Adaptive Immunity

Chapter 8: Adaptive Immunity

Chapter Objectives (1 of 4)

  • Characterize immunity, antigens, immunogens, and antibodies.

  • Define and describe these terms:

    • Haptens: Small molecules that can elicit an immune response only when bound to a larger carrier molecule.

    • Immunoglobulins: Another term for antibodies.

    • Allergens: Substances that can cause an allergic reaction.

    • Antigen determinants (epitopes): Specific parts of the antigen that are recognized by antibodies.

  • Describe the role of antigen-processing (presenting) cells (APCs).

  • Compare and contrast cellular and humoral immunity.

  • Compare and contrast active and passive immunity.

  • Describe clusters of differentiation (CDs).

  • Identify criteria that can influence the degree to which an antigen is immunogenic.

Chapter Objectives (2 of 4)

  • Describe tolerance.

  • Relate central and peripheral tolerance to an individual’s acceptance of self-antigens.

  • Describe the major histocompatibility complex (MHC) and human leukocyte antigens (HLAs).

  • Describe the role of the B cell in humoral immunity.

  • Describe the role of the T cell in cell-mediated immunity.

  • Identify the structure and an important role of each of the five classes of immunoglobulins (antibodies):

    • IgG

    • IgM

    • IgE

    • IgA

    • IgD

Chapter Objectives (3 of 4)

  • Identify and describe the structural components of an antibody.

  • Describe somatic recombination.

  • Characterize the cellular interactions within the immune response: actions of APCs, Th cells (Helper T cells), Tc cells (Cytotoxic T cells), Treg cells (Regulatory T cells), natural killer (NK) cells, B cells, plasma cells, and memory cells.

  • Compare and contrast the titer and the class of immunoglobulin in the primary and secondary immune response.

  • Describe the actions of antibodies that provide protection against infections.

Chapter Objectives (4 of 4)

  • Describe opsonization.

  • Describe the secretory immune system.

  • Describe the actions of cytokines within the immune response.

  • Compare fetal and neonatal immune function with immune function in the elderly.

Overview of Adaptive Immunity (1 of 6)

  • Works together with inflammation.

  • Recognizes foreign or "nonself" substances such as:

    • Antigens

    • Pathogens

    • Non-infectious environmental agents

    • Drugs

    • Vaccines

    • Transfusions

    • Transplants

  • Provides long-term protection.

  • Is slower than innate immunity but more specific.

  • Exhibits memory, allowing for faster responses upon re-exposure to pathogens.

Overview of Adaptive Immunity (2 of 6)

  • End products of adaptive immunity include:

    • Lymphocytes such as T cells and B cells

    • Antibodies, also known as immunoglobulins (Ig)

  • Generation of clonal diversity: Each T or B cell recognizes only one specific antigen, leading to a potentially vast range of specificities among T/B cells.

  • Primary lymphoid organs include the thymus for T cells and bone marrow for B cells.

Overview of Adaptive Immunity (3 of 6)

  • Secondary lymphoid organs including:

    • Spleen

    • Lymph nodes

    • Adenoids

    • Tonsils

    • Peyer patches (found in the intestines)

    • Appendix

  • High endothelial venules facilitate binding of lymphocytes to the endothelium via adhesion molecules.

Overview of Adaptive Immunity (4 of 6)

  • Clonal diversity:

    • Occurs in primary lymphoid organs

    • Involves the maturation of B and T cells

    • Cells migrate to secondary lymphoid organs for antigen encounters

  • Clonal selection:

    • Involves antigen processing and presentation by APCs

    • T-helper cells (Th) interact with APCs, leading to differentiation of B cells into plasma cells and T cells into effector cells.

Overview of Adaptive Immunity (5 of 6)

  • Humoral immunity:

    • Involves B cells and circulating antibodies as primary cells

    • Directly inactivates microorganisms or activates inflammatory mediators

    • Primarily protects against bacteria and viruses

  • Cellular immunity:

    • Involves differentiation of T cells

    • Primarily protects against viruses and cancer

  • Humoral and cellular immunity work together for protection and memory, leading to more rapid and efficient responses upon subsequent exposures to the same antigen.

Overview of Adaptive Immunity (6 of 6)

  • Question 1: Which statement indicates the nurse has an accurate understanding concerning passive immunity?

    • “Passive immunity… can be transferred from a donor to a recipient.”

Antigens (1 of 3)

  • Antigens are molecules that can react with antibodies or receptors on B and T cells, primarily being proteins, but can include other types of molecules.

  • An immunogenic antigen is capable of triggering an immune response.

  • Antigen’s binding site is called the antigenic determinant (epitope), while the antibody or lymphocyte’s binding site is known as the antigen-binding site (paratope).

Antigens (2 of 3)

  • Degree of immunogenic capability of an antigen can depend on:

    • Degree of foreignness to a host: Most critical factor

    • Size: Generally, larger antigens are more immunogenic

    • Small-molecular weight antigens are referred to as haptens; they cannot stimulate an immune response unless attached to a carrier protein.

    • Chemical complexity: The greater the structural diversity, the higher the immunogenicity

    • Amount: Extremely high or low levels can induce tolerance.

Antigens (3 of 3)

  • Superantigens:

    • These are molecules that are not processed by APCs, resulting in the activation of large populations of T lymphocytes irrespective of their specificity for the antigen.

    • They induce excessive cytokine production, leading to systemic inflammatory responses, including symptoms like fever, hypotension, and possibly fatal shock.

    • Examples include bacterial toxins from Staphylococcus aureus and Streptococcus pyogenes as well as certain viral particles.

Lymphocyte Development

  • Lymphocytes are molecules that recognize antigens and include:

    • Circulating antibodies

    • Antigen receptors present on B cells (B-cell receptors or BCRs)

    • Antigen receptors present on T lymphocytes (T-cell receptors or TCRs).

Development of B Lymphocytes (1 of 3)

  • B-cell receptor (BCR):

    • Located on the surface of B cells, consists of:

    • Antigen-recognition molecules

    • Membrane-associated IgM and IgD responsible for recognition and binding

    • Accessory intracellular signaling molecules like Ig-alpha and Ig-beta heterodimers, which relay activation messages for maturation and antibody production.

Development of B Lymphocytes (2 of 3)

  • B-cell maturation occurs in the bone marrow, involving the maturation of stem cells into B cells as they develop surface markers like:

    • Interleukin (IL)-7 receptor, critical for further differentiation and proliferation.

    • Production of BCRs utilizes heavy and light chain genes where light chains are organized by V (variable), J (joining), and C (constant) genes while heavy chains are organized by V, D (diversity), and J.

Development of B Lymphocytes (3 of 3)

  • Changes in characteristic surface markers during B cell maturation include:

    • CD21: Complement receptor

    • CD40: Adhesion molecule required for interactions with Th cells

  • Central tolerance involves the elimination of a significant proportion (over 90%) of autoreactive B cells when exposed to self-antigens, while peripheral tolerance involves autoreactive B cell clones that persist and need regulation by other mechanisms within lymphoid organs.

Development of T Lymphocytes (1 of 8)

  • T-cell receptor consists of:

    • An antibody-like transmembrane protein (TCR) responsible for recognition and binding

    • Accessory proteins referred to as CD3 for intracellular signaling, which activate and differentiate T cells.

Development of T Lymphocytes (2 of 8)

  • T-cell maturation occurs in the thymus as the central lymphoid organ where T cells migrate from the thymic cortex to the medulla:

    • During this process, TCRs and surface molecules develop, with released T cells entering the blood to reside in secondary lymphoid organs anticipating antigen encounters.

Development of T Lymphocytes (3 of 8)

  • T-cell maturation includes the production of TCRs:

    • Consisting of alpha (B1) and beta (B2) chains with variable and constant regions, including complementary-determining regions (CDRs) separated by framework regions (FRs) within each V region.

    • The sequence for the development of the alpha and beta chains diverges, facilitating the identification of numerous antigens.

Development of T Lymphocytes (4 of 8)

  • Maturation of T cells results in significant changes in surface markers:

    • Expression of CD2, a marker for T cells, and produces surface proteins CD4 and CD8.

    • CD4 cells recognize antigens presented by MHC class II molecules and develop into T-helper cells, while CD8 cells react with MHC class I molecules, differentiating into T-cytotoxic (Tc) cells that mediate cell-mediated immunity and directly kill other cells.

Development of T Lymphocytes (5 of 8)

  • Central tolerance pertains to the deletion of autoreactive T cells in the thymus via mechanisms like:

    • Clonal deletion where TCRs reacting strongly with MHC undergo apoptosis.

    • Negative selection where a developing T cell's TCR binds strongly to a self-antigen leading to elimination.

    • Positive selection where CD4 or CD8 molecules bind MHC class II or I respectively, resulting in a final population where approximately 60% are CD4+ and 40% are CD8+; peripheral tolerance mechanisms may also exist.

Development of T Lymphocytes (6 of 8)

  • T-cell activation initiates the cellular immune response:

    • Antigen binds to TCRs enabling:

    • Direct killing of foreign or abnormal cells by Tc cells (cytotoxic T lymphocytes [CTLs]).

    • Assistance and activation of other immune cells via T-regulatory (Treg) cells that ensure the immune response does not target “self.”

    • Generation of memory T cells capable of rapid response to subsequent exposures to the same antigen.

Development of T Lymphocytes (7 of 8)

  • Activation leads to cellular differentiation:

    • Produces active Tc cells adept at identifying and destroying infected or malignant cells through recognition of surface antigens.

    • This process also yields memory T cells that allow for quick reaction during subsequent exposures to corresponding antigens.

Development of T Lymphocytes (8 of 8)

  • T-cell activation necessitates cellular interactions:

    • Antigen presented via MHC class I molecules is critically recognized by CD8 T cells or TCRs restricted to class I.

    • Such interactions require various signaling pathways including B7 on the APC, CD28 and CD2 on the T cell, and additional adhesion molecules along with cytokines, particularly IL-2 produced by Th-1 cells for T cell maturation.

Clonal Diversity, Clonal Deletion, Clonal Selection, and Clonal Expansion (1 of 6)

  • Antigen-independent interactions between cells generate intracellular signaling events crucial for effective immune response.

Clonal Diversity, Clonal Deletion, Clonal Selection, and Clonal Expansion (2 of 6)

  • Clonal diversity involves the generation of all necessary receptor specificities, occurring in primary (central) lymphoid organs (thymus for T cells, bone marrow for B cells) resulting in immature but immunocompetent lymphocytes that migrate to secondary lymphoid structures anticipating antigen encounters.

Clonal Diversity, Clonal Deletion, Clonal Selection, and Clonal Expansion (3 of 6)

  • Generation of clonal diversity continues throughout life post-birth via the rearrangement of DNA during T and B cell development:

    • Immunoglobulins and TCR coding DNA undergo somatic recombination ensuring each cell is unique and reactive to different antigens.

Clonal Diversity, Clonal Deletion, Clonal Selection, and Clonal Expansion (4 of 6)

  • Clonal selection represents a later phase of the immune response where effector cells (Th, plasma, and Tc cells) and memory cells are generated; begins at birth and progresses throughout an individual’s life.

Clonal Diversity, Clonal Deletion, Clonal Selection, and Clonal Expansion (5 of 6)

  • T-regulatory lymphocytes (Tregs) play essential roles in suppressing immune responses by:

    • Reducing Th1 and Th2 activity, limiting antigen recognition and Th cell proliferation, maintaining peripheral tolerance, and controlling immune reactions to protect host tissues against autoimmunity.

Clonal Diversity, Clonal Deletion, Clonal Selection, and Clonal Expansion (6 of 6)

  • Tolerance indicates recognition between self and foreign elements; central tolerance eliminates lymphocytes with receptors for self-antigens, while peripheral tolerance ensures protection from lymphocyte and antibody recognition.

Antigen-Presenting Cells (1 of 2)

  • Antigens necessitate processing and presentation by antigen-presenting cells (APCs):

    • Dendritic cells

    • Macrophages

    • B lymphocytes: Present antigens to Th cells which help facilitate the humoral immune response.

    • Macrophages: Present antigens to memory Th cells to instigate secondary responses.

    • Dendritic cells: Transport processed antigens from inflammation sites to T-cell rich areas in lymph nodes.

Antigen-Presenting Cells (2 of 2)

  • Effective immune responses require APCs to process antigens adequately, express antigen-processing molecules on their surfaces, and some antigens can be processed by most cells while others need specialized cells.

Antigen Processing

  • Antigen processing involves linking exogenous and endogenous antigens to the appropriate MHC molecules:

    • Class I MHC molecules predominantly present endogenous antigens (inside cells).

    • Class II MHC molecules typically present exogenous antigens (outside cells).

Antigen Presentation (1 of 3)

  • Major histocompatibility complex (MHC) comprises glycoproteins present on all human cells except red blood cells (RBCs):

    • Human leukocyte antigens (HLA): Genes inherited codominantly to allow expression of both maternal and paternal alleles.

    • MHC class I genes consists of A, B, and C.

    • MHC class II genes are comprised of DR, DP, and DQ.

    • MHC class III genes govern the quality and quantity of immune responses.

Antigen Presentation (2 of 3)

  • Transplanted tissue harbors MHC surface antigens differing from the recipient; the host may mount an immune response against these foreign MHCs.

  • Haplotype represents a distinct combination of alleles at significant HLA loci on one chromosome.

Antigen Presentation (3 of 3)

  • CD1: Antigen-presenting molecules found on APCs and thymus cells, particularly presenting lipid antigens such as those from Mycobacterium tuberculosis and Mycobacterium leprae.

T-Helper Cells (1 of 2)

  • Th cells amplify antigen-driven maturation of B and T cells, facilitating interplay among APCs and immunocompetent lymphocytes via:

    • Interaction through antigen-specific and antigen-independent receptors.

    • Differentiation process leads to maturation.

    • Fully matured Th cells interact with plasma cells or T-effector cells.

T-Helper Cells (2 of 2)

  • APC-Th cooperation occurs when an antigenic peptide presented by an MHC class II molecule is recognized by Th cell surface molecules such as CD4 (class II restricted).

  • Proper differentiation necessitates costimulatory molecules such as B7 on APC recognized by CD28 on Th cells, with additional requirements including CD48 on the APC, CD2 on T cells, and the cytokine IL-2.

T-Helper Cells (3 of 2)

  • Th cell subtypes include:

    • Th1: Provides help for developing cell-mediated immunity and activating macrophages and Tc cells.

    • Th2: Assists in developing humoral immunity by activating B cells.

    • Th17: Aids the inflammatory response.

    • Tregs: Regulates and limits immune response; distinctions are based on cytokine production.

Humoral Immunity

  • Antibody (immunoglobulin, Ig):

    • Produced by plasma cells.

    • Contains various classes: IgG, IgA, IgM, IgE, IgD, each characterized by specific antigenic, structural, and functional differences.

Molecular Structure and Classes of Antibodies (1 of 8)

  • Antigen-binding fragment (Fab): Functions as recognition sites for antigenic determinants; binds antigens with two identical fragments.

  • Crystalline fragment (Fc): Responsible for biological functions including complement activation and opsonization.

  • Composed of four polypeptide chains: Two light chains, two heavy chains linked by disulfide bonds; heavy chains determine antibody class.

Molecular Structure and Classes of Antibodies (2 of 8)

  • Antigen binding occurs between amino acid sequences in variable regions of heavy and light chains, complemented by framework regions that control antibody configurations.

  • Antibody valence (binding sites) varies:

    • IgG, IgD, circulating IgA, IgE: 2 binding sites

    • Secretory IgA: 4 binding sites

    • IgM: Theoretically 10, usually 5 functioning sites.

Molecular Structure and Classes of Antibodies (3 of 8)

  • IgG:

    • Most abundant antibody class (80%-85%).

    • Capable of crossing the placenta.

    • Accounts for majority of protective activity against infections.

    • Divided into four subclasses: IgG1, IgG2, IgG3, IgG4.

Molecular Structure and Classes of Antibodies (4 of 8)

  • IgA:

    • Contains two subclasses:

    • IgA1 predominantly in blood

    • IgA2 primarily in secretions.

    • Secretory IgAs are dimers attached to the J-chain and possibly feature a protective “secretory piece.”

Molecular Structure and Classes of Antibodies (5 of 8)

  • IgM:

    • Largest immunoglobulin class.

    • Exists as a pentamer stabilized by J-chain.

    • First antibody produced responding to antigens.

    • Synthesized during fetal development.

Molecular Structure and Classes of Antibodies (6 of 8)

  • IgD:

    • Limited information on IgD function, low concentrations in blood.

    • Primarily located on surface of developing B lymphocytes, acting as a type of B-cell antigen receptor.

Molecular Structure and Classes of Antibodies (7 of 8)

  • IgE:

    • Least prevalent immunoglobulin in circulation.

    • Mediates many common allergic reactions and provides defense against parasites.

Molecular Structure and Classes of Antibodies (8 of 8)

  • Question 2: Which statement best describes IgAs?

    • “IgAs are: found in saliva and other secretions, measureable in low blood concentrations.”

Functions of Antibodies (1 of 3)

  • Provides protection against infection via direct and indirect mechanisms:

    • Directly through:

    • Neutralization: Inactivates/block binding of antigen to receptor.

    • Agglutination: Clumps insoluble antigen particles.

    • Precipitation: Converts soluble antigen into insoluble precipitate.

    • Indirectly through involvement with complement and phagocytes.

Functions of Antibodies (2 of 3)

  • Neutralization mechanisms inactivation include:

    • Covering receptors to prevent antigen binding; efficacy of some vaccinations resides in this principle.

    • Antibody titers indicate levels of circulating antibodies; toxoids refer to chemically inactivated toxins retaining immunogenic qualities.

Functions of Antibodies (3 of 3)

  • Indirect effects facilitated via the Fc portion encompass:

    • Opsonization augmenting phagocytosis rates.

    • Complement system activation potentially leading to pathogen destruction and heightened opsonic activity through C3b deposition.

Immunoglobulin E

  • Specialized antibody protecting against larger parasitic worms and serving as the primary mediator in allergic reactions; eosinophils are crucial for forming granulomas around parasites and triggering their degranulation.

Secretory Immune System

  • The lymphoid tissues that defend external body surfaces contain antibodies in tears, sweat, saliva, mucus, and breast milk.

  • The primary role of secretory immunoglobulins focuses on preventing viral and bacterial invasion while dominant immunoglobulin is IgA; smaller quantities of IgG and IgM can also be found.

Primary and Secondary Humoral Immune Responses (1 of 3)

  • Primary immune response:

    • Occurs during initial antigen exposure, features a latent or lag phase while B cells differentiate.

    • After a span of 5-7 days, IgM antibodies appear specific to the antigen, with IgG following shortly after.

    • Immune system becomes primed.

Primary and Secondary Humoral Immune Responses (2 of 3)

  • Secondary (anamnestic) immune response:

    • Exhibits quicker response than primary, generating larger antibody quantities.

    • Rapid response owes to memory cells that avoid differentiation; while IgM levels remain comparable to the primary response, IgG quantities rise significantly.

Primary and Secondary Humoral Immune Responses (3 of 3)

  • Question 3: Which is true regarding the secondary immune response?

    • “IgG is significantly increased while a latent phase occurs; however, memory cells do not require development.”

T-Cytotoxic (Tc) Cells

  • Responsible for eliminating cancer cells or virus-infected cells through apoptosis:

    • Utilize perforin for pore formation in target cells' membranes and entry of granzymes, which activate caspases responsible for apoptosis.

    • Direct receptor interactions activate Fas pathways driving cells towards apoptosis.

Natural Killer (NK) Cells (1 of 2)

  • Complement Tc cell functions; do not mature in the thymus or possess antigen-specific receptors, targeting abnormal cells lacking MHC class I.

  • Engage in antibody-dependent cellular cytotoxicity, linking with IgG through Fc receptors to initiate normal killing processes.

Natural Killer (NK) Cells (2 of 2)

  • Question 4: Regarding NK cells, a suitable answer for a nurse may be:

    • “NK cells lack antigen-specific receptors.”

Macrophages

  • Engage in chronic inflammation where T cells stimulate macrophage activation to enhance phagocytic efficiency, increase proteolytic enzyme production, retain macrophages at inflammatory sites, and enhance adhesion between Th1 and macrophages.

Pediatric Considerations

  • Newborns have an underdeveloped immune response, characterized by deficient antibody functions; they can primary produce an IgM response but unable to perform IgG challenges.

  • Maternal antibodies provide protection with trophoblastic cells facilitating transport of maternal IgG across the placenta; newborn IgG levels may approach those of adults.

Geriatric Considerations

  • Aging is marked by reduced T-cell activities:

    • Thymic size decreases to 15% of its original dimension.

    • Specific antibody production declines, alongside decreases in circulating memory B cells and increases in circulating immune complexes and autoantibodies.