Host Immunity

Immunity Notes

Host Immunity

  • Instructor: Dr. Karl Meszaros

  • Textbooks Referenced:

    • Robbins: Basic Pathology

    • Ganong’s Review of Medical Physiology

    • Abbas: Cellular and Molecular Immunology

    • Wikipedia

General Introduction to Immunity

  • Recording Initiated: Smile! (Recording for educational purposes)

Exam Information

  • Slide Background Colors:

    • Blue Background: Material that will be on the exams.

    • Other Background Colors: Enrichment material; not part of the exams.

  • Main Textbook Access: Electronic copy of Robbins: Basic Pathology is available from TUC library.

Complexity of the Immune System

  • There’s a well-known joke involving an immunologist and a cardiologist highlighting the complications of immunology.

  • Key Aspects of Humor:

    • The immune system is incredibly intricate, comparable to multiple Rube Goldberg machines.

    • Important components include labels resembling secure passwords, such as CD8+, IL-1β, and IFN-γ.

Historical Background of Immunology

  • Phagocytosis Discovery:

    • Elie Metchnikoff (1880s): Discovered that mammalian leukocytes ingest bacteria.

    • Observation: Inflammation serves to recruit phagocytes to engulf bacteria.

    • Contradiction of Prevailing Theories:

    • Opposed Paul Ehrlich’s theory regarding serum factors.

  • Nobel Prize 1908: Shared by Metchnikoff and Ehrlich for contributions to humoral and cellular immunity.

Learning Objectives

  1. Understand Immune Defenses and Reactions:

  2. Conceptual Knowledge:

    • Terms: Hapten, Complement, MHC (Major Histocompatibility Complex), Monoclonal Antibodies.

  3. Innate Immunity:

    • Cells, Receptors, Effector Functions, Complement System.

  4. Adaptive Immunity:

    • Humoral and Cell-Mediated Immunity.

    • Lymphocyte Development, Antigen Structures, Recognition.

    • Receptor Diversity, Antigen Processing, Proliferation, Immunological Memory.

  5. Part II Topics:

    • Tolerance, Immunodeficient States.

Introduction to Immune Reactions

  • Defenses Against:

    • Bacteria

    • Viruses

    • Foreign Substances: Includes large molecules and small molecules acting as haptens.

    • Abnormal Cells: Tumor cells and transplants (non-self).

Impaired and Overactive Immune Reactions

  • Impaired Immune Reactivity:

    • Congenital immune deficiencies

    • Acquired Immune Deficiency Syndrome (AIDS)

    • Drug-induced immunosuppression (e.g., chemotherapy).

  • Out-of-Control Immune Reactions:

    • Hypersensitivity

    • Autoimmunity.

Concept of Haptens

  • Definition: Low-molecular weight substances that cannot elicit an immune response unless attached to a larger carrier molecule.

  • Examples:

    • Natural Compounds: Poison ivy toxin, low-molecular allergens.

    • Drugs: Penicillin, hydralazine, and others.

    • Metals: Gold, nickel (example: nickel allergy).

Types of Immunity

Innate Immunity

  • Characteristics:

    • Also termed non-specific, natural, or native immunity.

    • First line of antimicrobial defense present in most multicellular organisms.

    • Focused on defense against bacteria, viruses, and tumor cells.

    • Key in activating adaptive immunity.

  • Cells Involved in Innate Immunity:

    • Epithelial cells (mucosal barriers).

    • Phagocytic cells:

    • Macrophages

    • Neutrophils (Polymorphonuclear Neutrophil Leukocytes).

    • Natural Killer (NK) cells (large cytotoxic lymphocytes).

    • Dendritic Cells.

    • Plasma Proteins:

    • Complement System, other plasma proteins (e.g., lectins, lung surfactants).

Cellular Receptors in Innate Immunity

  • Types of Cellular Receptors:

    • Pattern Recognition Receptors (PRRs):

    • Functions: Detect components of extracellular pathogens, recognize dead microbes, and detect ingested pathogens.

    • Specific PRRs:

    • Toll-Like Receptors (TLRs): Recognize bacterial molecules, induce cytokine secretion.

    • Lectin Receptors: Detect fungal cell wall components and induce phagocytosis.

    • Cytosolic Receptors: NOD-like, RIG-like receptors, recognize dead microbial components.

Inflammasome

  • Description: A multi-protein complex that activates pro-inflammatory cytokines such as IL-1β through caspase-1 activation.

  • Roles: Induces phagocytosis and inflammation hence triggering the adaptive immune response.

The Complement System

  • Overview: A network of circulating proteins (C1-9) that activate proteolytic cascades.

  • Functions:

    • Binds to microbes, leading to their destruction via phagocytosis or direct lysis.

    • Induces inflammation by activating neutrophils.

Pathways of Complement Activation

  1. Alternative Pathway:

    • Initiated by hydrolysis of C3; C3b binds to microbes and is recognized by phagocytes.

    • C3a activates neutrophils, inducing inflammation.

  2. Classical Pathway:

    • Antibodies bind to microbes (opsonization).

    • Complement binds to antibody Fc regions. Causes destruction of microbes via C3 activation.

  3. Lectin Pathway:

    • Attacks fungi via lectins binding to surface sugars.

Membrane Attack Complex (MAC)

  • Mechanism:

    • C3b facilitates assembly of complement components into MAC, creating a channel in microbial membranes, leading to cell lysis and death.

Summary of Complement Pathways

  • Three types of pathways:

    • Alternative Pathway

    • Classical Pathway

    • Lectin Pathway

  • All pathways promote inflammation, initiate phagocytosis, and lead to direct lysis of microbes.

Adaptive Immunity

Overview

  • Concept: Adaptive immunity is also known as acquired or specific immunity, representing a more refined mechanism involving lymphocytes, allowing recognition of various antigens and a robust response.

  • Components:

    • B lymphocytes

    • T lymphocytes (both describe stages of adaptive response).

  • Development Mechanisms:

    • Variable region creation for antigen recognition, clone generation upon activation.

Historical Context

  • The Immunological Big Bang: Emerged around 500 million years ago with the advent of jawed vertebrates marking the origin of adaptive immune systems.

Lymphocyte Distribution

  • Approximate counts of lymphocytes in various tissues:

    • Lymph nodes: 190 × 10^9

    • Spleen: 70 × 10^9

    • Bone Marrow: 50 × 10^9

    • Blood: 10 × 10^9

    • Skin: 20 × 10^9

    • Intestines: 50 × 10^9

    • Liver: 330 × 10^9

    • Lungs: 10 × 10^9.

Antibody and Lymphocyte Structure

Structure of Antibodies

  • Composed of heavy and light chains forming variable (antigen binding) and constant (effector functions) regions.

  • Antigen Binding Site: Formed by the variable regions of heavy (VH) and light (VL) chains connected by disulfide bridges.

Learning Recommendation

  • Study structures and functions of different immunoglobulin (Ig) classes and their roles in immune responses.

Lymphocyte Diversity

  • The immense diversity of antigen receptors originates from DNA sequence variation during lymphocyte development.

  • Recognizing Antigens: Each lymphocyte exhibits unique specificities due to varied receptors, recognizing numerous antigens (on the order of hundreds of millions).

  • Mechanism of Diversity:

    • Involves genetic recombination (V, D, J segments), junctional diversity, nucleotide additions/removals, and somatic mutations during lymphocyte maturation.

Adaptive Immunity Details

Humoral Immunity

  • Mediated by: B lymphocytes against extracellular microbes and toxins.

  • Processes Involved:

    • Immunoglobulin production.

    • Neutralization and opsonization.

  • Memory Formation: Produces long-lived memory B cells post-infection.

Cell-Mediated Immunity

  • Mediated by: T lymphocytes derived from thymus.

  • Functions:

    • Assist in killing of infected or tumor cells.

    • Specific T-cell types include helper and cytotoxic T cells.

  • Natural Killer (NK) Cells: Part of innate immunity, play a role in recognizing and destroying stressed or abnormal cells.

Antigen Receptor Mechanisms

B Cell Activation

  1. Antigen Binding initiates B cell activation.

  2. Involves cytokine stimulation and clonal expansion into plasma and memory cells.

T Cell Receptors

  • Key Features:

    • Unique specificity for antigens presented on MHC complexes; cannot bind free antigens.

    • Activation results in T cell proliferation and differentiation into various effector functions.

Major Histocompatibility Complex (MHC)

Types of MHC

  1. Class I MHC: Present on all nucleated cells, presenting endogenous peptides to CD8+ T cells.

  2. Class II MHC: Present on APCs (e.g., macrophages, dendritic cells), presenting exogenous peptides to CD4+ T cells.

Antigen Processing Pathways

  • Endogenous Pathway: For MHC Class I, where cytosolic proteins are processed through proteasomes before presentation.

  • Exogenous Pathway: For MHC Class II, where extracellular antigens are phagocytosed and processed before presentation to helper T cells.

Immune Responses Overview

Cytokines Overview

  • Roles:

    • Messengers of the immune system, mediating both innate and adaptive responses such as inflammation and lymphocyte activation.

  • Main Cytokines:

    • Innate: TNF, IL-1, IL-12.

    • Adaptive: IL-2, IL-4, IL-5, IL-17.

Vaccination and Immunological Memory

  • Concept: Vaccination provides long-lasting immunity by eliciting memory responses from both B and T cells, which facilitate quick responses on re-exposure to pathogens.

  • T-cell Therapy in Cancer:

    • Two specific methods: TIL therapy and CAR T-cell therapy are utilized to enhance patient's own T cells to fight tumors.

Autoimmunity

Self-Recognition and Tolerance

  • Recognition of Self: Self-antigens may provoke immune responses if tolerance is failed.

  • Mechanisms of Tolerance:

    • Central tolerance occurs in thymus (for T cells) and bone marrow (for B cells).

    • Failure can result in autoimmune diseases and complications such as transplant rejection.

Conclusion and Upcoming Topics

  • Next steps include discussions on the humoral immune response, immunodeficiencies, monoclonal antibody applications, autoimmune diseases, and their management strategies.