Superantigens and Their Role in Difficult Diseases

Paul Reller, L.Ac.

Superantigens are the subject of much research in the last decade or two. They are implicated in chronic diseases, autoimmune disorders, cancers, and other immune-mediated diseases that have evaded successful treatment protocols. Superantigens may not only be involved in the original onset of these diseases, but may be implicated in recurrence even when the superantigen was not involved in the original disease mechanism. Superantigens are also involved in the spread of a disease in the body via epitopes, which are simple chemicals on the antigen membrane that can react with antibodies or selective T cell receptors. Superantigens are potent activators of the CD4+ T cells, which cause a rapid cascade of cytokine production and proliferation and attraction of various types of immune cells in the complement system. CD4 T cells are also implicated in immunodeficiency syndrome (AIDS), and CD4 that are altered by retroviruses or viruses such as HIV can have devastating results. On the other hand, research has revealed that some superantigen mechanisms may exploit strong immune responses that our body uses to counter some threatening diseases, such as cancers. The subject of superantigens may reveal much to patients and physicians about various treatment protocols and preventative measures.

Although superantigens present a very complicated scenario to the patient, there is much to bring away from knowledge of the superantigen threat to health. The most important point to consider is that we need to help the individual body with natural defenses against superantigens, and not sit back and assume that modern science will produce technical cures and prevention. Superantigens will not be eliminated from our world any time soon. In fact, we can expect a growing problem with superantigens as we continue to produce an environment that challenges the natural environmental balance that has evolved to protect our species. Until science starts to look holistically at participating in natural community defenses against health threats, threats such as superantigens are sure to increase. Current technology in medical science is focused upon specific treatments that can make a maximum profit. When we have a threat such as superantigens, continued development of specific pharmaceuticals will never keep up with the diversity of the threat. The patient can turn to the type of medical science that seeks to enhance natural homeostatic defenses, though. This type of medicine is called Complementary and Integrative Medicine, and specifically Traditional Chinese Medicine, which as always had this medical goal of improving natural homeostatic immune defenses.

What is a superantigen?

An antigen is defined as any substance, not only infectious agents, but also environmental toxins, drugs, food molecules, and altered membrane molecules, that induce a state of sensitivity and/or immune responsiveness after a latent period of days to weeks, and which reacts with antibody proteins and/or other immune mediators, of a sensitized subject. Superantigens are a class of antigens that cause non-specific T-cell activation, and massive release of immune cytokines. Superantigens are able to activate up to 20% of the body's T-cells, which would explain the link between respiratory and skin allergies, and probably intestinal sensitivity and allergic reaction. Superantigens would disrupt the strength of our adaptive immune system, which is the learned ability to target antigens with a high specificity. Of course, in early infants, this immune system is still undeveloped, and the infant relies on the innate immune system, passed via colustrum in the mother's milk, as well as imprinted upon the genetic code. The decrease in breast feeding in modern times, as well as the incidence of childbearing at a late age, and the rise in the use of artificial fertility methods and incidence of triplets, have all been implicated in the dysfunction of the early infant's immune responses.

Scientists have discovered that superantigens can activate auto-reactive T cells and induce severe relapses in multiple sclerosis, where the body goes through periods where the immune system attacks its own nerve sheaths, or myelin. In animal studies, the superantigens were able to activate auto-reactive T cells not involved in the initial bout of the multiple sclerosis. Superantigens have also been implicated in acute diseases, such as food poisoning and toxic shock syndrome. We see that superantigens present quite a health threat.

Some examples of superantigens are proteins found on the membranes, or secreted from, microbes such as Staphylococcus and Streptococcus bacteria, which are called exotoxins. These bacteria are quite common in the environment, and exist naturally on the skin and in the intestinal tract of humans. The bacteria are able to evolve genetic traits that protect them from danger, and we see more and more antibiotic resistant strains occurring in our world with the overuse of antibiotics and antimicrobial agents. One way for the bacteria to evolve genetic means of self-preservation is by utilizing viral genes. Viruses are nothing more than a bit of DNA or RNA encapsulated by a protein membrane. They are not living organisms, but are believed to be a way to pass on genetic information within the whole entity of life on the planet, to achieve constant evolution of life. Unfortunately, viruses also produce dysfunction and threat to life, which is countered by a evolution of genetic responses to these viral threats. Some superantigens are thus proteins associated with common bacteria and viruses.

Non-bacterial superantigens have also been identified, including viral, reotroviral and fungal superantigens. Each year, scientific research is uncovering more useful information on superantigens. Our bodies have developed adaptive defenses to these superantigens, but we cannot afford to wait till symptoms become severe to do something about this health threat. This may be too late. One increasingly common threat to the immune responses that we need to address to counter the threat to superantigens is the increased use of synthetic steroids in medicines and even health products. Corticosteroid synthetics are now being added to even over the counter beauty products. Products used to lighten the skin have produced alarming health problems due to the addition of steroid synthetics to the creams (see the link to a health article below). While most medical doctors downplay the health threat of corticosteroid creams and medications, the adverse effects of long term use of low dose corticosteroids has been well documented. For example, studies at the Albert Einstein College of Medicine in New York (PMID:1682792) showed that: “Long-term low dose corticosteroid use may reversibly decrease B-cell counts and specific antibody responses.” The increased risks of fungal overgrowths, such as candidiasis, and other immunodeficient threats are routinely listed as side effects of low dose corticosteroid use, and routinely ignored. This, of course, leaves our natural immune defenses less prepared to deal with the threat of superantigens. Decreasing overuse of these medications and utilizing Integrative Medicine to protect against side effects are sensible strategies the the patient may adopt.

To protect ourselves against superantigens, our bodies have evolved the major histocompatibility complex (MHC) on our genetic code, which is used to identify molecules that are a threat, and those that are not, so that our immune system is not attacking our own cells. This is of course disrupted in autoimmune disorders, and possibly in many cancers. When we mate, we combine MHC to form new genetic codes that evolve with the changes in the overall life system. In fact, scientific study has shown that men and women with differing MHC are naturally attracted to each other sexually, and that this seems to be the predominant biological mechanism seen in study of sexual attraction. Hence, people are born with differing T cell binding regions, or receptors, that react differently to various superantigens. Superantigens cross-link the individual MHC with the types of T cell receptors that evolve due to immune needs in the body. This cross-linking results in a complex immune response, often times leading to episodes of chronic disease, and sometimes autoimmune reactions.

The body responds to unwanted superantigen effects by using a feedback mechanism that uses excessively generated immune modulators, or cytokines, to suppress T cells and destroy activated cells that threaten the body's health, returning the body to a healthy homeostasis. In this way we have evolved a natural means of modulating superantigen effects in our bodies. A variety of factors may alter or inhibit this self-protective mechanism, though. Superantigens may also produce an immune cascade effect that alters the B cells to respond to different types of antibodies than they normally respond to. Sometimes, the effect of this self-protective mechanism results in a period of immunodeficiency, as the unhealthy, or dysfunctional, immune cells are deleted and replaced. When this period of immunodeficiency is experienced in relation to superantigen exposure, the body may have insufficient immune response to counter endotoxins. Endotoxins are toxins that are associated with certain bacteria, but are not secreted by the bacteria. Endotoxins are part of the bacteria that are believed to be released when our immune system destroys the bacteria. In this way superantigens may indirectly cause disease and toxicity in the body.

One of the most well known disease-causing endotoxins is the lipopolysaccharide found in the outer membrane of various gram-negative bacteria. A lipopolysaccharide is a complex of sugar (polysaccharide) and fat (lipid). The lipid portion is responsible for the toxic effects. As the body destroys unwanted bacteria, the release of the lipid endotoxin produces common symptoms, such as fever, inflammation, coagulation, and even a drop in blood pressure. Certain chemicals evolved in plant medicines have been shown to have anti-lipopolysaccharide effects, making these herbs useful in the treatment protocols of difficult diseases associated with superantigens. In our history, as nature has evolved complex threats to health, it has also evolved ways for the organism to counter these threats. This is why the complex nature of herbal chemistry is so important to our health care, as an effective complement to standard man-made pharmaceuticals.

Diseases associated with superantigens include eczema, psoriasis, rheumatoid arthritis, diabetes mellitus, multiple sclerosis, Kawasaki Disease, toxic shock syndrome, scarlet fever, and more. Difficult chronic diseases such as Epstein Barr Virus syndrome, Cytomegalus virus syndrome, and others, including some HIV associated syndromes have been attributed to superantigens. Addressing the healthy immune responses to superantigens with holistic medicine can decrease one's risks of developing these diseases, as well as afford patients more tools to decrease symptoms and manage these diseases.

Testing for superantigens is complex. Polymerase chain rection (PCR) is used to detect specific DNA sequences if they can be isolated for growth in the laboratory. Antibodies to the toxins are nonspecific. Western blot analysis is another promising test that is being explored. At present, there is no adequate testing system to identify specific superantigens. Although diagnosis is problematic, the threat of superantigens has been clearly defined by scientific study, and the best means of addressing this health problem is currently throught utilization of Complementary Medicine.

Treatment in Complementary Medicine to counter Superantigens

Research continues to explore treatment options with superantigens. One therapeutic tool is the enhancement of the immune complement system with stimulation of interferon. Synthetic interferon has been used for some time, especially to treat difficult cases of Hepatitis C, treated with interferon alpha. Unfortunately, the side effects of synthetic interferon treatment are harsh, and many patients discontinue use. Intereron beta drugs were approved to treat multiple sclerosis in 1993, yet the harsh side effects of bone marrow suppression and weight loss discourage current use. A variety of herbs will stimulate the interferon system. European mistletoe, or Viscum alba, is now used extensively for this purpose. Various herbal immune stimulants are also purported to stimulate the immune cytokine and interferon responses. There are a number of interferons produced by our immune system, and certain types may be beneficial to counter the effects of superantigens, while other types may be implicated in the superantigen disease mechanism. Herbal medicine offers the unique synergy of multiple chemicals that may modulate the interferon responses.

Another novel approach in treatment is the induction of interleukin 10. A research article cited below shows how a combination of common Traditional Chinese herbal formulas immunomodulates by increasing IL-10 while decreasing other cytokines and serum IgE. This approach was successful in treating perennial allergic rhinitis. The formulas included Xin yi san, Xiao qing long tang, and Xiang sha liu jun zi tang, and were continued for 3 months. Another study at the Mie University School of Medicine in Japan found that a formula with 7 herbs modulated a decrease of IL-10 and increases in other cytokines seen in the blood of hepatitis C patient. The herbs studied were Scutellaria baicalensis (Huang qin) and Glycyrrizha root (Gan cao) in the formula Sho-saiko-to.

An additional treatment approach considered is caspase inhibition, which has the capacity to suppress various superantigen T cell proliferation and production of cytokines and chemokines that drive superantigen disease. Caspases are enzymes that are responsible for many of the biochemical and morphoogical changes that occur during apoptosis, or normal cell death. Various caspases have been implicated in superantigen driven diseases, and it appears that an immunomodulatory effect on specific caspases, promoting caspase 3, and inhibiting others, may be the most effective therapeutic activity. This immunomodulatory effect has been noted in the Chinese herb Lei gong teng. The herbal chemical triptolide, from the Chinese herb Lei gont teng, or Trypterygium wilfordii, has also been shown to attenuate superantigen endotoxins and exotoxin-induced T cell proliferation and production of cytokines and chemokines.

One more novel therapeutic activity proven to decrease effects of endotoxin superantigens is lipoxygenase inhibition. This too has been studies for many years, and the USDA website entitled Dr. Duke's Phytochemical and Ethnobotanical Databases lists these herbs with this activity: Coptis chinensis (Huang lian), Phellodendron amurense (Huang bai), Hydrastis canadensis (Goldenseal), Bilberry, Fennel, Berberis, Wild Chamomile, and Rosemary.

Many commonly used herbs are now proven to exert immunomodulatory effects that counter the excessive cytokine and chemokine activity seen in superantigen driven chronic diseases. Coriolus versicolor, Curcuma longa (E zhu), Polygala tenuifolia (Yuan zhi), Poria cocos (Fu ling), Silybum marianum (Shui fei ji), Smilax glabra, Acanthopanax gracilistylus (Wu jia pi), Uncaria tomentosa (Cat's claw), Allium sativum (Da suan, or aged garlic), and Echinacea are mentioned in a review of published research cited below.

As research continues, the medical community and the public gains increased confidence in the treatment claims of herbal medicine, especially in the realm of treatment of complex disease mechanisms in the body. Such disease mechanisms as superantigens affect both plants and animals in the same or similar ways, and over long periods of time, plants have evolved complex activities to counter these disease mechanisms. We too can take advantage of Nature's laboratory with Traditional Chinese Medicine.

Information Resources

1. The role of superantigens in psoriasis has been the subject of much of the research to find cures in the last decade. This research summary is from Duke University Medical Center, Durham, North Carolina, in 2001: http://www.ebmonline.org/cgi/content/abstract/226/3/164
2. A history and explanation of superantigens, from their inception into the environment as biological weapons in the early 1960s to the present medical research: http://www.ijmm.org/article.asp?issn=0255-0857;year=2004;volume=22;issue=4;spage=204;epage=211;aulast=Hemalatha
3. Superantigens are implicated in a number of common chronic airway diseases, such as rhinitis, asthma, COPD, and nasal polyps: http://content.karger.com/produktedb/produkte.asp?doi=10.1159/0000100897&typ=pdf
4. 2005 research at the Department of Immunology and Molecular Biology of the United States Army Medical Research Institute of Infectious Diseases showed that the Chinese herb Lei gong teng, or Trypterygium wilfordii, has potent immunosuppressive effects that counter the effects of superantigens. : http://www.ncbi.nlm.nih.gov/sites/entrez PMID: 15803859 Immunopharmacology Immunotoxicology 2005;27(1):53-66
5. 2003 research at the Stanford University Medical Center in California also confirmed the unique immunosuppressive and anti-inflammatory effects of lei gong teng, which led to the U.S. Army Medical Research Institute study. : http://www.ncbi.nlm.nih.gov/sites/entrez
6. A 2004 review of research of Lei gong teng from various University Schools of Medicine in Japan. : http://www.ncbi.nlm.nih.gov/pmc/articles/PMC373449/
7. 2001 research at the Department of Immunology and Molecular Biology of the United States Army Medical Research Institute of Infectious Diseases showed that the Chinese herb Huang Qin, or Scutellaria baicalensis, may be therapeutically useful for mitigating the pathogenic effects of superantigens by inhibiting cytokine signalling pathways : http://www.ncbi.nlm.nih.gov/sites/entrez
8. 2009 research published in Toxicology 2009 Oct.7, reveals that a variety of Chinese herbal formulas exert immunomodulation of cytokine activity, including interleukin 10, making them potent therapeutics to counter superantigen diseases: http://www.ncbi.nlm.nih.gov/pubmed/19818374
9. A 2006 review of research data by the Tai Sophia Institute of Maryland found that a number of Chinese herbs were proven to have potent immunomodulating chemicals potentially useful in treatment of superantigen driven autoimmune and chronic degenerative diseases: http://www.ncbi.nlm.nih.gov/pubmed/16813462
10. A 2001 research study at the Nationl Yang-Ming University School of Medicine in Taiwan found that a combination of herbal formulas increased IL-10 production while inhibiting other cytokines and serum IgE levels to effect an immunomodulatory effect applicable to the treatment of superantigen driven disease: http://www.ncbi.nlm.nih.gov/pubmed/11407311
11. Lipoxygenase inhibition has been proven as a novel approach to counter endotoxin superantigens. As usual, synthetic drugs are proven effective, but come with harsh side effects. Herbal chemicals have long been studied to achieve this same effect: http://www3.interscience.wiley.com/journal/120090304/abstra
12. To illustrate the pervasive threat to the immune protection from synthetic steroids added even to over the counter beauty products, this 2010 New York Times article reveals the problems in skin lightening creams with steroids added and not regulated by the FDA: http://www.nytimes.com/2010/01/16/health/16skin.html?hp

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