Human-derived Natural Antibodies: Biomarkers and Potential Therapeutics

Xiaohua Xu; Sher May Ng; Eamonn Hassouna; Arthur Warrington; Sang-Hyun Oh; Moses Rodriguez


Future Neurology. 2015;10(1):25-39. 

In This Article

Abstract and Introduction


The immune system generates antibodies and antigen-specific T-cells as basic elements of the immune networks that differentiate self from non-self in a finely tuned manner. The antigen-specific nature of immune responses ensures that normal immune activation contains non-self when tolerating self. Here we review the B-1 subset of lymphocytes which produce self-reactive antibodies. By analyzing the IgM class of natural antibodies that recognize antigens from the nervous system, we emphasize that natural antibodies are biomarkers of how the immune system monitors the host. The immune response activated against self can be detrimental when triggered in an autoimmune genetic background. In contrast, tuning immune activity with natural antibodies is a potential therapeutic strategy.


Antibodies reactive to self-antigens play a key role in both healthy individuals and patients with autoimmune disorders. To avoid autoimmunity, the development of self-reactive B-cell clones and generation of antibodies reactive to the self-antigens should be closely monitored and put under control. The identification of B-1 cells in mice that produce many self-reactive antibodies has indicated how the immune system interacts with self- molecules and cells.[1,2] Studies in this field have revealed clues to developing therapeutics to treat human diseases.[3] As a result, human-derived antibodies that react to self-antigens have been developed and tested in disease models, and clinical trials are being carried out in patients to evaluate their efficacy.[4] Here we review the generation of self-reactive antibodies, the nature of the self-antigens and the development of human natural antibodies as therapeutics for human diseases. We focus on the IgM class of human natural antibodies that recognize the surface antigens on neural cells.

Although self-reactive antibodies from patients with autoimmune diseases can cause nerve damage,[5] some antibodies from healthy individuals that recognize self-antigens on neural cells play critical roles in physiology and maintenance of health.[4] Approximately 2–3% of healthy people carry antibodies that recognize self-antigens in the nervous system. These antibodies can enter the brain tissue but do not contribute to neuropathology.[6] Here, we refer to the self-antibodies identified in autoimmune diseases as auto-antibody (AutoAb), whereas antibodies from healthy individuals without any previous known exposure to the antigens recognized by the antibodies will be known as natural antibody (NAb). Nevertheless, the repertoire of antibodies binding to self-antigens on neural cells can serve as biomarkers indicating functional changes of the nervous system and may lend themselves as potential therapeutics.

AutoAbs that target the nervous system arise in two situations: AutoAb identified in autoimmune disease; or AutoAb arising in cancer patients. Autoantibodies against exogenous antigens can cross-react with self-antigens of the nervous system. The immune responses triggering the generation of these AutoAbs may be initiated by self-antigens or microbial, food and other exogenous antigens. In the autoimmune host, the developed immunological memory continues after the exogenous antigen is cleared. For example, anti-DNA[7,8] and ribosomal P[9] AutoAbs can cross-react with neuronal antigens. Additionally, the immune system can generate AutoAbs that target a specific neural-antigen. In patients with neuromyelitis optica, a pathogenic antibody against astrocytic aquaporin-4 water channel protein was identified.[10] Tumor antigens can induce the secretion of antibodies that cross-react with structurally similar patterns in the nervous system.[11,12] In general, dysfunctional immune tolerance facilitates AutoAb production, which may be a sustained process or have a relapsing/remitting course. Whether clinical symptoms develop depends on the reversibility of the pathologic process initiated by the antibodies. A full restoration of neural function is possible when the AutoAbs are cleared and no permanent neurological deficits develop. However, when components of the neural circuits are damaged irreversibly, the functional loss can be permanent and may require rehabilitation therapies.[6] The genetic susceptibility to these autoimmune diseases is also an issue that needs further investigation.

NAbs are generated without prior immune activation. It has been known that B cells can proliferate and secrete antibodies in response to lipopolysaccharide (LPS) from the Gram-negative bacterial cell membrane independent to the specific B-cell receptor (BCR).[13] B-1 cells in mice are positively selected on the basis of self-reactivity and proliferate to form a pool of self-renewing B cells that produce most of the circulating natural IgM antibodies.[14] In laboratory mice, B-1 cells mainly reside in the peritoneal and pleural cavities. B-1 cells are CD5 positive and are rare in lymph nodes.[1] B-1 cells expressing CD5 are known as B-1a cells, whereas CD5-negative B-1 cells are known as B-1b cells[15] (see review[16,17]).

The self-reactive BCR repertoire enables B-1 cells to carry out their unique functions in regulating immunity. Additionally, NAbs can cross-react with pathogen epitopes, which ensures the early and continuous protection to the host independent of the previous invasion of a specific pathogen. However, it is unknown how the self-antigens shape the BCR repertoire of B-1 cells, which may function as templates for the selection of antibody specificities. Nevertheless, regulation of the activation and NAb production of this auto-reactive B-cell subset is under control of the immune system.