How Are Antibodies Produced Naturally?

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Natural antibodies are the organism’s first line of defense and are produced spontaneously in germ-free conditions without specific immunization. They are the newborn organism’s first line of defense when it encounters antigens for the first time. Below, we are going to discuss how antibodies are produced naturally.

The origin and role of natural antibodies

B1 lymphocytes, a subset of B lymphocytes, are generated in waves during ontogenesis (the origin and development of an organism), primarily during the fetal and post-fetal periods. They are not produced later in life. Significantly, they are distinguished by distinct gene transcription and protein expression.

B1 lymphocytes perform the same primary function as B lymphocytes in that they help in antibody production, which is critical for the organism’s defense against pathogens. Natural antibodies are most likely produced by B1 lymphocytes and B lymphocytes of the marginal zone in humans and mice. It is proposed that B-1 cells have 80-90 percent serum resting IgMs and 50 percent serum resting IgAs (the major isotope of switched B-1 cell immunoglobulin).

In humans and mice, IgMs are the most studied natural antibodies. Natural antibodies are autoreactive, polyreactive, and have a low anti-microbial affinity. Additionally, polyreactivity ensures different heterology for a single antibody but also depends on widely distributed surface antigens, which may increase avidity. Their high efficiency is due to the unique nature of their conformational changes in the Fc region.

Role of natural antibodies in human health and disease

Natural antibodies have been linked to various infectious diseases and disorders in humans, including cancer, cardiovascular disease, diabetes, and neurological disorders. High levels of self-binding natural antibodies are usually associated with the protection or the absence of disease, whereas low levels are generally associated with disease onset and progression.

Human self-binding natural antibody profiles are proposed as surrogates or fingerprints for people’s health and physiological status, including parasitic diseases such as schistosomiasis and malaria. However, lower homeostatic natural antibody levels are associated with a relative loss of protection against molecules involved in diseases whose incidence increases with age, implying that people who have suffered a significant loss may be at the greatest risk of infection. As a result, natural antibodies are considered surrogates for susceptibility to various age-related diseases.

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Anti-Gal or anti-Gal natural antibodies play an important role in preventing illnesses, including autoimmune diseases, which may be related to Henoch-Schönlein purpura and Crohn’s disease. Also, they treat bacterial infections and degenerative diseases caused by toxic particle accumulation.

Natural antibodies have been programmed during an organism’s origin and development, facilitating the normal development of mammals by ensuring all necessary functions and protection against common pathogens, where adaptive antibodies will not be present at this early stage. This state impacts immunological balance and tissue homeostasis, which are critical in anticancer and infectious disease protection.

What about natural antibodies?

Natural antibodies are also involved in tumor prevention. Natural antibodies bind to the tumor antigen NGcGM3, which may be present during lung cancer, resulting in the elimination of cancer cells via a complement-dependent or oncosis-like mechanism. Natural antibodies are also found in reactions with Alzheimer’s amyloid, the ganglioside of neurons in Guillain-Barré syndrome, and the Thomsen-Friedenreich tumor antigen.

As a result, natural antibodies could be used as biomarkers in clinical trials for these diseases. Natural antibodies also play a significant role in transplantation immunology and allograft rejection. Significantly, a mismatched blood transfusion results in hyperacute transplantation rejection with severe clinical consequences.

Graft B-cells infiltrate the coronary arteries, causing cardiac allograft vasculopathy, an accelerated form of coronary artery disease that limits long-term survival after cardiac transplantation. Half of 100 B-cell clones isolated from three coronary artery disease cases are oligo-reactive to apoptotic cells, insulin, dsDNA, LPS, and cardiolipin.

Natural antibodies have long been recognized as the first defense against infectious agents. Additionally, natural IgM antibodies may play a role in tuberculosis because low serum IgM levels against phospholipids were observed after intensive phase treatment, which could be attributed to a decrease in bacterial burden. Nonetheless, a decline in IgM contrasts with other models, where a reduction of natural antibodies is usually a negative sign of disease.

In humans, there is an age-dependent decrease in IgM natural antibodies against pneumococcal capsular polysaccharides and IgG natural antibodies against a pool of virulence-associated proteins of various Streptococcus pneumoniae strains, which can increase susceptibility to S. pneumoniae infection.


Though natural antibodies were discovered nearly half a century ago, there is still a lot that we do not know about them. However, we still find their varieties and functions in the human body. Their fundamental property is the protection of our bodies after birth. They ensure specific homeostasis by reacting to self-antigens and neo-determinants formed, e.g., during apoptosis or oxidation. Moreover, they bind with phosphorylcholine – a constituent of many cell membranes. Approximately 80% of all-natural antibodies circulating in the human body are natural IgMs, the best-known immunoglobulins.

Recent studies focus on discovering the role of natural IgG and IgA. These immunoglobulins, together with IgM, are formed mainly by B1 lymphocytes and lymphocytes of the marginal zone of the spleen. Additionally, developing new research methods might soon enable us to characterize natural antibodies in greater detail, and the medical community might recognize their potential in combating diseases in the infantile period.