The immune system defends the body against various threats, including bacteria, viruses, and toxins. Antibodies, also known as immunoglobulins, are specialized proteins produced by this system. Their primary role is to identify and neutralize foreign invaders, called antigens, initiating their removal from the body.
What is IgG1?
Immunoglobulin G1 (IgG1) is the most abundant type of antibody found in human serum, making up approximately 60-65% of all IgG antibodies and about 75-80% of all circulating immunoglobulins. It belongs to the immunoglobulin family, which includes IgA, IgM, IgE, and IgD. IgG1 is widely distributed throughout the body, circulating in the bloodstream and extracellular fluids to combat infections in tissues. This antibody plays a primary role in providing long-term immunity against pathogens.
The Architecture of IgG1
Human IgG1 is a Y-shaped protein, with an approximate molecular weight of 150 kilodaltons. This structure consists of two identical heavy chains and two identical light chains. These chains are linked together by disulfide bonds.
The IgG1 molecule has distinct functional regions. The two upper arms of the “Y” are called the Fab (Fragment antigen-binding) regions. Each Fab region contains a variable domain from the heavy chain (VH) and a variable domain from the light chain (VL), forming the antigen-binding sites. These regions allow them to specifically recognize and bind to a particular antigen, much like a lock and key.
The stem of the “Y” is known as the Fc (Fragment crystallizable) region, composed of the constant domains (CH2 and CH3) of both heavy chains. While the Fab regions are responsible for antigen recognition, the Fc region mediates various effector functions by interacting with other components of the immune system. A flexible hinge region connects the Fab and Fc parts, allowing the antibody to adapt its shape when binding to antigens.
How IgG1 Protects the Body
IgG1 antibodies protect the body through several mechanisms to combat pathogens and toxins. One way is neutralization, where IgG1 binds directly to pathogens or toxins, preventing them from interacting with host cells or causing harm. For example, neutralizing antibodies can block viruses from attaching to and entering target cells. Once neutralized, these pathogen-antibody complexes are often taken up and degraded by immune cells like macrophages.
Another mechanism is opsonization, where IgG1 antibodies coat the surface of pathogens, marking them for destruction. This tagging makes it easier for phagocytic cells, such as macrophages and neutrophils, to recognize, engulf, and eliminate the marked invaders. IgG1 has a high affinity for Fc receptors on phagocytic cells, which enhances this process.
IgG1 also participates in antibody-dependent cell-mediated cytotoxicity (ADCC). In this process, IgG1 antibodies bind to antigens displayed on the surface of infected or cancerous cells. Natural killer (NK) cells, a type of immune cell, have Fc receptors that recognize the Fc region of the bound IgG1. This binding activates the NK cell, prompting it to release cytotoxic chemicals that induce the death of the target cell.
Furthermore, IgG1 can trigger complement-dependent cytotoxicity (CDC). The complement system is a group of proteins in the blood that can directly lyse (burst) pathogens. When IgG1 binds to an antigen on a pathogen’s surface, it can activate the classical pathway of the complement system. This activation leads to a cascade of events that ultimately forms pores in the pathogen’s membrane, causing it to rupture and die.
Generating IgG1 Diversity
The immune system’s ability to recognize a vast array of antigens stems from processes that generate immense antibody diversity. A primary mechanism for this diversity is V(D)J recombination, which occurs in the variable regions of both heavy and light chains of developing B cells. This process involves the random selection and joining of different gene segments—Variable (V), Diversity (D), and Joining (J) segments for heavy chains, and V and J segments for light chains. This random assembly results in a unique sequence for the antigen-binding site of each developing B cell, allowing for millions of potential antibody specificities.
After initial antigen exposure and B cell activation, two additional genetic modifications further refine antibody diversity and function. Somatic hypermutation introduces small, random mutations at a high rate within the V(D)J recombined variable regions. This process fine-tunes the antibody’s affinity for the antigen. B cells producing antibodies with higher affinity are preferentially selected, leading to an improved immune response over time.
Finally, class switch recombination (CSR) allows B cells to change the type of antibody they produce while maintaining the same antigen specificity. B cells initially produce IgM antibodies, but through CSR, they can switch to producing IgG1. This involves recombination in the heavy chain constant gene segments, leading to the expression of a new constant region, such as the gamma (γ) chain that defines IgG1. This genetic rearrangement ensures that the immune response can adapt to different types of infections by deploying antibodies with distinct effector functions.
IgG1’s Role in Medicine
The comprehensive understanding of human IgG1’s sequence and structure has paved the way for significant advancements in medicine. Therapeutic monoclonal antibodies (mAbs) are a prime example, with engineered IgG1 molecules being widely utilized. These laboratory-made antibodies are designed to target specific molecules involved in various diseases, including cancers, autoimmune disorders, and infectious diseases. IgG1 is frequently chosen as the backbone for these therapeutics due to its stability, long serum half-life, and ability to effectively trigger immune effector functions.
In cancer therapy, for instance, IgG1 mAbs can bind to specific antigens on tumor cells, either directly blocking their growth signals or tagging them for destruction by the patient’s immune system through mechanisms like ADCC and CDC. For autoimmune conditions, IgG1 antibodies can neutralize inflammatory molecules or block receptors involved in disease progression. Beyond treatment, IgG1 antibodies are also employed in diagnostic tests to detect disease biomarkers or pathogens with high sensitivity and specificity.