BLOCK 3: IMM: (3.2) ANTIBODIES PT. 1

IgG Molecule

• An IgG molecule is composed of two identical heavy chains and two identical light chains.
• Carbohydrate is attached to the heavy chains.
• The amino-terminal regions of the heavy and light chains are variable in sequence.
• The remaining regions of the heavy and light chains are constant in sequence.
• A flexible hinge region is located between the two arms and stem of the IgG molecule.

Fragmentation of IgG by Protease

• A protease can cleave the hinge of each heavy chain resulting in two Fab fragments and an Fc fragment.
• The Fab fragment contains the light chain and the amino-terminal half of the heavy chain.
• The Fc fragment contains the carboxy-terminal halves of the two heavy chains.
• The Fc fragment was named because it was readily crystallized in early studies of IgG antibody structure.

Epitopes

• A linear epitope is formed from contiguous amino acids.
• A discontinuous epitope is formed from amino acids from different parts of the polypeptide chain.

Shiv Pillai, MD, PhD

• Director of the Harvard Immunology PhD program.
• His lab studies B lymphocytes.
• Pillai's lab has discovered novel treatments for B-cell leukemias and autoimmune diseases.
• They study how immune cells can "go rogue" in autoimmune diseases.

IgG Hinge Flexibility

• The flexible hinge of the IgG molecule allows it to bind to many different arrangements of antigens on the surfaces of pathogens.

Human Immunoglobulin Isotypes

• The different immunoglobulin classes (IgG, IgA, IgM, IgD, & IgE) differ in the length of their heavy-chain C regions, the locations of disulfide bonds, and the presence of a hinge region.
• The isotypes differ in the distribution of N-linked carbohydrate groups.
• Each antibody isotype is designated by a Greek letter (where we get their names).
• All immunoglobulins are monomers in their membrane-bound form.
• In their soluble, secreted form, IgD, IgE, & IgG are monomers.
• IgA forms monomers and dimers.
• IgM forms pentamers.

Immunoglobulin Domains

• Immunoglobulin chains fold into compact and stable protein domains.
• Each Fab and Fc fragment is composed of four immunoglobulin domains that produce a similarly shaped globular structure.

Antibody Diversity

• The antigen-binding site of an antibody is formed from the hypervariable regions (HV or HVR) of the heavy and light-chain V domains.
• CDR = HVR
• Variability is the ratio of the number of different amino acids found at a position to the frequency of the most common amino acid at that position.
• The maximum value possible for variability is 400 (square of 20 - the number of different amino acids found in antibodies).

Bone Marrow Structure and Function

• Medullary cavity: Hollow part of the bone that contains bone marrow.
• Reticular cells: Structural cells that provide support and framework for bone marrow.
• Reticular fibers: Synthesized by reticular cells, creating a network that allows immune cells to move around.
• Hematopoiesis: Process of blood cell formation, regulated by reticular cells.
• Endosteal niche: Complex structure within bone marrow containing stem cells, progenitor cells, stromal cells (including reticular cells), growth factors, and extracellular matrix.
• Vascular niche: Network of blood vessels within the endosteal niche, supplying oxygen and nutrients to the bone marrow.
• Cytokines: Signaling molecules that travel through the blood vessels to communicate with bone marrow cells.

B Cell Development

• B cell development: Takes place in bone marrow, unlike thymus, where T cell development occurs.
• IgD: Immunoglobulin molecule that's function is not fully understood but may play a role with mast cells and basophils.
• Plasma cells: Specialized B cells that secrete antibodies with the same antigen specificity as the B cell receptor of the cell they differentiated from.
• Clonal expansion: The process of increasing the number of B cells and plasma cells specific to an antigen, ensuring effective immune response.

Immunoglobulin Molecule

• IgM: Pentameric immunoglobulin molecule with a star-shaped form, one of the first molecules produced in the immune system.
• Resting B cell: A B cell that is not currently actively involved in an immune response.