Immunology Lecture Part 2- Adaptive Immunity: Detailed Notes

Adaptive Immunity: The Fourth Layer of Defense

Two Forms of Adaptive Immunity

• Antibody-mediated immunity

• Cell-mediated immunity

Barriers to Infection (Recap)

• Physical barriers: skin, mucous membranes

• Physiological barriers: fever, nutrient/oxygen requirements

• Inflammatory responses: granulocytes, macrophages

• These are part of the innate immune system.

Limitations of Innate Immunity

• May not always be effective, especially against virulent microorganisms.

• Adaptive immunity engages but takes about a week to become fully activated.

• Innate barriers are crucial for holding off infection while adaptive immunity gears up.

Specific Adaptive Immunity

• Adapts to the infection, improving as it progresses.

• Involves B and T lymphocytes.

• Key feature: specificity, meaning the ability to distinguish among different pathogens.

• Different pathogens have different ways of causing harm, requiring specific responses.

• Macrophages in the innate immune system primarily phagocytose, acting as garbage collectors.

• Adaptive immunity identifies specific pathogens (bacteria, viruses, etc.) and generates specific weapons to neutralize them based on their unique activities.

• The immune system continuously improves throughout an infection for guaranteed success.

• Often eliminates infections without noticeable symptoms.

Lymphocytes: Main Players in Adaptive Immunity

• Constitute about 15% of white blood cells.

• More sophisticated functions compared to other leukocytes.

• Come from hematopoietic stem cells (CD34 positive).

• Myeloid lineage: monocytes, macrophages, neutrophils.

• Lymphoid lineage: lymphocytes participating in specific adaptive immune responses.

Hallmarks of Adaptive Immunity

Diversity

• Diverse array of cells and mediators provide protection against various microbes.

• Many different kinds of lymphocytes, broken down into subsets with specific functions.

• Innate immune cells like macrophages are less diverse.

Specificity

• Each pathogenic microbe is recognized independently with its specialized characteristics.

• The immune system distinguishes between viruses and bacteria and among different genuses/species of bacteria (e.g., strep vs. staph).

• This ability focuses attention and creates weapons against the right pathogen.

Memory

• The immune system remembers previous exposure to a particular microbial pathogen.

• Subsequent exposure leads to a much greater effectiveness in eliminating the pathogen.

• Memory lymphocytes are rapidly engaged and activated, with an intense ability to destroy the pathogen.

Lymphoid Tissues: Where Lymphocytes Live

Lymph Nodes

• Clusters of tissue situated in strategic locations throughout the body.

• Common in the throat (oral route infections), gut (mesenteric lymph nodes for intestinal infections), and behind the knees (popliteal lymph nodes).

• Act as sentries guarding against pathogens.

Spleen

• Delicate organ producing red blood cells and housing leukocytes (myeloid and lymphoid lineages).

Tonsils

• Lymphoid tissues in the throat, not as well-formed as lymph nodes.

Thymus

• Gland important for the development of the immune system.

• T lymphocytes mature in the thymus (T for thymus) after being born in the bone marrow.

Peyer's Patches

• Histologically unorganized tissue lining the intestines.

• Important for providing lymphocyte activities against gastrointestinal infections.

Antigen Recognition and Immunogenicity

• Antigen: any substance (often foreign) that the immune system can recognize and bind to.

• Specificity of immune response begins with the ability to recognize foreign antigens.

• Immunogenicity: the ability of an antigen to stimulate an effective immune response.

• High immunogenicity: effectively generates immune response.

• Low or no immunogenicity: does not generate immune response.

Biochemical Complementarity in Antigen Recognition

Recognition as Binding

• Recognition implies a binding event.

• Lymphocyte recognizing an antigen means it's capable of physically binding to it.

• Biochemical complementarity: ability of two molecular structures with different biochemistries to attract each other.

Positive Association

• Antibody: protein made of amino acids with different charges, hydrophobicity, and sizes.

• Positive and negatives attract.

• Example: antibody one with alternating charges attracts antigen one with complementary charges, allowing them to stick together.

Negative Association

• Antibody one with charges repels antigen two with similar charges, resulting in no interaction.

• Antibody one is specific for antigen one but not for antigen two.

Clonal Selection: Basis for Lymphocyte Specificity

Lymphocyte Receptors

• Lymphocyte one has a receptor specific for one antigen.

• There are typically 25,000 identical receptor molecules on the surface of a lymphocyte.

• The receptor acts as a lock, and the antigen serves as a key.

• If the antigen has biochemical complementarity with the receptor, it will fit into the lock and activate the lymphocyte.

Activation and Clonal Expansion

• Lymphocyte two has a receptor for a different antigen.

• Lymphocyte three has a receptor that fits perfectly with a specific antigen.

• The antigen drives a signal into the cell, leading to cell division.

• The original cell divides into two genetically identical daughter cells, each with the same receptor.

• The process repeats, creating a clone of genetically identical cells numbering in the thousands.

Resulting in Clonal Selection

• Clonal selection guarantees large numbers of lymphocytes specific against a pathogenic microorganism.

Antigens on Bacterial Cells

Diverse Molecules

• Bacterial cells have many different molecules (mostly proteins) on their surface with various functions.

• These molecules are foreign and recognizable by lymphocytes.

• The typical cell average 30 different molecules that the immune system is capable to recognize. Molecules may include flagella, adhesion molecules or transport nutrients.

Fingerprint

• The exact collection of antigens differs depending on the genus and species of the bacterium.

• Each collection represents a fingerprint of the microorganism.

• Knowing the collection helps determine the bacterium, guiding antibiotic use and anticipating the infection's course and symptoms.

Immune Responses

• Each molecule is biochemically distinct, so lymphocytes recognizing them have biochemically complementary receptors.

• Different antigens stimulate different clones. The host is capable of stimulating 30 immune response due to the amount of different antigens.

• After clonal expansion, lymphocytes may produce antibodies against different antigens (e.g., purple triangle, yellow box, blue star).

Parallel Immune Response

• Independent, parallel immune responses occur against different antigens on the same pathogen.

• The diversity increases our chances by creating weapons/antibodies that can neutralize bacteria.

Self and Non-Self

• Immune system distinguishes between self and non-self.

• Crucial to avoid responding against our own tissues and antigens, which would cause autoimmune diseases.

Two Major Arms of Adaptive Immunity

Antibody-Mediated Immunity

• Best suited for combating extracellular infections (pathogens generally live outside host cells).

• Example: most bacterial infections.

• Soluble proteins (antibodies) hunt down, bind to, and destroy pathogens.

• Originally called humoral immunity (humors in the blood).

• The term "humoral immunity" persists despite efforts to rename it.

Cell-Mediated Immunity

• Activated lymphocytes actively hunt down pathogens at the infection site and work face-to-face and go out into the trenches with the enemy to do work.

• Best suited for combating intracellular infections (pathogens live inside host cells).

• Example: viral infections (viruses are obligate parasites that can't function outside cells).

Division of Labor in Humoral Immune Response

Innate vs. Adaptive

• Innate immune system has one major cell type (e.g., macrophages) doing most of the work.

• Adaptive immune response involves multiple cell types that communicate to produce a coordinated protective mechanisms to avoid accidental activation.

Three Main Cell Types Involved in Humoral Immunity

B Lymphocytes

• Make antibodies.

• Differentiate into plasma cells.

• Do not require going to the thymus; mature in the bone marrow (B for bone marrow-derived).

• Historically, B refers to Bursa of Fabricius in chickens where lymphocytes were first discovered.

T Lymphocytes

• Must go to the thymus to fully develop.

• One subset (helper T cells) enhances the activities of B lymphocytes.

Dendritic Cells

• Related to macrophages; ingest and digest antigens.

• Digest antigens into fragments and transport fragments to their surface membrane.

• Present antigen fragments to lymphocytes (primarily T lymphocytes).

• Called antigen-presenting cells (APCs).

• T lymphocytes cannot be activated without antigen presentation on APCs.

Antibodies: Messengers of Death

Properties

• Produced by lymphocytes from the B cell lineage and secreted into the circulation.

• Proteins (glycoproteins) made of amino acids.

• Four chains of amino acids: two identical heavy chains and two identical light chains.

• Two larger chains are identical heavy chains, two smaller ones are identical light chains.

Antigen Binding Site

• Pocket or groove at the amino terminal end of the light chain and heavy chain.

• This is where antigen recognition occurs.

• The biochemical complementarity determines the binding between the antibody and particular antigen.

• Each antibody molecule has two identical antigen-binding sites.

Implications

• Ability to bind to one antigen molecule with each antigen-binding site, bridging and cross-linking them.

FAB and FC Regions

• Analysis of molecule indicates 3 regions. An "arm" for each "side" and the "trunk"

• Each arm has a green light chain and the top half of the red heavy chain in one side, and yellow light chain with the top half of the blue heavy chain.

• Fragments that could bind antigen, called fragment antigen binding regions (FABs).

• The "trunk" is insoluble in aqueous solutions and will form crystals upon cut away from the two FABS: fragment crystallizable or Fc.

• Prototypic antibody has two FABs and one Fc region.

Antibody Structure: Detailed Explanation

Chains

• Two identical heavy chains and two identical light chains.

• Amino terminal ends form antigen-binding sites.

Disulfide Bridges

• Cysteine amino acids at the carboxy-terminal end of the light chain and halfway down the heavy chain.

• SH groups combine to form disulfide bridges (SS bonds).

• These bonds holds light chains with heavy chain and the two heavy chains together, providing stability.

Hinge Region

• Regions with flexibility, containing proline amino acids.

• Allows FABs to swing around for antigen binding.

Binding Site

• Fc region also known as fragment crystallizable plays no role in antigen specificity.

• At amino terminal ends are the antigen-binding sites

• There's opportunities to bind different antigens. There can be over a billion antigens recognizable by antibodies in our antigenic universe.

Classes and Subclasses of Antibodies

Heavy Chains

• Five major classes of antibodies (nine classes and subclasses).

• Determined by heavy chain: : $mu$, $delta$, $gamma$, $epsilon$, and $alpha$ heavy chains.

Antibodies

• IgM: with $mu$ heavy chain

• IgD: with $delta$ heavy chain

• IgG: with $gamma$ heavy chain (four subclasses: IgG1, IgG2, IgG3, IgG4).

• IgE: with $epsilon$ heavy chain.

• IgA: with $alpha$ heavy chain (two subclasses: IgA1, IgA2).

Functional Differences

• Significant functional differences exist among the different antibodies.

• IgM and IgG are good in the bloodstream.

• IgG crosses the placenta and gives immune protection to the fetus.

• IgE defends against parasitic infections.

• IgM and IgG activate the complement cascade.

• IgA protects against gastrointestinal infections.

• IgD has a receptor function.

Light Chains

• Two types: kappa and lambda.

• Either one can associate with any of the heavy chain types.

• There will never be any antibodies that have kappa and lambda in it at the same time

• Human antibody populations is about 50/50, half of kappa antibody and half of lambda.

Mechanism: Overview of the Antibody Response

Activation Signals

• Antigen enters the body and interact with B lymphocytes

• B cell receptors for specific antigen are biochemically complementary.

• Binding of B cell with antigen causes cells to want to divide but still requires some activation.

• Helper T Cells (activated by the same antigen): provide a second signal that activates b lymphocytes
  *T-cells cannot be activated unless presented to an antigen presenting cell like dendritic cells.

Because there can be destructive force caused by incorrectly created antibodies, both signals make sure there is the right combination of T-Cells and lymphocytes.

Result of the lymphocyte reaction

• B Lymphocytes react and undergo clonal expansion, causing multiple signals.
  *The same b cell types then turn into Plasma Cells.
  *Plasma cells do not have receptors, but are able to produce huge amounts of proteins that produce antibodies (90% of protein production) that squirt, float around, bind antigen and destroy the pathogen.

Antibody Response

*If we plot serum antibody on the Y axis and time in weeks on the X axis we can see how antibodies are made
*Antibodies do not show immediately in the serum, this is the Lag Phase.

*After exposure, 5-7 days, antibodies for antigen are produced
*Antibody levels rise and eventually plateau depending on the presence of antigen

After the antigen disappears the production halts.

Antibody response

*Sometimes, some of the b-cells that become plasma cells cannot, and so those turn into memory B-cells that participate in secondary or memory antibody response

*Memory antibody response can be used to create immunologic protection as seen in many vaccines
*This response is highly specific; if you measure the antibodies produced against a secondary, unrelated antigen, then there will usually be no reactivity against that antigen