Humans have five antibody isotypes: IgG, IgM, IgA, IgE, and IgD, each defined by a distinct heavy chain type and tailored to specific immune functions. Despite sharing a core structure, these isotypes differ in their size, form (monomeric versus polymeric assemblies), distribution in the body, and roles in immunity. Below, we examine each antibody class in turn, highlighting its main function, structural features, bodily distribution, and unique attributes that contribute to immune defense.
IgM (Immunoglobulin M)
IgM (Immunoglobulin M) is the first antibody isotype produced during an immune response. Naïve B cells (before encountering an antigen) display IgM on their surface as part of the B cell receptor. Upon activation, IgM is secreted mainly as a pentamer (five Y-shaped units joined together, yielding ten antigen-binding sites). This gives IgM extremely high avidity as it can bind strongly to repetitive antigens like bacterial surfaces, even if each individual binding site has modest affinity
IgM’s primary immune functions include agglutinating pathogens (clumping antigens together for easy clearance) and activating complement. In fact, pentameric IgM is the most efficient activator of the classical complement pathway, initiating a cascade that can directly lyse microbes or mark them for destruction. IgM is critical in early stages of infection before the immune system refines its antibody response. For example, detection of IgM against a virus often indicates a recent infection.
Due to its large size, IgM mostly stays in the bloodstream and lymphatic fluid. It provides a front-line defense in the blood, where it can rapidly trap pathogens and activate complement. IgM is also co-expressed with IgD on naive B cell surfaces, functioning as a B-cell receptor that senses antigens.
A special J chain polypeptide in secreted IgM allows it to bind the polymeric immunoglobulin receptor (pIgR) on epithelial cells. This enables IgM transport across mucosal surfaces into secretions, analogous to IgA. Indeed, a fraction of IgM is secreted at mucosal linings (often as a “secretory IgM”) to help contain infections in the gut and respiratory tract alongside IgA. IgM’s role as a rapid-response antibody is highlighted by patients with hyper-IgM syndrome (who cannot class-switch to other isotypes) .They suffer recurrent infections, showing that IgM alone cannot handle all threats.
Despite its clear advantages (strong complement activation, target clustering, and multivalent binding), no IgM therapeutics are yet approved. The only IgM monoclonal ever approved, nebacumab (Centoxin), reached European clinics in 1991 and was withdrawn in 1993.
IgG (Immunoglobulin G)
IgG (Immunoglobulin G) is the most abundant antibody in human blood and tissues, making up about 70–80% of serum immunoglobulins. It is a 150 kDa Y-shaped monomer of two γ (gamma) heavy chains and two light chains. Humans make four IgG subclasses (IgG1–4) that differ in hinge length and constant-domain sequence.
IgG antibodies are produced mainly during secondary immune system responses and bind pathogens tightly. Its Fc region engages Fcγ receptors on phagocytes and natural killer cells, triggering opsonization and antibody-dependent cellular cytotoxicity.
IgG (especially IgG1 and IgG3) also activates the classical complement cascade via C1q, lysing or neutralizing microbes and toxins.
A key clinical feature of IgG is its ability to cross the placenta. Neonates acquire maternal IgG through FcRn receptors in the syncytiotrophoblast, giving newborns passive systemic immunity. FcRn also recycles IgG in adults to extend its half-life (~21 days). In practice, IgG provides long-term immunity against viruses and bacteria and is the main immunoglobulin isotype used in intravenous immunoglobulin therapies.
IgA (Immunoglobulin A)
While IgA makes up about 10–15% of immunoglobulins in serum, it dominates in secretions such as saliva, tears, mucus, and breast milk. The body crafts IgA as a dimer for secretion; two IgA monomers are linked by a J chain and paired with a secretory component, a protein fragment that protects IgA from being degraded by enzymes in the gut or respiratory tract.
IgA’s primary function is to neutralize pathogens and toxins on mucosal surfaces without excessive inflammation. It blocks bacteria and viruses from attaching to epithelial cells in the respiratory, gastrointestinal, and urogenital tracts. By opsonizing pathogens in mucus, IgA facilitates their clearance via peristalsis, ciliary movement, or sneezing, all while avoiding strong complement activation that could damage delicate mucosal tissue.
IgA is abundant in colostrum and breast milk, where it helps protect an infant’s gut from infections and shapes the microbiome. Within the gut lumen and airways, IgA creates an immune barrier that maintains tolerance to benign commensal microbes yet intercepts invasive organisms. Individuals lacking IgA suffer higher rates of respiratory and gastrointestinal infections. These patients can experience recurrent sinusitis, lung infections, and chronic diarrhea, demonstrating how IgA normally safeguards those entry points.
Notably, IgA exists in two subclasses (IgA1 and IgA2). IgA2 is more common in the colon where bacterial load is high, as it’s more resistant to bacterial proteases. IgA generally does not strongly engage complement or NK cells, a strategic feature for mucosal immunity, preventing unnecessary inflammation in sensitive tissues.
For scientists, IgA’s ability to operate in harsh environments (like the gut) makes it an intriguing template for therapeutic antibodies targeting mucosal pathogens or tumors. Dimeric IgA antibodies are being explored for neutralizing viruses at the site of entry (e.g. nasal IgA against respiratory viruses) and for recruiting neutrophils in cancer immunotherapy.
IgE (Immunoglobulin E)
IgE circulates at very low concentrations, 0.02–0.2 µg mL-¹ (20–200 ng mL-¹) but plays a powerful role in allergy and parasitic infection defense. Most IgE in the body is not free-floating, but bound to high-affinity Fcε receptors on mast cells and basophils. This means tissues like the skin, lungs, and gut are primed with IgE-“armed” cells.
When IgE antibodies on these cells bind their specific antigen (for example, an allergen like pollen or a worm antigen), the antibodies cross-link and instantly trigger the cell to degranulate. Mast cell granules release histamine and other inflammatory mediators. The result is the classic Type I hypersensitivity response: vasodilation, mucus secretion, itching, bronchoconstriction, which attempts to expel the intruder. This is helpful against parasites; for instance, IgE-mediated reactions recruit eosinophils that can attack helminth worms. The same mechanism underlies hay fever or asthma when the immune system mistakes harmless allergens for threats.
IgE operates mainly at barrier sites and within tissues. It has the shortest half-life in plasma (~2 days), but once bound to mast cells, IgE can persist for weeks, keeping these cells on standby. Evolutionarily, IgE-mediated explosive inflammation is thought to protect against venom and parasites by rapidly flushing them out (through sneezing, coughing, vomiting, etc.).
In modern environments, this response often overshoots, causing allergies. Yet, the importance of IgE is seen in parasitic regions. People with higher IgE levels can have some resistance to worm reinfections. Therapeutically, IgE is a double-edged sword. It is the target of allergy medications (e.g. anti-IgE antibodies for asthma) but also a template for new therapies.
IgD (Immunoglobulin D)
IgD is the rarest immunoglobulin in blood( <0.05 mg/mL), and its exact functions are still emerging. It is a 180 kDa monomer of δ (delta) heavy chains, structurally similar to IgG but with a longer “tail”. IgD is co-expressed with IgM on the surface of most naïve B cells as a second B cell receptor.
It is primarily found as a membrane-bound receptor on naive B cells, alongside IgM, where it functions in B cell activation. When a B cell first leaves the bone marrow, it displays IgM and IgD that recognize the same antigen. Unlike other isotypes, IgD doesn’t have a clear pathogen-fighting specialty. Secreted IgD is scant, roughly 1% of antibodies produced by plasma cells, even after activation. It also does not fix complement, hinting that any IgD action is likely regulatory rather than directly microbicidal.
IgD-expressing B cells tend to populate upper respiratory mucosa and tonsils. Evidence now suggests secreted IgD antibodies can bind to basophils and mast cells through a receptor called galectin-9 (distinct from the IgE receptor). This interaction doesn’t trigger full degranulation; instead, it causes these cells to release immune-modulating factors. For example IgD binding induces basophils to produce IL-4, IL-5, and IL-13, cytokines that influence B cell class switching and promote a Th2 (parasite/allergy-type) immune environment.
Intriguingly, IgD signaling in basophils tones down IgE-mediated responses, acting as a brake on overzealous allergy reaction. Thus, IgD may serve as a local “immune surveillance” antibody that helps calibrate responses at mucosal sites: encouraging a baseline readiness (Th2 priming) while preventing overreaction to common antigens.
Translating Isotype Diversity into Therapeutic Applications
Isotype diversity not only underpins natural immunity but also inspires the development of engineered therapeutic antibodies. Understanding how each antibody class functions in nature allows immunologists and bioengineers to design antibody based interventions that exploit specific isotype properties beyond traditional IgG.
IgM based therapeutics are in development to harness IgM's ultra high avidity through pentameric structure and superior complement activation via multiple C1q binding sites. Engineered pentameric IgM antibodies have entered clinical trials for cancer and viral diseases, demonstrating how natural multivalent binding can be therapeutically leveraged. Similarly, IgE is being tested as a therapeutic class. A first in class IgE antibody showed safe activation of macrophages in tumor tissue through FcεRI engagement, suggesting IgE's degranulation apparatus can be redirected from allergic responses to anticancer immunity.
AI driven design is accelerating this field as machine learning algorithms can predict antibody structures, suggest mutations to improve stability or binding affinity, and even generate antibodies de novo. Computational models have optimized antibody frameworks for human use and designed multi epitope binding nanobodies with polyspecific binding capabilities that would be arduous to obtain by conventional methods.
.