The difference between antigens vs. haptens is one the most concerning issues for people who are not familiar with them. As a matter of fact, antigens and haptens are similar in many ways. They are both molecules triggering immune responses and acting as antigenic agents. And they both work as immunogens and bind to antibodies although haptens in a different manner.

What distinguishes an antigen mostly from a hapten is that antigens are complete molecules spontaneously triggering immune response whereas haptens are fragmentary small molecules that are unable to elicit immune responses unless they are conjugated to a larger molecule, known as a carrier.

What are Antigens?

Antigens, including proteins, peptides, and polysaccharides, are immunogen molecules that can trigger immune responses or naturally bind to immune components. An antigen may have one or more epitopes, which are the determinants of recognition and binding to antibodies. Based on the resource and the way of generation, antigens could be classified into exogenous antigens, endogenous antigens, autoantigens, and neoantigens.

What are haptens?

Haptens, on the contrary, are incomplete antigens with molecular weight less than 2-5 kDa and not immunogenic for the lack of epitopes. They are small molecules, such as toxins, drugs, and hormones that are not capable of invoking immune responses when injected directly into animals. These small molecules can only elicit immune responses when attached to carrier macromolecules that are immunogenic. A lot of allergic reactions are a result of haptens, such as penicillin, chemically reaction with proteins in the body after drug injection or ingestion.

How a Hapten Triggers an Immune Response?

The term hapten is derived from the Greek haptein, meaning “to fasten”. So, haptens need to tightly conjugate with additional carriers like proteins through covalent bonds and form hapten-carrier molecule complexes, which will make haptens immunogenic and result in the production of anti-hapten antibodies. The attractive point is that these anti-hapten antibodies can tell and bind to the same hapten upon a second exposure, even if the hapten is in the absence of the carrier molecule.

Scientists now can take advantage of the immuno-chemical properties of haptens, such as the chemical structure, composition, immunogenicity, and analogues, to design and synthesize small-molecule haptens, inducing powerful immune responses to produce antibodies that bind to haptens with high affinity.

Common Drugs As Haptens

Drugs, which can be haptens, usually are small molecules that attach to proteins in the blood, such as BSA (bovine serum albumin) and KLH (keyhole limpet hemocyanin). The immune response triggered by a hapten will eventually display as an immune reaction to the drug, leading to skin eruptions, anaphylactic shock, or even life-threatening syndromes.

Antibiotics and anesthetics are common pharmaceutical drugs that can be haptens.

Penicillins, known for their anti-bacterial properties, are a group of antibiotics with the beta-lactam mechanism of action. However, beta-lactamase enzymes' resistance to beta-lactam antibiotics will break down penicillins and lead to the production of benzylpenicilloyl derivatives that bind to other proteins, further eliciting immune responses. This is why your doctor asks about your allergic history to penicillins and cephalosporins. Severe immune responses, or adverse immune-mediated reactions to subsequent exposure to haptens, include urticaria, asthma, angioedema, and drug allergic reactions.

Haptens could also be synthetic substances, such as the organic compounds benzene arsonate, trinitrophenol, and halothane, as well as naturally occurring polysaccharides, such as lactose.

Conclusion

Haptens mainly differ antigens from the ability to induce an immune response. Haptens are incomplete small molecules that require additional conjugation with other molecules such as carrier proteins to be immunogens while antigens can elicit immune responses by themselves. And haptens become immunogens the next time they are exposed to anti-hapten antibodies.
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