Immunology

1. The Immune System: A Two-Tiered Defense (Innate & Adaptive)

The immune system is a remarkably versatile defense system that has evolved to protect animals from invading pathogenic microorganisms and cancer.

Two main branches. The immune system operates through two interconnected branches: innate and adaptive immunity. Innate immunity provides a rapid, non-specific first line of defense, acting within hours of exposure. Adaptive immunity is slower to develop but highly specific, tailoring responses to particular pathogens and remembering past encounters.

Innate immunity's tools. This ancient system includes physical barriers like skin and mucous membranes, chemical defenses like antimicrobial peptides and complement proteins, and phagocytic cells like macrophages and neutrophils that engulf and destroy invaders. It recognizes broad patterns common to microbes but absent in the host.

Adaptive immunity's power. Adaptive immunity, found only in vertebrates, is characterized by specificity, diversity, memory, and self/nonself recognition. It relies on lymphocytes (B and T cells) and antibodies to target specific antigens, mount stronger secondary responses, and avoid attacking the body's own tissues.

2. Cells and Organs: The Immune System's Distributed Network

Carried within the blood and lymph and populating the lymphoid organs are various white blood cells, or leukocytes, that participate in the immune response.

Leukocytes are key players. All immune cells originate from hematopoietic stem cells in the bone marrow, differentiating into various leukocytes like lymphocytes, phagocytes, and granulocytes. Lymphocytes (B, T, NK cells) are central to adaptive immunity, while others support both innate and adaptive responses.

Organs provide structure. Immune cells reside and interact within specialized organs. Primary lymphoid organs (bone marrow, thymus) are where lymphocytes mature and gain their antigen specificity. Secondary lymphoid organs (lymph nodes, spleen, MALT) are strategically located to trap antigens and facilitate encounters between mature lymphocytes and pathogens.

Circulation connects everything. Blood and the lymphatic system serve as highways, transporting immune cells and antigens throughout the body. This constant recirculation ensures that lymphocytes can patrol tissues, reach sites of infection, and gather in lymphoid organs to coordinate responses.

3. Antigens: The Targets Recognized by Immune Receptors

Substances that can be recognized by the immunoglobulin receptor of B cells, or by the T-cell receptor when complexed with MHC, are called antigens.

Recognition is specific. Antigens are molecules or substances that immune receptors can bind to. Immunogenicity is the ability to induce an immune response, while antigenicity is the ability to bind to immune products (antibodies, TCRs). All immunogens are antigenic, but not all antigens (like haptens) are immunogenic on their own.

Factors matter. A molecule's immunogenicity depends on its foreignness, size, chemical complexity, and ability to be processed and presented by MHC molecules. The host's genetics, the dose and route of exposure, and the use of adjuvants also play crucial roles.

Epitopes are the binding sites. Immune cells don't recognize the entire antigen, but discrete regions called epitopes.

• B-cell epitopes are often on the surface, can be sequential or conformational, and bind directly to antibodies.
• T-cell epitopes are typically internal peptides, exposed only after processing, and recognized only when presented by MHC molecules.

4. Antibodies: Humoral Immunity's Diverse, Specific Weapons

Antibodies are the antigen-binding proteins present on the B-cell membrane and secreted by plasma cells.

Basic structure. Antibodies (immunoglobulins, Ig) are Y-shaped proteins composed of two identical heavy (H) chains and two identical light (L) chains linked by disulfide bonds. The tips of the Y form the variable (V) regions, which bind antigen, while the base forms the constant (C) region (Fc), mediating effector functions.

Diversity and specificity. The vast diversity of antibody binding sites is generated by genetic rearrangement of V, D, and J gene segments during B-cell development, junctional flexibility, and somatic hypermutation after antigen exposure. Each B cell expresses antibodies with a single, unique specificity.

Classes and functions. There are five main antibody classes (isotypes: IgM, IgG, IgA, IgE, IgD), distinguished by their heavy chains.

• IgM: First responder, pentameric, high avidity.
• IgG: Most abundant, crosses placenta, opsonization, complement activation.
• IgA: Secretory antibody, protects mucosal surfaces.
• IgE: Mediates allergy and antiparasitic responses.
• IgD: On naive B cells, function unclear.

5. T-Cell Receptors: Cellular Immunity's MHC-Restricted Sensors

The antigen-specific nature of T-cell responses clearly implies that T cells possess an antigen-specific and clonally restricted receptor.

MHC restriction is key. Unlike antibodies, most T-cell receptors (TCRs) do not recognize free antigen. Instead, they recognize processed peptide fragments presented within the groove of a self-MHC molecule on the surface of another cell. This is called MHC restriction.

Structure mirrors antibodies. TCRs are membrane-bound heterodimers, usually composed of alpha and beta chains, with variable and constant domains structurally similar to antibody Fab fragments. Their variable regions contain hypervariable loops (CDRs) that form the antigen-binding site.

Diversity generation. TCR gene organization and rearrangement (V(D)J recombination) are remarkably similar to Ig genes, generating diverse receptors. However, TCR genes do not undergo somatic hypermutation after antigen exposure, maintaining the specificity established during development.

6. MHC: Self-Markers Presenting Antigens to T Cells

Every mammalian species studied to date possesses a tightly linked cluster of genes, the major histocompatibility complex (MHC), whose products play roles in intercellular recognition and in discrimination between self and nonself.

Central to T-cell recognition. MHC molecules are cell surface glycoproteins that bind and display peptide fragments derived from protein antigens. T cells recognize these peptide-MHC complexes, making MHC central to adaptive immunity.

Two main classes.

• Class I MHC: Found on most nucleated cells, present peptides from endogenous (intracellular) antigens to CD8+ T cells (CTLs).
• Class II MHC: Found primarily on antigen-presenting cells (APCs), present peptides from exogenous (extracellular) antigens to CD4+ T cells (TH cells).

Polymorphism and polygeny. The MHC is highly polymorphic (many alleles at each locus) and polygenic (multiple genes for each class). This diversity ensures that a population can present a wide range of peptides, contributing to species survival against diverse pathogens, but makes transplantation challenging.

7. Antigen Processing & Presentation: Preparing Antigens for T-Cell Recognition

Recognition of foreign protein antigens by a T cell requires that peptides derived from the antigen be displayed within the cleft of an MHC molecule on the membrane of a cell.

Antigens must be processed. Protein antigens are not recognized by T cells in their native form. They must be degraded into smaller peptides through a process called antigen processing. These peptides then associate with MHC molecules for presentation on the cell surface.

Two distinct pathways.

• Cytosolic Pathway (for endogenous antigens): Proteins are degraded by proteasomes in the cytoplasm. Peptides are transported into the endoplasmic reticulum by TAP transporters, where they bind to newly synthesized Class I MHC molecules.
• Endocytic Pathway (for exogenous antigens): Antigens are internalized by endocytosis or phagocytosis into vesicles. They are degraded in acidic endosomal/lysosomal compartments, where peptides bind to Class II MHC molecules.

MHC-peptide assembly. In the endocytic pathway, the invariant chain guides Class II MHC molecules to endosomal compartments and prevents premature peptide binding. HLA-DM facilitates the exchange of invariant chain fragments (CLIP) for antigenic peptides.

8. Lymphocyte Development: Shaping a Self-Tolerant, Antigen-Reactive Repertoire

The potential antigenic diversity of the T-cell population is reduced during maturation by a selection process that allows only MHC-restricted and nonself-reactive T cells to mature.

Maturation in primary organs. Lymphocytes develop from stem cells in primary lymphoid organs. B cells mature in the bone marrow, undergoing Ig gene rearrangement and negative selection against self-antigens. T cells mature in the thymus, undergoing TCR gene rearrangement and rigorous selection.

Thymic selection is crucial. Developing T cells (thymocytes) face two selection hurdles:

• Positive Selection: Only thymocytes whose TCRs can recognize self-MHC molecules survive, ensuring MHC restriction.
• Negative Selection: Thymocytes with high-affinity receptors for self-MHC or self-peptide/self-MHC are eliminated (clonal deletion), ensuring self-tolerance.

Survival of the fittest (immunologically). This stringent selection process eliminates the vast majority of thymocytes (over 98%), ensuring that the mature T-cell repertoire is both self-MHC restricted and largely self-tolerant, ready to respond to foreign antigens.

9. Lymphocyte Activation: Triggering Immune Responses

Activation of mature peripheral T cells begins with the interaction of the T-cell receptor (TCR) with an antigenic peptide displayed in the groove of an MHC molecule.

Two signals needed. Naive lymphocytes require multiple signals for full activation. For T cells, signal 1 is TCR engagement by peptide-MHC. Signal 2 is a co-stimulatory signal, often from B7 on APCs binding CD28 on T cells. Without signal 2, T cells may become anergic (unresponsive).

BCR signaling. B-cell activation begins with antigen binding and crosslinking of membrane Ig (signal 1). For T-dependent antigens, signal 2 comes from TH cells, often via CD40-CD40L interaction and cytokines. The B-cell coreceptor (CD19/CR2/TAPA-1) amplifies signal 1.

Signal transduction cascades. Receptor engagement triggers intracellular signaling pathways involving protein tyrosine kinases (like Lck, ZAP-70, Syk) and second messengers (like IP3, DAG, Ca2+). These cascades activate transcription factors that alter gene expression, driving proliferation and differentiation.

10. Cytokines: The Immune System's Communication Language

Cytokines are low-molecular-weight regulatory proteins or glycoproteins secreted by white blood cells and various other cells in the body in response to a number of stimuli.

Immune system's messengers. Cytokines are soluble mediators that facilitate communication between immune cells and other body cells. They bind to specific receptors on target cells, triggering signal transduction and altering gene expression.

Diverse actions. Cytokines exhibit pleiotropy (one cytokine, multiple effects), redundancy (multiple cytokines, same effect), synergy (combined effect greater than sum), antagonism (one cytokine inhibits another), and cascade induction (one cytokine induces others). They regulate inflammation, hematopoiesis, and lymphocyte activity.

TH1 vs. TH2 profiles. CD4+ TH cells differentiate into subsets with distinct cytokine profiles that shape the immune response.

• TH1: Secrete IFN-, IL-2, TNF-. Promote cell-mediated immunity (CTLs, macrophages, DTH).
• TH2: Secrete IL-4, IL-5, IL-6, IL-10. Promote humoral immunity (B cell help, antibody production, especially IgE).

11. Effector Mechanisms: How the Immune System Eliminates Threats

The principal role of cell-mediated immunity is to detect and eliminate cells that harbor intracellular pathogens.

Humoral effectors. Antibodies are the main effectors of humoral immunity. They neutralize toxins and viruses, opsonize pathogens for phagocytosis, and activate the complement system.

Complement's power. The complement system is a cascade of serum proteins activated by antibodies (classical pathway), microbial surfaces (alternative pathway), or lectins (lectin pathway). It mediates:

• Lysis of cells via the membrane-attack complex (MAC).
• Opsonization (coating pathogens for phagocytosis).
• Inflammation (via anaphylatoxins).
• Clearance of immune complexes.

Cell-mediated effectors.

• CTLs: CD8+ T cells that kill infected or abnormal self-cells via perforin/granzymes or FasL.
• NK cells: Lymphoid cells that kill target cells lacking normal MHC I expression or coated with antibody (ADCC).
• Macrophages/Neutrophils: Phagocytose and destroy pathogens, contribute to inflammation.

12. Immune System in Disease: When Defenses Fail or Attack Self

When the system errs by failing to protect the host from disease-causing agents or from malignant cells, the result is immunodeficiency, which is the subject of this chapter.

Immunodeficiency. Failure of immune components leads to increased susceptibility to infection. Primary immunodeficiencies are genetic defects (e.g., SCID, XLA, LAD). Secondary immunodeficiencies are acquired (e.g
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Last updated: May 6, 2025