Antigen Receptors

Antigen Receptors

• Lymphocytes (B & T cells) mediate acquired immunity by recognizing antigens via specific receptors: B-cell Receptors (BCRs, antibodies), T-cell Receptors (TCRs), and MHC proteins.

B-cell Antigen Receptors (Antibodies)

• Function: Membrane-bound antibodies (BCRs) recognize antigens on B cells; secreted antibodies trigger immune effector functions (e.g., neutralization, opsonization, complement activation).

• Structure:

  • Composed of 2 identical heavy (H) chains and 2 identical light (L) chains, linked by disulfide bonds.

  • Fab region: Variable region, binds antigen.

  • Fc region: Constant region, mediates effector functions (binds to Fc receptors on cells, complement).

  • Hinge region: Provides flexibility for optimal antigen binding.

• Light Chains: Two isotypes, $\kappa$ (kappa) or $\lambda$ (lambda); an individual antibody molecule contains one type, never both. This is crucial for detecting B-cell clonality (e.g., in lymphomas).

• Valence: IgG has $\text{valence} = 2$ antigen-binding sites.

Immunoglobulin Classes (Isotypes) - Key Clinical Relevance

• IgG:

  • Most abundant in serum.

  • Only Ig that crosses the placenta (provides passive immunity to fetus/neonate).

  • Potent opsonizer, neutralizer (toxins/viruses), activates classical complement pathway.

  • Dominant antibody in the secondary immune response.

• IgM:

  Primarily found as a pentamer in secretions (with J chain).

  • First antibody produced in the primary immune response.

  • Very effective at activating complement.

  • Exists as a monomer on the surface of naive B cells (BCR).

• IgA:

  • Found as a monomer in serum, and a secretory dimer (with J chain and secretory component) in mucosal secretions (tears, saliva, breast milk, GI/GU tract).

  • Critical for mucosal immunity (prevents pathogen adherence).

• IgE:

  • Binds to Fc receptors on mast cells and basophils.

  • Key mediator of allergic reactions (Type I hypersensitivity) and defense against parasites.

• IgD:

  • Primarily membrane-bound on naive B cells, acts as an antigen receptor.

  • Low serum levels; exact effector functions are not fully defined.

Effector Functions of Antibodies

• Neutralization: Blocks pathogen binding (e.g., viruses, toxins) to host cells.

• Opsonization: Antibodies coat pathogens, promoting Fc receptor-mediated phagocytosis by macrophages/neutrophils.

• Complement Fixation: Activates the classical complement pathway, leading to pathogen lysis (Membrane Attack Complex), opsonization (C3b), and inflammation (C3a, C5a).

• Antibody-Dependent Cellular Cytotoxicity (ADCC): Fc region of antibodies on target cells recognized by NK cells, leading to target cell lysis.

• Agglutination/Precipitation: Cross-links particulate (agglutination) or soluble (precipitation) antigens, facilitating clearance.

Immunoglobulin Variability

• Isotypic: Differences between Ig classes/subclasses (e.g., IgG vs IgM).

• Allotypic: Genetic differences of an isotype within a species (e.g., between individuals).

• Idiotypic: Unique antigenic specificity of the antigen-binding site (variable region), contributing to vast antibody diversity.

T-cell Antigen Receptors (TCRs)

• Specificity: Unlike BCRs, TCRs only recognize linear peptide fragments of protein antigens when presented by MHC molecules; they do not bind free antigen.

• Structure:

  • Most are $\alpha\beta$ heterodimers (a minority are $\gamma\delta$), linked by disulfide bonds.

  • Variable regions bind antigen; constant regions provide structural support.

  • Short cytoplasmic tails; associate with the CD3 complex for signal transduction.

• Signaling: The CD3 complex contains ITAMs (Immunoreceptor Tyrosine-based Activation Motifs), essential for transducing activation signals into the T cell upon TCR-MHC-peptide binding.

• Co-stimulation: T cell activation requires two signals:

  1. TCR-MHC-peptide binding.

  2. A co-stimulatory signal (e.g., B7 family molecules like CD80/CD86 on APCs binding to CD28 on T cells). Lack of co-stimulation leads to T cell anergy (unresponsiveness), a mechanism to prevent autoimmunity.

Major Histocompatibility Complex (MHC) Molecules

• Function: Highly polymorphic proteins that present peptide antigens to T cells.

• Human MHC: Known as HLA (Human Leukocyte Antigen).

• MHC Class I (HLA-A, HLA-B, HLA-C):

  • Expression: Expressed on virtually all nucleated cells.

  • Presentation: Presents endogenous (intracellular, e.g., viral, tumor) peptide antigens.

  • Restriction: Recognized by CD8+ cytotoxic T cells (Class I-restricted).

• MHC Class II (HLA-DR, HLA-DQ, HLA-DP):

  • Expression: Expressed primarily on Antigen-Presenting Cells (APCs): macrophages, dendritic cells, and B cells.

  • Presentation: Presents exogenous (extracellular, e.g., bacterial) peptide antigens.

  • Restriction: Recognized by CD4+ T helper cells (Class II-restricted).

High-Yield Comparisons & Concepts

• BCR vs. TCR:

  • BCR (Ig): Recognizes diverse antigens (proteins, lipids, carbs, nucleic acids); recognizes both linear & conformational epitopes; can bind free antigen; directly mediates effector functions via Fc region.

  • TCR: Recognizes only linear peptides presented by MHC; no free antigen binding; signalling via CD3; requires co-stimulation.

• MHC I vs. MHC II:

  • MHC I: Endogenous antigens, all nucleated cells, CD8+ T cells.

  • MHC II: Exogenous antigens, APCs, CD4+ T cells.

• Combinatorial Diversity: Both BCRs and TCRs generate vast diversity through gene rearrangements, allowing recognition of countless antigens. MHC polymorphism expands peptide presentation diversity.

Key Formulas and Values

• IgG Valence: $\text{valence} = 2$

• Peptide length for TCR: $9 \leq \text{peptide length} \leq 15\text{ aa}$

• Co-stimulation molecules: B7 family (CD80, CD86) on APCs bind CD28 on T cells.

• ITAM motif: Immunoreceptor Tyrosine-based Activation Motif (critical for TCR/CD3 signaling).