Adaptive Immunity

Third Line of Defense: Acquired, Developed, or Adaptive Immunity

• This type of immunity develops later in life after microbial infection.
• Acquired immunity is facilitated by humoral components (antibodies and cytokines).
• B, T-lymphocytes, and plasma cells are cellular components.
• Components of acquired immunity (antibodies and cells) are specific to particular microorganisms.
  • It is also known as specific immunity.
• The characteristics are specificity, self/non-self-recognition, immunological memory, and diversity. There are two types:
• Active immunity.
• Passive immunity.

Active Immunity

• If a host produces antibodies, it is called active immunity.
  • There are two types; Artificial and Natural.
  • Artificial active immunity is immunity provided by vaccination.
  • Natural active immunity is immunity provided by natural infection.

Passive Immunity

• If a host does not produce antibodies itself, but antibodies produced in another host provides immunity.
  • It is of two types; natural passive immunity and artificial passive immunity.
  • Natural passive immunity is when IgG antibodies produced in the mother cross the placenta.
    • This protects the fetus up to 6 months old.
  • Artificial passive immunity is when preformed antibodies are injected into a host.
    • An example is Anti-venom.
    • Another example is the Rabies vaccine, which is a preformed anti-rabies antibody.

Differences Between Innate And Adaptive Immunity

• Innate immunity is already present in the body, generally inherited, and present at birth.
• Adaptive immunity is created in response to exposure to a foreign substance.
  • It cannot be inherited and develops during a person's lifetime.
• Innate immunity is non-specific.
• Adaptive immunity is specific and can distinguish between self and non-self.
• Innate immunity fights any foreign invader rapidly.
• Adaptive immunity fights only specific infections slower, around 1-2 weeks.
• Innate immunity has limited and lower potency.
• Adaptive immunity has high potency.
• Innate immunity has no memory.
• Adaptive immunity has long-term memory.
• Innate immunity works against microbes.
• Adaptive immunity works against microbes and non-microbial substances called antigens.
• Innate immunity has limited diversity.
• Adaptive immunity has high diversity.
• Innate immunity's complement system uses alternative and lectin pathways.
• Adaptive immunity's complement system uses the classical pathway.
• The innate immune system comprises physical and chemical barriers, phagocytic leukocytes, dendritic cells, natural killer cells, and plasma proteins.
• The adaptive immune system comprises B and T cells.

Adaptive Immune Cells: Lymphocytes and Plasma Cells

• The adaptive immune system consists of the humoral and cellular systems.
• Each of these arms of the system has mechanisms to attack invading pathogens.
• The immunologically specific cellular component organizes around T and B lymphocytes.
• Lymphocytes recognize foreign antigens, destroy cells, or produce antibodies as plasma cells.

Virgin or Naive Lymphocytes

• These cells have not encountered their specific antigen.
  • They express high molecular-weight variants of leukocyte common antigen.

Memory Cells

• These are long-lived T or B cells stimulated by an antigen.
  • They quickly respond to previously encountered antigens.
• Memory B cells carry surface IgG as their antigen receptor.
• Memory T cells express the CD45RO variant of the leukocyte common antigen and increased levels of cell-adhesion molecules.
• Chemical mediators in inflammatory processes throughout the body are included.

Development of T Lymphocytes

• Most lymphocytes in circulating blood are T cells from bone marrow progenitor cells matured in the thymus gland.
• Responsible for cellular immune responses and involved in regulation of antibody reactions with B lymphocytes.

Percentage Of Lymphocytes Based On Organ

Organ | T Lymphocytes (%) | B Lymphocytes (%)

• ------ | -------- | -------- Thymus | 100 | 0 Blood | 80 | 20 Lymph nodes | 60 | 40 Spleen | 45 | 55 Bone marrow | 10 | 90

Early Cellular Differentiation and Development

• T cells are key players in most adaptive immune responses.
  • They participate directly in immune responses and regulate the activities of other cells.

Types of T Cells

• CD4+ T cells: make up approximately two-thirds of mature CD3+ T cells.
  • CD4 molecules on the surfaces recognize a non-peptide-binding portion of MHC class II molecules.
  • CD4+ T cells, also known as helper T (Th) cells, are "restricted" to the recognition of pMHC class II complexes.
  • Some act as Regulatory T cells, which maintain tolerance and inhibit auto-reactive lymphocytes.
  • Treg cells express both CD4 and CD25 molecules.
    • They inhibit immune-mediated inflammatory diseases like inflammatory bowel disease.
• CD8+ T cells: account for approximately one-third of all mature CD3+ T cells.
  • CD8 molecules on the surfaces recognize the non-peptide-binding portion of MHC class I molecules.
    • CD8+ T cells are "restricted" to the recognition of pMHC I complexes.
  • Functionally, CD8+ T cells are also known as cytotoxic T (Tc).
    • Some act as suppressor T (Ts) cells.
  • Tc cells identify and eliminate body cells infected with intracellular organisms like viruses and intracellular bacteria.
  • Ts cells down-regulate and control adaptive immune responses.

Bone Marrow-Derived Cells

• Cells of lymphoid lineage remain and develop within the bone marrow.
  • They are precursors of immunoglobulin-producing lymphocytes.
• B lymphocytes or B cells synthesize immunoglobulin and display it on their surfaces, where it functions as their BCR.
• Plasma cells are derived from differentiated, mature B cells and both synthesize and secrete immunoglobulin.
  • B cells are specific, producing immunoglobulin of only one antibody specificity that recognizes only one epitope.
  • The extreme diversity among B cells generates the overall diversity of the immunoglobulin (or antibody) response.
  • Plasma cells derive from terminally differentiated B cells, producing and secreting immunoglobulin.

Natural Killer Cells

• Approximately 5% to 10% of peripheral blood lymphocytes lack T-cell (CD3) and B-cell (surface immunoglobulin) markers.
  • Known as natural killer (NK) cells, they kill certain virally infected and tumor cells without prior sensitization.
  • Their granular appearance is caused by cytoplasmic granules containing perforin and granzyme.
    • The granules can be released to damage the membranes of the cells they attack.
  • NK cells develop within the bone marrow and lack TCR produced by rearrangement of TCR genes.
• They bear killer activation receptors (KARs) and killer inhibition receptors (KIRs). KARs and KIRs allow them to recognize host cells that might need to be destroyed.
• A unique subset of T cells, designated NKT, shares some functional characteristics with NK cells.
  • NKT cells develop within the thymus and express a rearranged TCR of extremely limited repertoire
  • Unlike conventional T cells, NKT cells respond to lipids, glycolipids, or hydrophobic peptides presented by a specialized, non-classical MHC class I molecule.
    • NKT cells secrete large amounts of cytokines.

Immunogens And Antigens

• Immune responses arise as a result of exposure to foreign stimuli.
• The compound that evokes the response is referred to as either an antigen or immunogen.
  • An antigen is any agent capable of binding specifically to components of the immune system.
  • The B cell receptor (BCR) on B lymphocytes and soluble antibodies are the substances that they bind to.
    • An immunogen is any agent capable of inducing an immune response and is therefore immunogenic.
  • The distinction between the terms is necessary because there are many compounds that cannot induce an immune response, yet they can bind the components of the immune system that have been induced specifically against them.
• All immunogens are antigens, but not all antigens are immunogens.
  • This difference is obvious in the case of low molecular weight compounds, a group of substances that includes antibiotics and drugs.
  • By themselves, these compounds cannot induce an immune response but when coupled with much larger entities (proteins), the resultant conjugate induces an immune response.

Antigenicity

• Antigenicity refers to the ability of a compound to bind with antibodies or with cells of the immune system.
  • This binding is highly specific.
• The immune components can recognize various physicochemical aspects of the compound.
  • The binding between antigens and immune components involves several weak forces operating over short distances.
• Weak forces include van der Waals forces, electrostatic interactions, hydrophobic interactions, and hydrogen bonds.
• There are no covalent bonds involved in binding.

Immunogenicity

• Immunogenicity is the ability of a particular substance (antigen or epitope) to provoke an immune response.
• It can include either:
  • Humoral responses
  • Cell-mediated immune responses.

Epitope

• Epitope refers to immunologically active regions of an immunogen (or antigen) that bind to antigen-specific membrane receptors on lymphocytes.
  • Also called antigenic determinants.

Hapten

• A hapten is a small foreign molecule that is not antigenic.
  • This type of antigen elicits production of antibodies only when combined with another antigenic molecule.

Chemical Nature of Antigens (Immunogens)

• Proteins: The vast majority of immunogens are proteins.
  • They may be pure proteins, glycoproteins, or lipoproteins.
    • Proteins are generally very good immunogens.
• Polysaccharides: Pure polysaccharides and lipopolysaccharides are good immunogens.
• Nucleic Acids: Nucleic acids are usually poorly immunogenic.
  • However, they may become immunogenic when single-stranded or complexed with proteins.
• Lipids: In general, lipids are non-immunogenic, although they may be haptens.

Types of Antigens Based on Their Class (Origin)

• Exogenous antigens:
  • These antigens enter the body or system and circulate in body fluids.
    • They are trapped by antigen-presenting cells (APCs) like macrophages and dendritic cells.
  • Uptake of exogenous antigens by APCs is mainly mediated by phagocytosis.
    • Examples are bacteria, viruses, and fungi.
      • Some antigens start as exogenous and later become endogenous, like intracellular viruses.
• Endogenous antigens:
  • These are the body's own cells, sub-fragments, compounds, or antigenic products produced.
• The endogenous antigens are processed by macrophages and later accepted by cytotoxic T – cells.

Requirements For Immunogenicity

• A substance must possess the following characteristics to be immunogenic:
  • Foreignness.
  • High molecular weight.
  • Chemical complexity.
  • Degradability and interaction with host major histocompatibility complex (MHC) molecules.

Foreignness

• Animals normally do not respond immunologically to self.
  • For example, if a rabbit is injected with its own serum albumin, it will not mount an immune response because it recognises the albumin as self.
    • By contrast, if rabbit serum albumin is injected into a guinea pig, the guinea pig recognizes the rabbit serum albumin as foreign and mounts an immune response.
  • Compounds that are part of self are not immunogenic.
    • However, there are exceptional cases in which an individual mounts an immune response against his or her own tissues.
      • This condition is termed autoimmunity.

High Molecular Weight

• The second feature that determines whether a compound is immunogenic is its molecular weight.
• Small compounds (less than 10KDa) are not immunogenic.
• Molecular weights between 1,000 and 6,000Da may or may not be immunogenic.
• Molecular weights equal to or greater than 10KDa are generally immunogenic.
• Relatively small substances have decreased immunogenicity.

Chemical Complexity

• Proteins and polysaccharides are among the most potent immunogens.
  • Relatively small polypeptide chains, nucleic acids, and even lipids can, under the right circumstances, be immunogenic.
• Large heterologous proteins express a wide diversity of antigenic determinants.
• Noted the immunogenicity of a protein is influenced by its chemical composition.
• The more complex a substance is chemically, the more immunogenic.
• Presence of an aromatic radical is essential for rigidity and antigenicity.

Degradability

• Antigens that are easily phagocytosed are generally more immunogenic.
  • This is because the development of an immune response requires that the antigen be phagocytosed, processed, and presented to helper T cells by an antigen-presenting cell (APC).

Other factors:

• Age can also influence immunogenicity.
  • The very young and very old have a diminished ability to elicit an immune response.
• Some substances are immunogenic in one species but not in another.
  • Similarly, some substances are immunogenic in one individual but not in others (i.e., responders and non-responders).
• The species or individuals may lack the genes coding for the receptors for the antigen on B cells and T cells.
• They may not have the appropriate genes needed for the APC to present antigen to the helper T cells.

Adjuvants

• Various additives or vehicles are used to enhance the immune response to a given immunogen.
  • An adjuvant is a substance that, when mixed with an immunogen, enhances the immune response against the immunogen.
• Distinguish between a carrier for a hapten and an adjuvant.
• A hapten will become immunogenic when conjugated covalently to a carrier.
  • It will not become immunogenic if mixed with an adjuvant.
  • An adjuvant enhances the immune response to immunogens but does not confer immunogenicity on haptens.
• The identification of adjuvants for use with vaccines is growing because many new vaccine candidates lack sufficient immunogenicity.

Adjuvant mechanisms include

• Increasing the biological or immunological half-life of vaccine antigens.
• Increasing the production of local inflammatory cytokines.
• Improving antigen delivery, processing, and presentation by APCs, especially dendritic cells.

Primary and Secondary Responses

• The first exposure of an individual to an immunogen is referred to as the primary immunization, which generates a primary response.

1. Cells process antigen.
2. This triggers antigen-specific lymphocytes to proliferate and differentiate.
3. T-lymphocyte subsets interact with other subsets and induce the latter to differentiate into T lymphocytes with specialized function.
4. T lymphocytes also interact with B lymphocytes, inducing them to synthesize and secrete antibodies.

• A second exposure to the same immunogen results in a secondary response.
  • This may occur after the response to the first immune event has leveled off or has totally subsided (within weeks or even years).
  • This secondary response differs from the primary response. -Most notably and biologically:
  • Quicker onset.
  • Higher magnitude of response.
• In a sense, the secondary exposure behaves as if the body remembered that it had been previously exposed to that same immunogen.
• Secondary responses exploit the expanded number of antigen-specific lymphocytes generated in response to the primary immune event.
  • The secondary response is also called the memory or anamnestic response.
    • The B and T lymphocytes that participate in the memory response are termed memory cells.