Adaptive Immunity I: B-Cells, B-Cell Receptors and Antibodies

Severe Combined Immunodeficiency (SCID)

• Clinical hallmarks

  • Recurrent, severe viral and fungal infections appearing in the first months of life

  • If left untreated ⇒ death before 2 years of age

• Most common molecular cause discussed in lecture

  • X-linked mutation(s) in the common \gamma-chain of the \text{IL-2R} (also shared by IL-4, IL-7, IL-9, IL-15, IL-21 receptors)

  • Immunological consequence

  • Very few T cells and NK cells

  • Absence of functional B cells

  • Net result ⇒ virtually no adaptive immunity and partially crippled innate immunity

• Historical illustration: David Phillip Vetter ("the boy in the bubble", 1971–1984)

  • Lived in a sterile isolator for 12 years

  • Ethico-philosophical reflection: H. G. Wells’ quote from “The War of the Worlds” reminds us that immunity is mankind’s birth-right earned through evolutionary struggle

Learning Outcomes (as stated by lecturer)

• Discuss the structure, function, development and maturation of B-cell recognition molecules (immunoglobulins, BCR, antibodies)

• Explain how B cells contribute to protection against pathogens

Innate v. Adaptive Immunity (Systems of Immunity)

• Innate (1st line)

  • Rapid (hours)

  • Fixed, germ-line encoded recognition elements

  • Limited specificity, no memory

• Adaptive (2nd line)

  • Slow to mount (days–weeks)

  • Somatically generated, variable recognition elements

  • Highly specific; generates immunological memory ⇒ faster & stronger upon re-exposure

• Both systems share common effector mechanisms for pathogen destruction (e.g. phagocytosis, complement, cytotoxicity)

Key Definitions

• Antigen

  • Any molecular determinant that can be recognised by antibodies, BCR or TCR and can induce an adaptive immune response

  • Most are proteins; some are carbohydrates, lipids or nucleic acids

• Immunogen

  • Any molecule that can elicit (innate and/or adaptive) immune responses

  • Relationship: All antigens are immunogens, but not all immunogens are necessarily antigens

Cellular & Molecular Players of Adaptive Immunity

• Cells

  • B-lymphocytes (produce antibodies)

  • T-lymphocytes: T{\text{C}} (CD8⁺), T{\text{H}} (CD4⁺; TH1, TH2, etc.), T_{\text{REG}}

• Soluble molecules

  • Antibodies (humoral immunity)

  • Cytokines & chemokines

• Cell-associated receptors

  • B-cell receptors (BCR)

  • T-cell receptors (TCR)

Developmental Pathway of Adaptive Immune Cells

• Bone-marrow haematopoietic stem cell ⇒ lymphoid progenitor

  • B cells mature & undergo negative selection in bone marrow (with possible finishing steps in spleen)

  • T cells migrate to thymus for positive/negative selection (CD4, CD8, TREG differentiation)

• Output ⇒ mature naïve lymphocytes that express clonally unique BCR or TCR

B-Cell Antigen Recognition Molecules

• Generic name: Immunoglobulins (Ig)

  • Membrane-bound form ⇒ B-cell receptor (BCR)

  • Soluble form ⇒ Antibody

• Shared core structure

  • 2 identical light (L) chains (either \kappa OR \lambda per B cell – allelic exclusion)

  • 2 identical heavy (H) chains

  • Each chain possesses

  • Variable (V) region ⇒ antigen-binding site

  • Constant (C) region ⇒ effector and structural functions

  • Disulfide bonds stabilise the tetrameric Y-shaped structure

Antibody Molecular Classes (isotypes)

• Defined by heavy-chain constant region

  • IgM (μ), IgD (δ), IgG (γ1–γ4), IgA (α1–α2), IgE (ε)

• Quaternary structures

  • IgG, IgD, IgE ⇒ monomers

  • IgA ⇒ monomer (serum) or dimer (secretions)

  • IgM ⇒ pentamer (serum) held by J chain

Functional Fragmentation (Papain digestion model)

• Fab (fragment antigen-binding)

  • Contains complete light chain + VH, CH1 of heavy chain

  • Responsible for antigen specificity; two identical per antibody

• Fc (fragment crystallisable)

  • Contains CH2, CH3 (and CH4 in IgM/IgE) regions of heavy chains

  • No direct antigen binding

  • Binds Fc receptors (FcR) on innate effector cells and C1q of complement

The J-Chain & Transcytosis

• Small polypeptide (≈15 kDa) covalently links IgA dimers and IgM pentamers

• Essential for binding to polymeric Ig receptor (pIgR / polyIgR) on epithelial cells

  • \text{Blood} \;\xrightarrow{pIgR} \; \text{Epithelial cell} \;\xrightarrow{transcytosis} \; \text{Lumen}

  • During passage, extracellular part of pIgR remains bound ⇒ “secretory component” that protects IgA from proteolysis in mucosal fluids

B-Cell Receptor (BCR) Signalling Cascade

• BCR = membrane-anchored IgM or IgD (in naïve B cells)

  • Heavy chain has transmembrane domain + cytoplasmic tail (only 3 aa ⇒ incapable of signalling)

  • Signal transduction provided by non-covalently associated Igα/Igβ heterodimer (contains ITAM motifs)

• Antigen binding ⇒ receptor clustering ⇒ ITAM phosphorylation ⇒ downstream pathways (Syk, BLNK, PLC-γ2, Ca²⁺ influx, NF-κB, NFAT, AP-1 activation)

• Biological outcomes

  • Enhanced survival (anti-apoptosis)

  • Clonal proliferation

  • Differentiation into antibody-secreting plasma cells and long-lived memory B cells

Effector Functions of Antibodies

• I. Neutralisation

  • High-affinity binding to viruses, bacteria, toxins ⇒ blocks attachment or entry into target cells

• II. Opsonisation

  • Fc region of antibody bound to microbe engages FcγR / FcαR on phagocytes ⇒ promotes phagocytosis and intracellular killing

• III. Classical Complement Activation

  • C1q binds to Fc regions in antigen-bound IgM (most efficient) or multiple IgG molecules ⇒ triggers C1 \to C4 \to C2 \to C3 cascade ⇒ membrane attack complex formation, opsonisation (C3b) and inflammation (C3a/C5a)

• IV. Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC)

  • NK cells express FcγRIII (CD16) – the only FcR on NKs

  • IgG-coated target cell ⇒ FcγRIII clustering ⇒ NK degranulation (perforin, granzymes) or FasL engagement ⇒ apoptosis of infected or malignant cells

  • Other FcγRIII⁺ cells (macrophages, neutrophils) & FcαRI⁺ eosinophils can also perform ADCC

• V. Degranulation (allergy & anti-parasite)

  • IgE bound to FcεRI on mast cells, basophils, eosinophils

  • Cross-linking by allergen or parasite antigen ⇒ release of

  • Histamine ⇒ vascular permeability, smooth-muscle contraction

  • Leukotrienes, TNF-α, proteases, ROS

  • Result: worm expulsion, local inflammation, or immediate hypersensitivity reactions (allergy)

Functional Specialisation of Antibody Isotypes

• IgA

  • Predominant in mucosal secretions (gut, respiratory tract, breast milk, saliva)

  • Neutralises pathogens/toxins before they breach epithelium

  • Protease-resistant due to secretory component

• IgM

  • First antibody secreted during primary response (no class-switch yet)

  • Pentameric ⇒ 10 antigen-binding sites ⇒ high avidity

  • Potent activator of classical complement

  • Good opsoniser despite relatively low intrinsic affinity

• IgD

  • Co-expressed with IgM on mature naïve B cells

  • Regulates B-cell activation and tolerance; functions still not fully elucidated

• IgG (subclasses 1-4)

  • Most abundant in serum; long half-life (≈21 days)

  • Neutralisation, opsonisation, complement activation

  • Crosses placenta via FcRn ⇒ passive immunity to neonate (lasts 3–6 months)

  • Mediates ADCC via FcγRIII on NK cells

• IgE

  • Binds FcεRI at very high affinity (≈10^{10} L·mol⁻¹)

  • Triggers degranulation of eosinophils, mast cells, basophils

  • Key in defence against helminths & responsible for type I hypersensitivity (allergic) reactions

Exam-Style Prompt Provided by Lecturer

• “Describe the molecular structure of the five antibody classes and discuss their function in relation to protection and defence against pathogens.”

  • Strategy tip: organise answer isotype-by-isotype; link structural peculiarities (e.g. pentameric IgM, dimeric IgA with J chain) to specific effector roles (complement activation, mucosal immunity, etc.)

Broader Connections & Real-World Relevance

• Clinical importance of antibodies → basis for vaccines, antivenoms, monoclonal antibody therapies (e.g. rituximab, trastuzumab)

• Defects in antibody production/class-switch ⇒ agammaglobulinaemia, hyper-IgM syndrome

• SCID highlights necessity of functional adaptive immunity and underpins newborn screening programs

• Allergic diseases and asthma rooted in inappropriate IgE responses; therapeutic targeting of FcεRI or IgE (omalizumab)

Suggested Reading

• Kuby Immunology, 8th ed., Chapter 6 (antibodies)

• Janeway’s Immunobiology, Chapters 3, 5, 8, 9

• Parham, “The Immune System”, Chapters 3, 5, 8, 9

• Roitt’s Essential Immunology, corresponding chapters