Immunology

What Is Immunity?

  • Learning Objectives:

    • Discuss the organization of the immune system.

    • Describe differences between:

    1. Innate and adaptive immunity.

    2. Leukocytes and lymphocytes.

    3. Lymphoid and myeloid cells.

    4. Inflammation and infection.

    5. Primary (1˚) and secondary (2˚) lymphoid organs.

    6. Primary and secondary immune responses.

    7. Active and passive immunity.

    • List the principal cells of:

    1. Lymphocytes.

    2. Antigen-presenting cells.

    3. Granulocytes.

    • Describe their functional differences.

Organizational Layers of the Immune System

  • Distinction of "Us" vs. "Them"

Functions of the Immune System

  • Prevent infections.

  • Defense against tumors.

  • Eradicate established infections.

  • Barrier to transplantation.

Overview of Host Defense Mechanisms

Surface Barriers

  • Skin, mucous membranes.

Internal Defenses

  • Phagocytes.

  • NK (natural killer) cells.

  • Inflammation.

  • Antimicrobial proteins.

  • Fever.

Types of Immunity

  • Humoral immunity: B cells.

  • Cellular immunity: T cells.

  • Classification:

    • Innate defenses: natural/native.

    • Adaptive defenses: acquired/specific.

Development of Immune Cells

Myeloid and Lymphoid Lineage Cells

  • Origin from pluripotent hematopoietic stem cells in bone marrow.

Distinction between Leukocytes and Lymphocytes

  • Myeloid precursor cells (e.g., megakaryocytes, myeloblasts).

  • Lymphoid precursor cells (e.g., B cells, T cells).

Detailed Cell Types in the Immune System

Lymphoid Cells

  • B lymphocytes.

  • T lymphocytes.

  • Natural killer cells.

Myeloid Cells

  • Monocytes/macrophages.

  • Dendritic cells.

  • Granulocytes:

    • Neutrophils (NEU/PMNs).

    • Eosinophils (EO).

    • Basophils (BP).

    • Mast cells (MC).

    • All blood cell types develop from a common pluripotent hematopoietic stem cell.

Classes of Lymphocytes

  • Types:

    • B lymphocytes: Microbe recognition and antibody production.

    • Helper T lymphocytes: Activation via antigen-presenting cells.

    • Cytotoxic T lymphocytes (CTL): Target infected cells.

    • Natural killer (NK) cells: Kill infected cells.

  • The morphologic similarity of lymphocytes is distinguished by surface proteins (CD: cluster of differentiation).

Myeloid Immune Cells

Special Roles of Myeloid Cells

  • Mononuclear phagocytes:

    • Monocytes (blood) -> macrophages (tissue).

    • Involved in innate immunity and inflammation.

  • Dendritic cells: Specialized APCs initiating adaptive immunity.

  • Granulocytes:

    • Neutrophils: Ingest and destroy pathogens.

    • Eosinophils: Respond to helminth infections and allergies.

    • Basophils: Involved in allergic reactions and helminth infections.

    • Mast cells: Role in allergies.

Immune Cell Analogies

  • Neutrophils act as street cops (rapid response).

  • Eosinophils function as fumigators (kill parasites).

  • Basophils act as firemen (respond to inflammation).

  • Macrophages serve as riot police (long-lasting response).

  • Dendritic cells function as signalmen (relaying information).

  • Lymphocytes (B and T cells) act as special forces (specific targeted response).

Primary Lymphoid Organs (Generative, Central)

  • Lymphocytes mature in these organs over weeks to months.

  • Characteristics of naive lymphocytes:

    • Immunologically inexperienced; immunocompetent.

  • Anatomic defects in thymus development (e.g., DiGeorge syndrome).

Secondary (Peripheral) Lymphoid Organs

  • Immune responses initiated here (e.g., spleen, lymph nodes).

  • Blood-borne antigens filter through the spleen.

  • Lymph-borne antigens are drained from epithelial tissues and enter lymph nodes.

  • Consequences of asplenia and splenectomy discussed.

Distribution of Lymph Nodes

  • Connection to major vessels:

    • Internal jugular vein.

    • Entrance of right lymphatic duct into vein.

    • Entrance of thoracic duct into vein.

  • Regional lymph nodes:

    • Cervical, axillary, inguinal nodes.

Mucosal-Associated Lymphatic Tissue (MALT)

  • Key components include:

    • Tonsils (in pharyngeal region).

    • Thymus (most active during youth).

    • Spleen (curves around the left side of stomach).

    • Peyer's patches (intestine).

    • Appendix.

  • Protects the digestive and respiratory systems from foreign invasion.

Adaptive vs. Innate Immunity

  • Adaptive Immunity:

    • Specific, second line of defense, slow response (days).

    • Recognizes specific microbial antigens; high diversity; immunologic memory.

  • Innate Immunity:

    • Nonspecific, first line of defense, rapid response (minutes).

    • Recognition of common molecular structures; limited diversity; no memory.

    • Present in primitive invertebrates.

Principal Mechanisms of Innate and Adaptive Immunity

  • Time After Infection Responses:

    • Innate immunity activates within hours.

    • Adaptive immunity is engaged after days.

  • Components:

    • Phagocytes, NK cells, B lymphocytes, T lymphocytes.

Innate Immune Response Triggers Inflammatory Response

  • The inflammatory response is triggered by injury (physical, chemical, infection).

  • Beneficial Effects Include:

    • Preventing the spread of damaging agents.

    • Disposing of debris and pathogens.

    • Facilitating tissue repair.

  • Cardinal Signs of Inflammation:

    • Redness, heat, swelling, pain, and sometimes impairment of function.

Inflammatory Mediators

  • Released by injured tissues, phagocytes, granulocytes, and lymphocytes:

    • Pro-inflammatory cytokines.

    • Histamine (released by mast cells).

    • Other mediators: kinins, prostaglandins (PGs), leukotrienes.

    • C-reactive protein (CRP).

    • Complement.

Vasodilation and Vascular Permeability in Inflammation

  • Inflammatory mediators cause:

    • Dilation of arterioles (hyperemia).

    • Increased permeability of capillaries (exudate & edema).

Overview of Effector Functions

  • The goal of the immune response is to eliminate foreign antigens:

    • Innate Response: Involves antigen capture and presentation by dendritic cells.

    • Adaptive Response Mechanisms:

    • Humoral response by B cells followed by antibody production.

    • Cell-mediated response by T cells.

Strategies for Antigen Elimination during Adaptive Immunity

  • Humoral Immunity:

    • Targets extracellular microbes.

    • Functions by B lymphocytes.

  • Cell-mediated Immunity:

    • Targets intracellular microbes (e.g., viruses).

    • Functions are performed by Helper T lymphocytes and Cytotoxic T lymphocytes.

Properties of Adaptive Immunity

  • Characteristics include:

    • Specificity and diversity.

    • Clonal selection hypothesis.

    • Memory.

    • Distinction between 1˚ and 2˚ responses.

    • Types of clonal expansion and specialization responses.

Clonal Selection Hypothesis Explained

  • Mature lymphocytes specific for diverse antigens undergo activation by those antigens.

  • Activation leads to immune responses tailored to specific pathogens.

  • Formation of lymphocyte repertoires that can grant immunity to multiple antigens.

Specificity and Memory Explained

  • Example B cell responses to different antigens illustrate faster and more efficient secondary responses.

  • Naive B cells may take longer to respond when facing unfamiliar antigens.

Phases of Immune Response

  1. Antigen capture.

  2. Activation of lymphocytes.

  3. Proliferation and differentiation of activated lymphocytes into effector and memory cells.

  4. The lag time for immune responses varies, typically ranging from 3 to 6 days.

Active and Passive Immunity

  • Active Immunity:

    • Can be naturally acquired (infection) or artificially acquired (vaccination).

    • Long-lasting immunity.

    • Involves memory.

  • Passive Immunity:

    • Can be naturally acquired (mother to fetus) or artificially acquired (injection of antibodies).

    • Short-lived immunity.

    • No memory.

Overview of Innate Immune System

  • Functions primarily as an early defense mechanism against infections.

  • It recognizes and responds to microbes and damaged host cells.

    • Features bidirectional communication between innate and adaptive immunity.

Characteristics of Innate Immunity

  • Specificity for common structures of microbes (PAMPs).

  • Limited diversity in receptors.

  • Immediate and general responses to pathogens, differentiating self from nonself.

Recognition of Microbes by Innate Immunity

  • Pathogen-associated molecular patterns (PAMPs) are crucial for recognition:

    • Examples:

    • Lipopolysaccharide in Gram-negative bacteria (LPS).

    • Terminal mannose residues in bacterial glycoproteins.

    • Unmethylated CpG oligonucleotides in microbial DNA.

  • Highly effective in defense due to the identification of essential survival structures of microbes.

Pathogen-Recognition Receptors (PRRs)

  • Types:

    • Toll-like receptors (TLRs) recognize specific PAMPs.

    • Various PRRs are expressed on innate immune cells including macrophages and dendritic cells.

Toll-Like Receptors (TLR)

  • TLRs recognize various PAMPs associated with different microorganisms (e.g., TLR4 for LPS, TLR3 for viral nucleic acids).

Components of the Innate Immune System

  • Key components include:

    • Epithelial barriers: Skin, mucous membranes protect against entry.

    • Phagocytes: Monocytes and neutrophils ingest pathogens.

    • Cytokines: Signaling molecules in immune responses.

    • Complement system: Over 20 proteins aiding immune responses.

Phagocytes

  • Functions: Cell types that ingest and destroy pathogens:

    • Monocytes/macrophages.

    • Neutrophils.

    • Dendritic cells.

Monocytes/Macrophages

  • Monocytes circulate in the bloodstream and migrate to tissues to become macrophages.

  • Major roles in inflammation, cleanup, and tissue repair.

Neutrophils

  • Polymorphonuclear leukocytes (PMNs) characterized by a multi-lobed nucleus.

  • Most abundant WBC and the first responders to infection, rapidly produced in bone marrow.

Dendritic Cells

  • Function as key antigen-presenting cells (APCs) that bridge innate and adaptive immunity.

Phagocytosis Process

  • Energy and size-dependent, PRRs bind to PAMPs in the process.

  • Results in internalization, fusion with lysosomes, and subsequent microbial killing.

Natural Killer (NK) Cells

  • Large granular lymphocytes that recognize and induce apoptosis in cells lacking self-surface receptors (e.g., virus-infected cells).

Activation of NK Cells

  • Balance between activating and inhibitory receptors defines NK cell activation, leading to targeted cell lysis.

Complement System Overview

  • Activation pathways include classical, alternative, and lectin pathways.

  • Functions such as opsonization of pathogens and formation of membrane attack complex (MAC).

Interferons

  • Produced in response to viral infections; these proteins help inhibit viral replication and activate immune responses.

  • Major types include Type I (IFNα, IFNβ) and IFNγ from lymphocytes.

Inflammatory Response Mechanisms

  • Triggered by tissue injury and characterized by signs of inflammation including redness, heat, swelling, and pain.

Migration of Leukocytes During Inflammation

  • Key steps include activation of endothelial cells by cytokines, rolling, adhesion, and diapedesis of leukocytes to sites of infection.

Case Study: Luisa’s Lousy Leukocytes

  • Patient Details: Four-week-old infant, high WBC count, history of family infections.

  • Diagnosis: Leukocyte adhesion deficiency leading to recurrent bacterial infections, treated by chemotherapy and bone marrow transplant.