly used in serology.

Application of Antibody Assays

  1. Detecting historical infections.

  2. Estimating prevalence.

  3. Understanding persistence and protection.

  • ELISA Method:

    • Binding antibodies.

    • The RBD of the Spike protein binds to the ACE2 receptor to infect human cells.

    • Neutralizing antibodies (Nabs) bind to the RBD and block the interaction, preventing virus entry into human cells.

Serology: Individual vs. Population

  • An antibody test in an individual provides data on a single person's infection or vaccine history.

  • A serosurvey is the collection and testing of blood from a defined population to estimate the prevalence of antibodies against an infectious pathogen as an indicator of exposure.

Seroprevalence Data (December 2020)

  • NZBS collected 10,156 samples, with 9,806 samples run on the screen.

  • 18 seropositive samples found.

  • 6 PCR positive, 4 with extensive overseas travel, 8 previously undiagnosed.

  • A crude seroprevalence (n=8) is 0.082%.

  • Applying statistics, the true prevalence is 0.103%.

  • In range with Australian studies at a similar time (0.15-0.79%) and MUCH lower than settings where COVID-19 was not well controlled (>10%).

Understanding Persistence and Protection

  • Neutralizing antibodies persist for up to 8 months post-infection (December 2020).

Variants and Vaccinations

  • Vaccinations were effective against the Delta variant.

  • A third dose was needed to protect against Omicron.

Hybrid Immunity

  • Eligible for a booster if >30 years old or immunocompromised and not had COVID for 6+ months.

Post-Pandemic Surges in Respiratory Infections

  • Distinct epidemiological effects of the elimination strategy.

  • An extended 2-year period of low pathogen exposure.

Immunity Dynamics Study

  • Screened 330 eligible donors who regularly donated in Auckland over the timeframe (Mar2020-Mar2023).

  • 150 selected based on Auckland demographics (2018 census).

Study Results

  • Significant reduction in all antibodies (except SpeA and HKU1) between 2020-2023.

  • Percent reduction ranged from 10-16%.

  • SAR-CoV-2 exponential increase over the same time.

    • Suggests reduced pathogen circulation impacted immunity.

    • Reduced immunity likely contributed to post-pandemic infection surges.

  • Informs how these unintended consequences can be better managed in future pandemic responses.

Lecture Summary

  • Innate Immunity: Defenses against general characteristics of invaders; first line of defense; general but rapid response.

    • Includes skin, mucous, and mucous membranes.

    • Processes include phagocytosis and inflammation.

  • Adaptive Immunity: Defenses against specific antigens; has memory; highly specific/effective but slower response.

  • Antibodies: Part of the adaptive immune response, highly specific molecules measured to understand infection and vaccination.