10.5 Innate & Adaptive Immunity
Key Takeaways
- Innate immunity provides rapid, non-specific defense via physical barriers, cellular phagocytes (macrophages, neutrophils), granulocytes, and Natural Killer (NK) cells that induce apoptosis in cells lacking MHC Class I ('missing self').
- The Complement System activates classical, lectin, or alternative pathways to generate C3b (opsonization), C3a/C5a (anaphylatoxins and neutrophil chemoattractants), and C5b-C9 Membrane Attack Complexes (MAC) for osmotic cell lysis.
- Humoral adaptive immunity relies on B lymphocytes maturing in bone marrow to secrete five antibody isotypes (IgM first responder pentamer, IgG most abundant crossing placenta, IgA mucosal dimer, IgE allergic monomer, IgD receptor) generated through V(D)J somatic recombination.
- Cell-mediated adaptive immunity requires thymic positive/negative selection: CD8+ cytotoxic T cells bind endogenous antigens on MHC Class I to release perforin/granzymes, while CD4+ helper T cells bind exogenous antigens on MHC Class II (APCs) to orchestrate Th1/Th2 cytokine responses.
Overview of Immune System Architecture
The immune system protects the organism against pathogenic microbes (viruses, bacteria, fungi, parasites) and neoplastic cells while maintaining self-tolerance. Immune defenses are broadly categorized into Innate Immunity (non-specific, immediate, no immunological memory) and Adaptive Immunity (antigen-specific, delayed onset, robust immunological memory).
[IMMUNE SYSTEM]
|
+-------------------------------+-------------------------------+
| |
[INNATE IMMUNITY] [ADAPTIVE IMMUNITY]
(Non-specific, Immediate) (Specific, Memory, Delayed)
| |
+------+------+ +------+------+
| | | |
Barriers Cellular & Humoral Humoral Cell-Mediated
- Skin - Macrophages, Neutrophils (B Cells) (T Cells)
- Lysozyme - NK Cells (Missing MHC I) | |
- Acid - Complement (C3b, MAC) Antibodies CD8+ (MHC I)
(IgM, IgG...) CD4+ (MHC II)
Innate Immunity: Barriers, Cellular Components & NK Cells
Innate immunity constitutes the first line of defense, operating continuously without prior pathogen exposure.
Anatomical & Chemical Barriers
- Skin (Integument): Continuous keratinized epithelium (stratum corneum) providing a physical barrier. Secretes antimicrobial peptides (defensins) and acidic sebum (pH $4.5\text{--}5.5$) to inhibit bacterial colonization.
- Lysozyme: Enzymatic component of tears, saliva, and mucosal secretions that cleaves $\beta(1\rightarrow4)$ glycosidic bonds in bacterial peptidoglycan cell walls.
- Stomach Acid: Highly acidic gastric secretion (pH $1.5\text{--}2.0$) that denatures microbial proteins and destroys ingested pathogens.
Cellular Components of Innate Immunity
- Macrophages: Tissue-resident phagocytes derived from circulating monocytes. Engulf pathogens, degrade them within phagolysosomes, present peptide antigens on MHC Class II, and release pro-inflammatory cytokines (IL-1, IL-6, TNF-$\alpha$).
- Neutrophils: Most abundant circulating white blood cells ($50\text{--}70%$). Rapidly undergo extravasation to sites of infection, executing phagocytosis via an oxidative burst driven by NADPH oxidase, which generates reactive oxygen species (ROS like superoxide $\text{O}_2^{\bullet-}$, $\text{H}_2\text{O}_2$, and hypochlorous acid $\text{HOCl}$). Neutrophils also expel chromatin structures known as Neutrophil Extracellular Traps (NETs).
- Eosinophils: Granulocytes specialized in defense against multicellular parasites (helminths) via Antibody-Dependent Cellular Cytotoxicity (ADCC). Release major basic protein (MBP) and eosinophil peroxidase; heavily involved in allergic responses.
- Basophils & Mast Cells: Granulocytes containing dense granules loaded with histamine, heparin, and leukotrienes. Surface expression of high-affinity $\text{Fc}\varepsilon\text{RI}$ receptors binds IgE; antigen crosslinking triggers degranulation, inducing vasodilation, vascular permeability, and bronchoconstriction.
- Natural Killer (NK) Cells: Innate cytotoxic lymphocytes that survey host cells for abnormal surface expression. Host cells normally express MHC Class I. Virally infected or transformed tumor cells often downregulate MHC Class I to evade cytotoxic T cells. NK cells detect this "missing self" signal and induce targeted target-cell apoptosis via Perforin and Granzymes.
| Leukocyte Type | Primary Immune Function | Key Effector Molecules / Mechanisms |
|---|---|---|
| Neutrophil | First-responder bacterial phagocytosis | Oxidative burst (ROS, NADPH oxidase), NETs |
| Macrophage | Phagocytosis, antigen presentation, cytokine release | Phagolysosome digestion, MHC Class II, TNF-$\alpha$, IL-1 |
| Eosinophil | Anti-parasitic defense, allergic responses | Major Basic Protein (MBP), ADCC |
| Mast Cell / Basophil | Inflammatory response, anaphylaxis | Histamine, heparin, IgE Fc$\varepsilon$RI crosslinking |
| Natural Killer Cell | Lysis of virally infected / tumor cells | Missing-self detection (no MHC I), Perforin/Granzyme |
The Complement System
The complement system is a cascade of over 30 soluble plasma proteins synthesized by the liver that circulate in inactive zymogen forms.
[Classical Pathway] [Lectin Pathway] [Alternative Pathway]
(Antigen-Antibody) (MBL-Mannose) (Spontaneous C3 Hydrolysis)
\ | /
\ v /
+-----------------> [C3 Convertase] <---------------+
|
v
[C3 Cleavage]
|
+---------------+---------------+
| |
v v
[C3a] [C3b]
(Anaphylatoxin) (Opsonization & C5 Convertase)
(Inflammation) |
v
[C5 Cleavage]
|
+---------------+---------------+
| |
v v
[C5a] [C5b]
(Anaphylatoxin & |
Chemoattractant) +---------+--------+
| C6, C7, C8, C9 |
v v
[Membrane Attack Complex (MAC)]
(Form Transmembrane Pores -> Lysis)
Activation Pathways & Convergent Cascades
- Classical Pathway: Triggered by antibody-antigen complexes binding complement component C1q (requires IgM or IgG).
- Lectin Pathway: Initiated when Mannose-Binding Lectin (MBL) binds specific carbohydrate motifs on microbial cell walls.
- Alternative Pathway: Initiated by spontaneous low-level hydrolysis of plasma C3 ($C3(H_2O)$) directly on foreign surfaces.
Complement Effector Functions
- C3b (Opsonization): Cleavage of C3 deposits C3b covalently onto pathogen surfaces. Phagocytes expressing C3b receptors bind and engulf opsonized microbes efficiently.
- C3a & C5a (Anaphylatoxins & Chemotaxis): Small soluble cleavage fragments. C3a and C5a induce mast cell degranulation (releasing histamine). C5a acts as a potent chemoattractant recruiting neutrophils to sites of infection.
- C5b-C9 Membrane Attack Complex (MAC): C5b recruits C6, C7, C8, and multiple polymerizing C9 molecules to assemble a hydrophobic ring pore across the target cell's phospholipid bilayer. MAC pores destroy osmotic integrity, causing water influx and cell lysis.
Adaptive Immunity: Humoral Branch & B Cells
Humoral immunity is mediated by B Lymphocytes and circulating Antibodies (Immunoglobulins).
B Cell Development & Antibody Structure
B cells develop and mature in the Bone Marrow. Upon encountering matching antigen via membrane-bound B Cell Receptors (BCRs), naive B cells proliferate and differentiate into:
- Plasma Cells: Effector B cells that synthesize and secrete soluble antibodies ($> 2,000\text{ molecules/sec}$).
- Memory B Cells: Long-lived quiescent cells that persist in secondary lymphoid organs, driving rapid secondary immune responses upon re-exposure.
An Antibody molecule is a Y-shaped heterotetrameric glycoprotein composed of two identical heavy (H) chains and two identical light (L) chains linked by interchain disulfide bonds:
- Fab Region (Fragment Antigen-Binding): Composes the amino-terminal variable ($V_H, V_L$) domains. Contains hypervariable complementarity-determining regions (CDRs) that confer precise antigen specificity.
- Fc Region (Fragment Crystallizable): Composes the carboxy-terminal constant ($C_H$) domains. Mediates biological effector functions (complement activation, binding Fc receptors on phagocytes/NK cells).
Antigen-Binding Site
\ / \ /
V_L V_H V_H V_L
| | | |
| C_H1 C_H1 |
+---+ +---+
| (Disulfide) | <--- Fab Region
--- Hinge Region ---
| |
C_H2 C_H2 <--- Fc Region
| |
C_H3 C_H3
Antibody Isotypes (Classes)
| Isotype | Physical Structure | Serum Abundance | Primary Functions & Clinical Features |
|---|---|---|---|
| IgM | Pentamer (with J chain) or Monomer BCR | $,\sim 10%$ | First antibody class secreted during primary response; highly potent complement activator |
| IgG | Monomer | $,\sim 80%$ | Most abundant serum isotype; only class that crosses the placenta; opsonizes pathogens, activates complement |
| IgA | Dimer (with J chain & secretory component) | $,\sim 15%$ | Primary mucosal secretory antibody (tears, saliva, colostrum/breast milk, GI secretions) |
| IgE | Monomer | $< 0.01%$ | Binds $\text{Fc}\varepsilon\text{RI}$ on mast cells/basophils; mediates type I hypersensitivity and anti-helminth defense |
| IgD | Monomer | $< 0.5%$ | Co-expressed with IgM on surface of naive B cells; functions as antigen receptor |
V(D)J Somatic Recombination
Antibody diversity ($,\sim 10^{11}$ unique binding specificities) is generated independently of antigen exposure via V(D)J Somatic Recombination in developing B cells. Recombinase enzymes (RAG-1 and RAG-2) randomly splice together Variable (V), Diversity (D), and Joining (J) genomic segments of the immunoglobulin heavy chain, and V and J segments of the light chain.
Adaptive Immunity: Cell-Mediated Branch & T Cells
Cell-mediated immunity is driven by T Lymphocytes, which mature in the Thymus.
Thymic Selection & Self-Tolerance
Progenitor T cells migrate from bone marrow to the thymus, undergoing two sequential selection processes to eliminate non-functional or autoreactive clones:
- Positive Selection (Thymic Cortex): Developing T cells must successfully interact with self-MHC complexes presented by thymic cortical epithelial cells. T cells unable to bind self-MHC undergo apoptosis (death by neglect). Ensures MHC restriction.
- Negative Selection (Thymic Medulla): T cells that bind self-antigens presented on self-MHC with excessively high affinity are induced to undergo apoptosis (or converted to Tregs). Establishes central self-tolerance, preventing autoimmune disease.
[Bone Marrow Progenitor]
|
v (Migration to Thymus)
[Double Negative T Cell (CD4- CD8-)]
|
v (TCR Rearrangement)
[Double Positive T Cell (CD4+ CD8+)]
|
v (Thymic Cortex: Positive Selection)
[Does TCR bind self-MHC?] === NO ===> [Apoptosis (Death by Neglect)]
|
YES
v (Thymic Medulla: Negative Selection)
[High affinity for self-antigen?] === YES ===> [Apoptosis (Central Tolerance)]
|
NO
v
[Single Positive Mature Naive T Cell]
/ \
[CD4+ Helper T Cell] [CD8+ Cytotoxic T Cell]
CD8+ Cytotoxic T Lymphocytes vs. CD4+ Helper T Lymphocytes
| Feature | Cytotoxic T Cells (CD8+ CTLs) | Helper T Cells (CD4+ Th Cells) |
|---|---|---|
| MHC Restriction | MHC Class I | MHC Class II |
| Antigen Origin | Endogenous (synthesized inside cytosol: viral proteins, mutated proteins) | Exogenous (extracellular pathogens phagocytosed by APCs) |
| Cellular Distribution of MHC | All nucleated host cells | Professional Antigen-Presenting Cells (APCs: Dendritic cells, Macrophages, B cells) |
| Primary Function | Direct killing of virally infected or neoplastic host cells | Orchestrating adaptive immune responses via cytokine secretion |
| Effector Mechanisms | Secretion of Perforin (pore formation) and Granzymes (caspase cleavage $\rightarrow$ apoptosis) | Th1: releases $\text{IFN}-\gamma$ (activates macrophages); Th2: releases IL-4/IL-5 (activates B cells) |
Rule of 8 Mnemonic:
- $\text{CD4} \times \text{MHC II} = 8$
- $\text{CD8} \times \text{MHC I} = 8$
Regulatory T Cells (Tregs)
Regulatory T cells represent a specialized subpopulation of $\text{CD4}^+$ T cells characterized by surface expression of $\text{CD25}$ (IL-2 receptor $\alpha$-chain) and the master nuclear transcription factor $\text{FoxP3}$ ($\text{CD4}^+\text{CD25}^+\text{FoxP3}^+$). Tregs suppress self-reactive lymphocytes by secreting immunosuppressive cytokines (IL-10 and TGF-$\beta$), maintaining peripheral self-tolerance.
Severe Immunodeficiency Syndrome can result from mutations in the FoxP3 gene. Patients carrying loss-of-function FoxP3 mutations lack functional regulatory T cells (Tregs). Which cellular phenotype and functional impairment characterize these patients?
A cell biologist analyzes host cell responses to intracellular viral infection. Virally infected host cells attempt to evade CD8+ cytotoxic T lymphocyte detection by downregulating cell-surface MHC Class I expression. Which innate immune cell type specifically recognizes and destroys host cells exhibiting this 'missing self' signal?
Which processing pathway and major histocompatibility complex (MHC) class correctly correspond to the presentation of phagocytosed bacterial antigens by a dendritic cell to activate helper T lymphocytes?