Lecture III

Lymphocytes: Key components of the adaptive immune system.
- Originates in bone marrow from lymphoid progenitors.
- Distinction between lymphoid and myeloid progenitors (myeloid gives rise to neutrophils, mast cells, etc.).
- After maturation in bone marrow, lymphocytes migrate to the periphery (e.g., spleen, lymph nodes).
T-cell Maturation:
- T cells complete maturation in the thymus.
- After maturation, they traffic through secondary lymphoid organs: lymph nodes, the spleen, and mucosal-associated lymphoid tissues.
B Cells and Antibodies:
- B cells have immunoglobulins on their surface before secreting them.
- They assemble genes coding for antibodies during maturation.
- Antibodies can interact with both soluble antigens and those associated with surface.

B Cell Activation:
- The binding of antigens to B cell receptors triggers signaling that leads to the next steps in the immune response.
- B cells require T cell help to produce antibodies.
Dendritic Cells:
- Role in activating T-cells by endocytosing antigens, processing them into peptides, and displaying them on Major Histocompatibility Complex (MHC) molecules.
Antigen Receptors:
- B cell receptors recognize intact antigens through their surface immunoglobulins.
- Each immunoglobulin has two binding sites for epitopes on antigens.
T Cell Receptors (TCRs):
- Recognize processed proteins presented by MHC molecules.
- T cells have unique functions: Helper T cells provide assistance to other immune cells, whereas cytotoxic T cells destroy infected cells.
- Regulatory T cells help prevent autoimmunity.

Basic Structure of Antibody:
- Composed of two identical heavy chains and two identical light chains, linked by disulfide bonds.
- Antigen Binding Sites: Located in variable domains within the heavy and light chains; enables binding to specific antigens.
- Fragment Antigen Binding (FAB): Refers to the arms of the antibody that bind to antigens.
- Fc Region: The constant domain part involved in interactions with immune components (e.g., Fc receptors).

Antibody Classes:
- Different isotypes provide diverse functions:
- IgM, IgG, IgA, IgE, IgD
IgM:
- Largest antibody (pentamer structure).
- First antibody to appear after infection, highly effective at activating complement (classical pathway).
- Best for agglutination; does not opsonize free pathogens.
IgG:
- Most abundant antibody in serum (monomer).
- Functions: opsonization, neutralization, complement activation, and can cross the placenta.
IgA:
- Secreted primarily in mucosal areas (dimeric form in secretions, monomeric in blood).
- Important for mucosal immunity and can be found in breast milk.
IgE:
- Monomeric form, low abundance in serum.
- Binds to basophils, mast cells and is important in allergic reactions and parasite defense.
IgD:
- Marker for B cell maturation, low serum levels.

Roles of Antibodies:
- Opsonization: Facilitates phagocytosis by tagging pathogens for destruction (Fc region binds to Fc recepts on phagocytes).
- Neutralization: Prevents pathogens from binding to host cells (important in viruses and toxins).
- Agglutination and Precipitation: Clumping of pathogens aids in clearance from the body.
- Complement Activation: Initiated by the binding of antibodies leading to the formation of the membrane attack complex, resultant in cell lysis.
- Antibody-dependent cellular cytotoxicity (ADCC): Similar function to cytotoxic T cells, targeting infected or cancerous cells via NK cells.

MHC Overview:
- MHC proteins present antigenic peptides on the cell surface.
- MHC Class I:
- Found on all nucleated cells, presents peptides from intracellular proteins to cytotoxic T cells (CD8+).
- MHC Class II:
- Found on antigen-presenting cells (dendritic cells, macrophages, B cells). Present extracellularly derived peptides to helper T cells (CD4+).
T Cell Activation:
- Requires recognition of both the MHC and the peptide by the T cell receptor.
- Costimulatory signals (e.g., from dendritic cells) enhance activation and inform T cell differentiation (e.g., Th1 vs. Th2).
Signal 1 and 2 for T Cells:
- Signal 1: TCR engagement with MHC-peptide complex.
- Signal 2: Costimulation through additional receptors/cytokines.

Upon activation, B and T cells may differentiate into different lineage branches:
- Memory Cells: Long-lived cells that can quickly respond to reencountered antigens.
- Plasma Cells (for B cells): Specialized in producing antibodies, especially IgM at first, with potential for isotype switching to IgG, IgA, or IgE.
Somatic Hypermutation: After initial activation, antibodies undergo mutation to enhance binding affinity to their specific antigen.

The complex interplay of B and T cell functions defines the adaptive immune response. Understanding the detailed mechanisms of MHC, T cell recognition, and antibody function is crucial for comprehending immunity.
Additional materials mentioned to further clarify concepts, especially on immunological diversity through VDJ recombination and somatic hypermutation.

To best remember the five classes of antibodies (isotypes) mentioned in the notes, you can use the mnemonic MAGED:

IgM (M for "Massive" or "Mainstream First"):
- The largest antibody (pentamer structure).
- The first to appear after infection.
- Excellent for agglutination but cannot opsonize pathogens.
IgA (A for "Any Secretion"):
- Primary antibody for mucosal immunity.
- Found in secretions (dimeric) and breast milk.
IgG (G for "Greatest" or "Gestation"):
- The most abundant antibody in serum ( $monomer$ ).
- The only one that crosses the placenta for fetal immunity.
- Key for opsonization, neutralization, and complement activation.
IgE (E for "Eek! Allergies"):
- Important in allergic reactions and defense against parasites.
- Binds to mast cells and basophils.
IgD (D for "Development"):
- Primarily serves as a marker for B cell maturation.

By linking the letter to their specific location or primary function, you can differentiate their roles in the adaptive immune response.