Natural antibodies and their role in innate immunity
The first barrier against pathogens are components of the innate immune system. Among the well-known physical barriers such as skin, mucous membranes, and cough or sneeze reflexes, there is a lesser-known factor which is natural antibodies (NAbs).
First discovered in the 1960s, NAbs are endogenous immunoglobulins present from birth. Despite this, they have historically been neglected or denied from the immunological society due to their contradiction to established immunological dogmas.
They are present even in the absence of exogenous antigens, evidenced by their presence in both pathogen-free and germ-free mouse models. A subset of NAbs known as natural autoantibodies (NAAbs) participate in anti-inflammatory activity via targeting damaged and senescent cells and facilitating antigen-mediated removal by phagocytosis; they also have a modest affinity for antimicrobial activity.
However, a minority of NAbs and NAAbs are thought to be involved in the pathogenesis of autoimmunity, inflammatory bowel disease, contact hypersensitivity, and sepsis.
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Observing natural antibody generation in Murine models
The origin of NAbs has been studied mostly in mice, where approximately 90% are secreted by B1 cells. These cells were observed to develop outside the mouse fetus in the yolk sac and para-aortic splanchnopleura, then the bone marrow and liver in the fetal periods, and the bone marrow in the first weeks after birth.
No specific progenitors are required for B1-cells, as they can reprogram B2-cells, but they are self-renewing and retain their innate properties throughout life. As a result, B1-cells are regarded as the main source of NAbs while B2-cells are considered the main source of conventional antibodies.
It has been suggested that the existence of NAbs is programmed into development as a protective measure against bacterial, viral, parasitic, or fungal infection to ensure normal development at a time where there is no adaptive immune response. Additionally, NAbs may have a role in anti-aging and anti-tumorigenesis.
Due to this and other factors, the use of NAbs is explored as a possible therapeutic agent, specifically for use in an elderly population where there is a notable decline in antibody production.
Three common immunoglobulins comprise natural antibodies
The most widely reported NAbs are immunoglobulins M and G (IgM, IgG), there is little known about immunoglobulin A (IgA) NAbs. Studies surrounding natural IgM found that its pentameric structure can recognize multiple phylogenetically conserved structures including nucleic acids, phospholipids, and carbohydrates. It plays a protective role against pathogens to bind, neutralize and clear while also priming the adaptive immune system for attack.
Whereas monomeric IgM can be found in patients with autoimmunity or chronic liver disease. IgG and IgA have more unclear, less well-defined roles due to a lack of research focus upon them.
Despite their presence in circulation, IgA and IgG are notably low affinity, nonspecific, and low valency. In some observations, they appear to be unreactive and deemed incapable of recognizing and eliminating pathogens. However, in more recent studies in both humans and mice, the role of IgG appears to be proactive in the systemic innate immune response.
Observed in AID-/- knockout mice which produced IgM but no other antibody subtype, was a susceptibility to infection that was remedied by intravenous administration of purified natural IgG. It is thought that IgG collaborates with pathogen-associated lectins to elicit antimicrobial action.
IgA is the most abundant immunoglobulin, in humans, it circulates in serum and functions as a potent pro-inflammatory agent and, due to its presence in mucosal sites, experiences the largest variety of antigens. It is crucial as a first-line defense against invading pathogens due to its ability to rapidly activate neutrophils.
Research on IgA NAbs lags far behind IgM and IgG, current research in domesticated animals points to the role of IgA in mucosal tissues to aid against the development of immunity to parasites.
Natural antibodies could be used as therapeutic agents
NAbs have an important anti-inflammatory and anti-tumorigenic function and have been shown to suppress tumor growth, promote remyelination in multiple sclerosis, and can neutralize pro-inflammatory responses.
Within the past 2 decades, intravenous immunoglobulins (IVIg) have shown promising effects in many diseases, consisting of purified immunoglobulins (over 95% IgG) from the plasma of a variety of healthy donors.
Animal model studies using IVIg have shown inhibitory effects on the growth and spread of a variety of different cancer cells, showing a surprising potential as a supportive treatment for metastatic cancer types.
Alternatively, in multiple sclerosis (MS), a natural serum antibody (HIgM22), can potentially bind to integrins on the surface of oligodendrocytes to induce the process of remyelination. This was based on observations using mice infected with Theiler’s virus which induced severe and extensive demyelination after 6-9 months, representative of MS in humans. These mice were treated intraperitoneally with monoclonal antibodies (mAbs) for 5 weeks thereafter spinal cord remyelination was observed and assessed to be almost fully complete.
Eight different mouse mAbs were identified that promoted remyelination, all through reactions of surface antigens on oligodendrocytes. All eight mAbs had relatively conserved germline DNA sequences which imply they were natural autoantibodies. Similar autoantibodies were identified in patients with multiple myeloma, Waldenstrom's syndrome, and monoclonal gammopathy of unknown significance.
Further observations in animal models have found that IgM antibodies can cross the blood-brain barrier and accumulate in the CNS when directed to a target within the area; this activity was not present in healthy animals uninfected with Theiler’s Virus.
NAbs are an important component of the innate immune response present from birth and implicated in a variety of protective anti-inflammatory and anti-aging responses and have the potential as a powerful therapy in severe diseases.
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