42.3 Antibodies

Antibody Structure and Function

Antibodies are Y-shaped proteins that recognize and bind to specific foreign molecules (antigens), marking them for destruction by the immune system. They're central to the adaptive immune response, and understanding how they work connects directly to topics like vaccination, disease, and autoimmunity.

Structure and function of antibodies

Antibodies, also known as immunoglobulins (Ig), are produced by B cells and built from four polypeptide chains: two identical heavy chains and two identical light chains, held together by disulfide bonds. The heavy chains determine which class the antibody belongs to (IgG, IgM, IgA, IgE, or IgD).

The Y shape creates two functionally distinct regions:

• Variable region (Fab): Located at the two tips of the Y. This is where the antibody binds to its target antigen. Each antibody's variable region has a unique shape, and the specific binding site on the antibody is called the paratope. The corresponding site on the antigen is the epitope. This lock-and-key fit is what gives antibodies their specificity.
• Constant region (Fc): Located at the stem of the Y. This region doesn't bind antigen directly. Instead, it communicates with the rest of the immune system by interacting with complement proteins and immune cells like macrophages and natural killer cells.

Antibodies carry out several key functions:

• Neutralization: Binding directly to toxins or pathogens to block their ability to infect cells
• Opsonization: Coating pathogens so phagocytes (like macrophages) can recognize and engulf them more efficiently
• Complement activation: Triggering the complement cascade, a series of proteins that punch holes in pathogen membranes
• Antibody-dependent cell-mediated cytotoxicity (ADCC): Flagging infected cells so natural killer cells can destroy them

Antibody Production

Process of antibody production

B cells originate from hematopoietic stem cells in the bone marrow. Each B cell displays a unique B cell receptor (BCR) on its surface, which is essentially a membrane-bound form of the antibody that cell will produce.

Here's how antibody production unfolds:

1. A B cell encounters an antigen that fits its BCR.
2. Antigen binding activates the B cell (often with help from T helper cells).
3. The activated B cell proliferates, producing many copies of itself (clonal expansion).
4. These clones differentiate into two types of cells:
   • Plasma cells: Short-lived but highly productive. They secrete large quantities of antibodies specific to the activating antigen. Their endoplasmic reticulum is greatly enlarged to handle this high rate of protein production.
   • Memory B cells: Long-lived cells that persist after the infection clears. If the same antigen shows up again, memory B cells rapidly differentiate into plasma cells, producing a faster and stronger secondary immune response. This is the principle behind how vaccines work.

Antibody Diversity and Maturation

Two processes fine-tune the antibody response over time:

• Affinity maturation: During an immune response, B cells undergo mutations in their variable regions. B cells that happen to bind the antigen more tightly are selected and survive, so the average binding strength (affinity) of antibodies increases as the response progresses.
• Isotype switching (class switching): A B cell can change the constant region of its antibody (for example, switching from IgM to IgG) while keeping the same variable region. This doesn't change what the antibody recognizes, but it changes what the antibody does, since different Fc regions trigger different immune effector functions.

Types of Antibody Preparations

These terms come up frequently in both research and medicine:

• Polyclonal antibodies: A mixture of antibodies from many different B cell clones. They recognize multiple epitopes on the same antigen, which makes them broadly reactive.
• Monoclonal antibodies: Identical antibodies produced from a single B cell clone (grown as a hybridoma in the lab). They bind one specific epitope. Because of this precision, monoclonal antibodies are widely used in diagnostic tests and targeted therapies.

Cross-Reactivity and Autoimmunity

Cross-reactivity in immune responses

Cross-reactivity occurs when an antibody binds to an antigen that is similar, but not identical, to the one it was originally made for. This happens because the two antigens share similar epitopes.

Cross-reactivity has both upsides and downsides:

• Positive: It can provide partial protection against related pathogens. For example, antibodies against one strain of influenza may offer some defense against a closely related strain.
• Negative: If a foreign antigen structurally resembles a self-antigen, antibodies may mistakenly attack the body's own tissues, potentially triggering an autoimmune disorder.

This process is called molecular mimicry, where a pathogen's antigen looks enough like a self-antigen that the immune system can't tell them apart. Two well-studied examples:

• Rheumatic fever: Antibodies produced against Streptococcus bacteria cross-react with proteins in heart tissue, causing inflammation and damage to heart valves.
• Multiple sclerosis: Antibodies originally targeting viral antigens may cross-react with myelin, the insulating sheath around nerve fibers in the central nervous system, leading to progressive neurological damage.