LR

Adaptive Immunity – Humoral Immunity & Antibody Vocabulary

Dual Nature of the Adaptive Immune System

  • Two cooperative arms of adaptive immunity
    • Humoral immunity
    • Mediated by B lymphocytes that mature in bone marrow
    • Produces soluble antibody proteins that circulate and bind extracellular antigens (e.g., toxins, viruses, bacteria)
    • Name historically derived from the Bursa of Fabricius in birds (site of B-cell maturation)
    • Cell-mediated immunity (brief mention for context)
    • Mediated largely by T lymphocytes (cytotoxic, helper, regulatory)
    • Critical for intracellular pathogens and tumor surveillance

Learning Objectives Tied to This Section

  • 17\text{-}5 Explain antibody function & describe structural / chemical characteristics
  • 17\text{-}6 State one key function of each of the 5 antibody classes
  • 17\text{-}7 Contrast T-dependent vs. T-independent humoral responses
  • 17\text{-}8 Differentiate plasma cells from memory B cells
  • 17\text{-}9 Define clonal deletion, selection & expansion
  • 17\text{-}10 Describe the genetic basis for antibody diversity
  • 17\text{-}11 List protective outcomes of antigen–antibody binding
  • 17\text{-}19 Distinguish primary from secondary immune responses

Immunoglobulins (Antibodies) – Core Concepts

  • Definition: Proteins produced in response to, and capable of specifically binding, an antigenic epitope
  • Specificity: Each antibody molecule binds exactly the antigen that elicited its production; cross-reactivity is rare and usually clinically relevant (e.g., autoimmunity)
  • Monomeric unit: Y-shaped, bivalent (valence =2); larger multimers exist for some classes
  • Antibody diversity: Combinatorial rearrangement of V(D)J gene segments + junctional diversity + somatic hypermutation generate >10^{11} distinct specificities (LO 17\text{-}10)

Basic Structure

  • 4 polypeptide chains per monomer
    • 2 identical heavy (H) chains
    • 2 identical light (L) chains
    • Chains linked by disulfide bonds
  • Regions
    • Variable regions VH & VL form the antigen-binding sites (at the tips of the Y arms); determine specificity and affinity
    • Constant regions CH & CL provide structural integrity; C_H defines isotype/class
    • Fc region (stem)
    • Comprised of C_H domains of heavy chains
    • Serves as effector platform: binds Fc receptors on phagocytes, NK cells, mast cells, basophils; interacts with complement component C1q; dictates antibody class functions

Functional Summary of Antibody Activity (LO 17\text{-}11)

  1. Neutralization – blocks attachment of toxins/viruses/bacteria to host receptors
  2. Agglutination – cross-links particulate antigens; enhances phagocytosis & settling
  3. Opsonization – Fc-mediated coating enhances phagocyte recognition & ingestion
  4. Complement activation (classical pathway) – Fc–C1q engagement triggers cascade → pathogen lysis/inflammation
  5. Antibody-dependent cell-mediated cytotoxicity (ADCC) – Fc engagement recruits NK cells, eosinophils or macrophages to release cytotoxic molecules against large targets (e.g., helminths, tumor cells)

The Five Immunoglobulin Classes (Isotypes)

(Note: class differences stem from unique constant heavy-chain regions.)

IgG

  • Serum abundance ≈ 80\%
  • Monomer (valence =2) → small; diffuses into tissues & across placenta (natural passive immunity to fetus)
  • Half-life ≈ 23 days (longest)
  • Key functions: neutralization, opsonization, complement activation, neonatal immunity, antitoxin & antiviral protection, secondary response dominance

IgM

  • Serum proportion ≈ 6\% (but first produced)
  • Pentamer linked by J chain; valence =10 → high avidity; large (confined to bloodstream)
  • First antibody in primary response; excellent agglutinator; most efficient classical complement activator
  • Exists as membrane-bound monomer on naïve B-cell surface (B-cell receptor, BCR)

IgA

  • Total body production highest (mucosal secretions); serum ≈ 13\%
  • Dimer in secretions with secretory component (protects from proteolysis); valence =4
  • Found in saliva, tears, colostrum, mucus; critical for mucosal immunity (blocks microbial attachment to epithelial surfaces)
  • Monomeric IgA circulates in blood

IgD

  • Trace serum level \approx0.02\%
  • Membrane-bound monomer on naïve B cells (co-expressed with IgM) acting as BCR; exact serum role unknown

IgE

  • Extremely low serum concentration \approx0.002\% (often tightly bound to FcεRI on mast cells & basophils)
  • Monomer; triggers degranulation → histamine release during type I hypersensitivity (allergies, anaphylaxis)
  • Critical for defense against large parasites (helminths); mediates eosinophil ADCC against worms

Terminology of B & T Lymphocyte States

  • Immature lymphocyte – no fully developed antigen-specific receptor
  • Naïve lymphocyte – expresses receptor, has not met cognate antigen
  • Activated lymphocyte – receptor bound by antigen & co-stimulation; enters cell cycle
  • Effector lymphocyte – executes immediate function (e.g., plasma cell secreting antibodies, TH secreting cytokines, CTL killing target)
  • Memory lymphocyte – long-lived, rapid responder upon re-exposure (basis of vaccines)

Clonal Concepts (applies to B & T cells)

  • Clonal deletion (negative selection) – autoreactive clones eliminated during maturation (apoptosis) to forestall autoimmunity
  • Clonal selection – antigen chooses a pre-existing specific clone to activate
  • Clonal expansion – selected clone proliferates, generating large population of identical effector + memory cells

B-Cell Biology & Self-Tolerance

  • B cells generated & mature in bone marrow
  • Each expresses a unique BCR (membrane-anchored antibody) specific for one epitope
  • Cumulative B-cell repertoire covers >10^{8}–10^{9} epitopes
  • During bone-marrow maturation, exposure to self-antigen → apoptosis (negative selection) preventing autoimmune disease

Humoral Response Pathways

T-Independent Antigen Response (usually polysaccharides, lipopolysaccharides with repetitive epitopes)

  • Does not require T-helper cell cytokines
  • Activation Steps
    1. Cognate B cell binds multivalent antigen via BCR → direct activation (clonal selection)
    2. Rapid clonal expansion
    3. Differentiation mainly into short-lived plasma cells
  • Characteristics
    • Predominantly IgM production, low affinity, little class switching
    • Weak, no memory generated → minimal secondary response
    • Clinically relevant for encapsulated bacteria (e.g., Streptococcus pneumoniae); vaccines often conjugate polysaccharide to protein to convert to T-dependent response

T-Dependent Antigen Response (protein antigens)

  • Requires antigen presentation on MHC II and T-helper (TH) cell help
  • Sequential Steps
    1. B cell binds antigen via BCR, internalizes & processes it → peptide-MHC II displayed on B-cell surface
    2. Cognate TH cell with matching TCR engages peptide-MHC II and supplies cytokines (IL-4, IL-5, IL-21)
    3. B cell fully activates → clonal expansion
    4. Differentiation into
    • Plasma cells – large ER, secrete up to 10^{3} antibodies/second
    • Memory B cells – long-lived, rapid responders to repeat exposure
  • Outcomes
    • Class switching (IgM → IgG, IgA, IgE depending on cytokine milieu)
    • Somatic hypermutation & affinity maturation in germinal centers → higher-affinity antibodies over time
    • Robust immunological memory → basis for long-term vaccine efficacy

Plasma Cells vs Memory Cells (LO 17\text{-}8)

  • Plasma cell
    • Short-lived (days-weeks) effector; eccentric "clock-face" nucleus, abundant rough ER
    • Secretes soluble antibodies; little surface Ig
  • Memory B cell
    • Long-lived (years-decades); recirculates through lymphoid organs
    • Expresses high-affinity surface Ig; minimal secretion until reactivation

Immunological Memory in Humoral Immunity

  • Primary response (first exposure)
    • Lag: 5–7 days before detectable serum antibodies
    • IgM dominates early; IgG follows but to lower peak titer
    • Total antibody concentration comparatively low
  • Secondary (anamnestic) response (re-exposure)
    • Lag shortened to 2–3 days (thanks to memory B cells)
    • Rapid class-switched IgG (or IgA/IgE) predominates; higher affinity
    • Antibody titers markedly higher & persist longer → better protection
    • With each additional exposure (boosters), quality & magnitude improve (affinity maturation + memory pool expansion)

Clinical & Practical Implications

  • Placental transfer of IgG provides newborns passive immunity for ≈ 6 months
  • Colostrum IgA protects infant mucosal surfaces; basis for breastfeeding recommendations
  • IgE-mediated allergy underscores importance of Fc-receptor interactions; therapies (e.g., omalizumab) target IgE or FcεRI to mitigate asthma/anaphylaxis
  • Vaccination mimics primary exposure, safely inducing memory B cells and high-affinity class-switched antibodies without disease burden
  • Monoclonal antibody therapeutics exploit specificity & effector functions (e.g., rituximab—anti-CD20 IgG triggers ADCC & complement lysis of B-cell lymphomas)
  • Complement deficiencies impair IgM/IgG classical pathway activation → susceptibility to encapsulated bacteria

Key Numerical / Structural Quick Reference

  • Valence per antibody unit: IgG 2; IgM 10; IgA dimer 4; IgD 2; IgE 2
  • Serum half-life (days): IgG 23 > IgA 6 > IgM 5 > IgD 3 > IgE 2
  • Serum percentages: IgG 80\%, IgA 13\% (higher in secretions), IgM 6\%, IgD 0.02\%, IgE 0.002\%