Adaptive Immune System

BIOL 4680: Pathophysiology - Adaptive Immune System

Learning Objectives

  • Identification of Lymphocytes:

    • Recognize the types of lymphocytes responsible for adaptive immunity.

    • Identify the molecules they use to bind antigens.

  • Antigen Presentation by APCs:

    • Explain how antigens are presented to lymphocytes by antigen presenting cells (APCs).

  • Structure of Major Histocompatibility Complex (MHC):

    • Describe the structure of MHC, the diversity and expression of human leukocyte antigen (HLA) genes, and the role of MHC in histocompatibility.

  • T-cell Receptor Structure:

    • Explain the structure of the T-cell receptor (TCR) and the organization of TCR genes.

  • T-cell Development:

    • Detail T-cell development including positive and negative thymic selection.

  • Immunoglobulins Structure:

    • Explain the structure of immunoglobulins (Ig) and the organization of Ig genes.

  • Genetic Recombination in Diversity:

    • Explicate how genetic recombination leads to tremendous diversity of both TCR and Ig structures enabling vast antigen recognition.

  • Role of Lymphoid Organs:

    • Discuss the role of lymphoid organs in antigen presentation and T-cell activation.

  • TH-cells and CTLs in Immune Response:

    • Explain the function of T-helper cells (TH-cells) and cytotoxic T-lymphocytes (CTLs) in the cell-mediated immune response.

  • Activation of B-cells:

    • Describe B-cell activation, differentiation into plasma cells, Ig class switching, and antibody effects against infection in the humoral immune response.

The Immune System

  • There are different lines of defense within the immune system:

    • 1st & 2nd lines:

    • Nonspecific and passive (innate).

    • Mediated by dendritic cells, phagocytic cells, inflammatory cytokines, and eicosanoids.

    • 3rd line:

    • Specific, active, and inducible (adaptive).

    • Mediated by lymphocytes and cytokines.

Lymphocytes

  • Activated B-cells:

    • Differentiate into antibody-secreting plasma cells.

  • Activated T-cells:

    • Differentiate into effector T-cells:

    • Helper T-cells (TH-cells): express CD4, labeled CD4+.

    • Cytotoxic T-cells (CTLs or killer T-cells): express CD8, labeled CD8+.

    • Regulatory T-cells (Tregs).

  • B-lymphocytes (B-cells):

    • Develop in the bone marrow and can be found in the blood.

  • T-lymphocytes (T-cells):

    • Develop in the thymus.

Antigens

  • Foreign molecules recognized by immunoglobulins (Ig, expressed by B-cells) or T-cell receptors (TCR, expressed by T-cells).

  • Types of Antigens:

    • Organism-specific biological molecules:

    • Proteins, polysaccharides, lipids, nucleic acids.

  • Recognition by TH-cells:

    • Bind to antigens displayed on the surface of APCs.

    • APCs are primarily dendritic cells, also macrophages, and B cells displaying antigen fragments.

  • Recognition by CTLs:

    • Bind antigens presented by infected cells.

Antigen Presentation to TH-cells

  • Foreign organisms can be engulfed by phagocytosis, or free exogenous antigens internalized via endocytosis.

  • Digestion of Antigens:

    • Lysosomal enzymes digest antigens into small fragments (typically 13-18 amino acids).

    • Fragments are bound to MHC (major histocompatibility complex) proteins and presented at the plasma membrane.

Antigen Presentation to CTLs

  • Infected cells break down foreign antigen molecules using proteasomes.

  • Process:

    • Small fragments are transported into the endoplasmic reticulum (ER) where they bind to MHC proteins and are then presented on the plasma membrane.

Major Histocompatibility Complex (MHC)

  • Role: Present antigens to both CTLs and TH cells.

  • Types of MHC:

    • MHC Class I: expressed by almost all nucleated cells.

    • MHC Class II: expressed only by APCs (dendritic cells, macrophages, B-cells).

    • The peptide-binding cleft of MHC proteins can bind a diverse range of antigen fragments.

Genes for MHC Proteins

  • MHC proteins are encoded by the HLA (human leukocyte antigen) genes.

  • Characteristics of HLA Genes:

    • Humans are polygenic for each HLA, with three distinct HLA genes co-expressed.

    • Expression of HLA genes is co-dominant, meaning genes from both parental chromosomes are expressed.

    • This co-expression increases the diversity of peptide fragments that can be bound and displayed.

MHC Population Diversity

  • There are thousands of alleles for each HLA gene, leading to millions of distinct haplotypes in the population—resulting in high polymorphism of MHC proteins.

  • Implications:

    • Responsible for histocompatibility (or histo-incompatibility).

    • HLA genes are closely linked on the same chromosome, resulting in little meiotic recombination; usually inherited together—siblings have a 25% chance of being histocompatible.

Antigen Binding by T-cells

  • Multiple additional proteins participate in T-cell and APC binding, including co-receptors (CD4 or CD8); only the TCR binds the antigen.

  • Unique Diversity of T-cells:

    • Each T-cell expresses TCRs capable of binding only one specific antigen, leading to a diverse T-cell population essential for recognizing numerous antigens.

T-cell Receptor Structure

  • Components:

    • Each TCR consists of alpha (α) and beta (β) subunits.

    • The antigen-binding portion of each subunit includes a variable (V) and a joining (J) region; for β subunit, a diversity (D) region is present.

  • Constant Region:

    • Present but does not participate in antigen binding.

  • Variability:

    • Many variants exist for each V, D, and J regions—70Vα, 61Jα; 52Vβ, 2Dβ, 13Jβ.

  • Genetic Recombination:

    • Each TCR results from the selection of a single variant of each region through recombinase enzymes (expressed by RAG-1 & RAG-2).

    • Mutations in RAG genes lead to severe combined immunodeficiency (SCID).

T-cell Development

  • Progenitor Cells:

    • Produced in bone marrow; express neither TCRs nor co-receptors—termed thymocytes (or double-negative).

  • Rearrangement:

    • TCR gene rearrangements select a single version of V and J for α chain and one of V, D, and J for β chain.

  • Clonal Expansion:

    • Following TCR establishment, cells proliferate into numerous clones with the same TCR.

  • Double-positive Phase:

    • Cells then express both CD4 and CD8 co-receptors.

Thymic Selection

  • Only 2% of thymocytes will survive maturation.

  • Positive Selection:

    • Cells capable of binding MHC proteins survive; others undergo apoptosis due to neglect—this provides MHC restriction.

  • Negative Selection:

    • APCs in thymus display self-antigens linked to MHC; thyocytes binding self-antigens or those with high affinity for MHC undergo apoptosis—this provides self-tolerance.

  • Final Differentiation:

    • Survivors differentiate into either TH cells or CTLs and enter the bloodstream.

Antigen Binding by B-cells

  • Immunoglobulins (Ig) expressed by B-cells are capable of binding antigens.

  • B-cell Specificity:

    • Each B-cell expresses an Ig capable of binding one specific antigen; diversity is critical for recognizing numerous antigens.

Immunoglobulin Structure

  • Comprises four polypeptide chains: 2 heavy and 2 light chains.

  • Binding Portions:

    • Both chains consist of variable (V) and joining (J) regions; heavy chains also include a diversity (D) region.

  • Variability in Regions:

    • Many variants per region exist; only a single variant is chosen during recombination.

Immunoglobulin Genes

  • Heavy Chain Gene Variants:

    • 48VH, 23DH, 6JH, 5C (Cµ, Cδ, Cγ, Cε, Cα).

  • Light Chain Genes Variants:

    • For lambda (λ): 34Vλ, 5Jλ, 4Cλ; for kappa (κ): 41Vκ, 5Jκ, 1Cκ.

B-cell Development

  • Progenitor lymphoid cells recombine heavy chain genes in the bone marrow.

  • Pre-B cells replicate and begin rearranging light chain genes.

  • Selection Process:

    • Only 10% display self-tolerance and remain, while 90% undergo negative selection leading to apoptosis.

    • Some self-reactive cells may survive through gene editing or expression of other light chain alleles.

  • Mature B cells:

    • Survivors express IgD in their membrane and enter the blood.

Recombination & Antibody Diversity

  • Genetic Recombination:

    • Combines different V & J segments in light chains, V, D, & J in heavy chains, allowing for millions of variable region segments.

  • Additional Modifications:

    • Alternative splice sites and nucleotide addition create “junctional diversity,” contributing tens of millions of variations in Ig and hundreds of billions in TCR.

Lymphoid Organs

  • Primary Lymphoid Organs:

    • Lymphocyte activation, development, and clonal expansion occur here; includes bone marrow and thymus.

  • Secondary Lymphoid Organs:

    • Antigen binding and full lymphocyte activation occur here; includes lymph nodes (immune surveillance of lymph), spleen (immune surveillance of blood), mucosa-associated lymphoid tissue (MALT) (immune surveillance at respiratory and gastrointestinal mucosae; notable examples: tonsils, Peyer's patches).

Lymph Node Surveillance

  • Lymphatic vessels collect and transport extracellular fluid through lymph nodes back to the vena cava.

  • Naïve B cells, naïve T cells, and dendritic cells are localized in the lymph nodes and other secondary lymphoid organs.

  • Any antigen present in lymph may be engulfed by dendritic cells, bound to MHC, and displayed to lymphocytes.

Cell-mediated Immunity

  • Involves autocrine signaling which further activates T-cells.

  • Differentiation:

    • Some T-cells transition into memory cells, remaining for years in blood.

  • TH cells:

    • Produce cytokines to support phagocytes and B cells.

  • CTLs:

    • Function to eliminate infected cells.

  • Dendritic cells present antigens (bound to MHC II) to T-cells in the paracortex.

  • Activated T-cells secrete IL-2 and express IL-2 receptors, proliferating and differentiating into effector cells migrating to infection sites.

Cell Killing by CTLs

  • CTLs bind to antigens presented by MHC I on infected cells, triggering the release of granzymes and perforin and the expression of FasL (Fas ligand).

Humoral Immunity

  • B-cell Activation:

    • Follicular dendritic cells present antigens bound to MHC I to B cells in primary follicles.

    • Proliferation of B cells leads to the formation of secondary follicles (germinal centers).

    • B cells also internalize antigens and display them via their own MHC II.

    • B cells migrate to paracortex to bind TH cells for co-stimulation.

  • After approximately 5-6 days, activated B cells differentiate into antibody-secreting plasma cells, migratng to the medulla of lymph nodes before entering the blood.

    • Some differentiate into memory cells, persisting in the blood for years.

Plasma Cells and Antibody Functions

  • Plasma cells secrete antibodies with the following capabilities:

    • IgM- Agglutination: The clumping of antigens.

    • IgG- Complement fixation & opsonization: Enhancing immune response against pathogens.

    • IgA- Secretions: Including in milk, sweat, and saliva.

    • IgE- Binding to mast cells: Facilitating allergic responses.

Ig Class Switching

  • The transition from one Ig constant region to another is termed class switching.

  • It is mediated by cytokines that trigger rounds of recombination; thus, class switching cannot revert back.