The Immune Response

Fig. 5.1 — Robbins & Kumar Basic Pathology: Innate immunity acts within hours; adaptive immunity develops over days.

1. Innate Immunity (Hours 0–12)

Components

Pattern Recognition

• PAMPs (Pathogen-Associated Molecular Patterns) — structures shared by groups of microbes (e.g., LPS on gram-negative bacteria)
• DAMPs (Damage-Associated Molecular Patterns) — signals from injured/necrotic host cells (e.g., uric acid, ATP)

The Inflammasome: Several NLRs signal via this cytosolic multiprotein complex → activates caspase-1 → cleaves pro-IL-1β into active IL-1β. This drives fever and inflammation. Gain-of-function NLR mutations cause autoinflammatory syndromes; recognition of urate crystals by NLRs underlies gout inflammation.

Reactions of Innate Immunity

1. Inflammation — cytokines + complement recruit leukocytes that destroy pathogens and clear dead cells
2. Antiviral defense — Type I interferons (IFN-α/β) produced by virus-infected cells degrade viral nucleic acids and inhibit viral replication in neighboring cells

2. Adaptive Immunity (Days 1–5+)

Cardinal Features

Cells of Adaptive Immunity

T Lymphocytes

Dendritic cells are the key bridge — they phagocytose antigens in peripheral tissues, process them, migrate to lymph nodes, and present peptides to naïve T cells to initiate the adaptive response.

B Lymphocytes & Antibodies

1. Proliferation and differentiation → plasma cells (effector B cells)
2. Antibody secretion (immunoglobulins: IgM, IgG, IgA, IgE, IgD)
3. Class switching — driven by cytokines from T helper cells (e.g., IFN-γ → IgG; IL-4 → IgE)
4. Memory B cell formation — enables rapid secondary responses

3. Innate–Adaptive Crosstalk

• Innate cells (especially DCs) activate adaptive immunity by presenting antigens + providing co-stimulatory signals
• Cytokine crosstalk (e.g., IL-12 from DCs → Th1 differentiation; IL-4 → Th2; IL-6/IL-23 → Th17) matches the adaptive response to the type of threat
• Under normal mucosal conditions: tolerance is maintained (Tregs + controlled Th2 → IgA secretion without inflammation)
• Under pathogen threat: protective inflammatory responses are mounted with appropriate T-helper polarization

4. Summary Comparison

Immune Response — Physiology

1. Physiological Sequence of Events

Pathogen entry
     │
     ▼
Innate recognition (minutes–hours)
     │
     ▼
Antigen capture & presentation by DCs (hours–day 1)
     │
     ▼
Adaptive activation: T cell & B cell responses (days 3–5)
     │
     ▼
Effector phase: antibodies, cytotoxic killing, macrophage activation
     │
     ▼
Memory formation + response contraction

2. Innate Immune Physiology

Pattern Recognition & Signal Transduction

Inflammasome physiology: NLRs (e.g., NLRP3) sense cell stress → assemble a cytosolic platform → activate caspase-1 → cleave pro-IL-1β into IL-1β → fever, leukocyte recruitment, systemic acute-phase response. This pathway underlies gout (urate crystals), autoinflammatory syndromes, and contributes to atherosclerosis and metabolic syndrome.

Innate Effector Mechanisms

• Cytokines (TNF-α, IL-1β, IL-6) and complement fragments (C3a, C5a) act on vascular endothelium
• Vasodilation + increased permeability → edema, heat, redness
• Leukocyte recruitment: selectins (rolling) → integrins (adhesion) → chemokines (migration to tissue)
• Recruited neutrophils and macrophages phagocytose and destroy pathogens

• Virus-infected cells produce Type I IFNs (IFN-α, IFN-β)
• IFNs act on neighboring cells → upregulate antiviral enzymes (RNase L, PKR) → degrade viral RNA, halt translation
• NK cells recognize loss of MHC I on infected/tumor cells → release perforin + granzymes → target cell apoptosis

3. Complement System Physiology

Fig. 2.8 — Robbins & Kumar: Three complement activation pathways all converge on C3 convertase.

Three Activation Pathways

Effector Functions of Complement

Regulation of Complement

• DAF (CD55) — displaces Bb from C3 convertase; prevents convertase assembly
• CD59 — blocks MAC formation on host cells
• Factor H — promotes iC3b formation (inactivates C3b); prefers sialic acid–rich host surfaces
• C1 INH — blocks classical pathway initiation; deficiency → hereditary angioedema
• Loss of GPI-anchored proteins (DAF + CD59) → paroxysmal nocturnal hemoglobinuria (PNH): uncontrolled complement lysis of RBCs

4. T Cell Activation Physiology

Without Signal 2: TCR engagement alone induces anergy (functional unresponsiveness) or apoptosis — a key mechanism of self-tolerance.

Physiological Sequence of T Cell Activation

Cellular and Molecular Immunology: Naive T cells are activated in lymphoid organs; effector cells migrate to peripheral tissues.

1. Naïve T cells circulate through secondary lymphoid organs (lymph nodes, spleen), guided by CCR7 along fibroblastic reticular cell (FRC) conduits
2. Mature DCs — loaded with antigen from peripheral tissues — migrate to T cell zones and display peptide–MHC complexes + B7 costimulators
3. TCR scanning: T cells make transient contacts with DCs; antigen recognition causes T cell arrest → stable immunological synapse forms
4. Signal cascade: TCR + CD28 → IL-2 secretion + upregulation of IL-2 receptor (CD25) → autocrine proliferation (clonal expansion)
5. Differentiation into effector subsets (driven by cytokine milieu) and memory cells
6. Effector T cells migrate to peripheral tissues; re-encounter antigen on local APCs/infected cells → execute effector functions

T Helper Subset Polarization (Signal 3)

CD8⁺ CTL Killing Mechanism

• Perforin: polymerizes in target cell membrane → forms pores
• Granzymes: serine proteases enter via pores → activate caspases → apoptosis
• Fas–FasL interaction: CTL expresses FasL → binds Fas on target → apoptosis
• CTLs are themselves protected from their own perforin by a lysosomal glycoprotein (LAMP-1)

5. B Cell Activation & Antibody Physiology

1. B cell receptor (BCR) binds antigen → internalizes and presents peptide on MHC II to helper T cell
2. CD40L (on T cell) engages CD40 (on B cell) → key costimulatory signal
3. Th2-derived IL-4/IL-13, Th1-derived IFN-γ, etc. → class switch recombination (CSR):
   • IgM (primary, no T help needed) → IgG (opsonization, complement) → IgA (mucosal) → IgE (parasite/allergy)
4. Somatic hypermutation in germinal centers → affinity maturation → selection of high-affinity B cell clones
5. Differentiation into plasma cells (antibody factories) and memory B cells

Antibody Effector Mechanisms

6. Physiological Resolution & Memory

• After pathogen clearance, 90–95% of effector cells undergo apoptosis (contraction) — mediated partly by withdrawal of survival signals (IL-2, costimulation)
• Surviving ~5% become long-lived memory cells (both T and B): lower activation threshold, faster kinetics, greater magnitude upon re-exposure
• Secondary immune response is faster (days not weeks), produces higher-affinity antibodies, and has qualitatively different effector mechanisms

Summary Flow

Pathogen → PRR signaling (TLRs/NLRs) → Cytokine release (IL-1β, TNF-α, IL-12)
                                              ↓
                                   Inflammation + DC maturation
                                              ↓
                           DC → lymph node → peptide–MHC presentation
                                              ↓
                   Signal 1 (TCR) + Signal 2 (CD28) + Signal 3 (cytokines)
                                              ↓
                     IL-2 → Clonal expansion → Th1/Th2/Th17/Treg / CTL
                                              ↓
              B cell help (CD40L, cytokines) → Germinal center → Antibodies
                                              ↓
                          Pathogen eliminated → Contraction → Memory