Life-Threatening Toxic Shock Syndromes, Superantigen Responses

The consequences of mold exposure reach well beyond historic beliefs that mold is simply involved in allergies.  Mold pathology has recognized mold, mainly as an antigen.  However, mold flourishes in multiple forms in the human body.  Mold has even been linked to life threatening superantigen responses.

Categories of Mold-related Superantigen Responses:

• Allergen: The human body has an IgE antibody response to identify, kill, and remember specific mold antigens.
• Pathogen: Mold colonizes and reproduces to infectious levels in warm, moist environments such as sinuses, lungs, or even on the skin.
• Toxigen: Several molds, particularly those associated with water damaged homes, produce potent mycotoxins. They induce diverse and powerful toxic effects in organ systems. They are categorized as carcinogenic, mutagenic, teratogenic, estrogenic, hemorrhagic, immunotoxigenic, nephrotoxic, hepatotoxic, dermatoxic and neurotoxic.
• Superantigen or Superantigen-like Immune Response: Some mold infections, either alone or in combination with bacterial endotoxins in biofilms, can create a life-threatening immune response referred to as a “Cytokine Storm”.

Superantigen Responses

Some infections accompanied by a superantigen response to mold or another coexisting microbial infection are referred to as cytokine storms. Cytokine storms are a specific type of severe immune system response where cytokines are rapidly reproduced and attack the body.  While the topic is complex, the superantigen response is distinctly different than the traditional body reactions to mold.  Patients present a severe, life-threatening illness that requires emergency hospital care.  It often presents as sepsis or a severe blood infection that must be immediately controlled or it can cause death. Mortality is very high in these occasions if not acutely addressed by emergency doctor responses.

Mold allergies are treated with antihistamines and steroids.  Pathogenic mold infections are surgically removed or treated with the few, potent anti-fungal medications. However, these medications come with their own toxicities. Mold mycotoxins, when recognized, are treated over time with very specific detoxification protocols involving nutritional supplements, lifestyle changes, environmental vigilance, and diet restrictions.

Superantigen responses have been linked to various systemic mold infections.  In these cases, superantigen responses expose patients to an immediate, massive immune system response.  These life-threatening responses are referred to as “cytokine storms”. A patient with a fungal respiratory infection might end up in an emergency room exhibiting symptoms suggesting acute infections like those seen in sepsis, Scarlet Fever, systemic skin infections, toxic shock syndrome, food poisoning, or cause or impact another autoimmune disease.

History of Superantigen Identification

Physicians first coined Toxic Shock Syndrome (“TSS”) from Staphylococcus and Streptococcus infections in the late 1970s and early 1980s.  The cause was determined to be highly absorbent tampons that were widely used by menstruating women. The result was a superinfection due to the induction of an exacerbated activation of autoimmune disease, in particular T-cells subsets.  Due to changes in tampon production, the incidence of tampon-induced TSS dramatically declined.  However, Toxic Shock-like incidences continued to be treated in hospital settings.

The term “Superantigen” was coined by researchers in 1990.  Prior to that, TSS was attributed to pyrogenic toxin T-cell superantigens, primarily from Staphylococcus Aureus and Streptococcus. Over time, newly discovered superantigens have been characterized by proteins produced by microbes that have become associated with a series of human disease conditions.  These include TSS, atopic dermatitis, infective endocarditis, pneumonia, sepsis, meningitis, and autoimmune disease.  TSS from streptococcus infections is most often seen in children and the elderly.  Other people at risk include those with diabetes, a weak immune system, chronic lung disease, or heart disease.

Superantigens in Disease

According to the Encyclopedia of Infectious Disease, “Bacterial Superantigen responses have been implicated as a causative agent in several acute pathological conditions, including food poisoning, toxic shock associated with staphylococcal sepsis, toxic shock syndrome, scalded skin syndrome, and Scarlet fever. The common symptom of these diseases is massive systemic immune-activation, as reflected by high serum levels of cytokine chemical messengers. Associated toxic shock is likely, at least in part, to be due to excessive release of cytokines.” [1]  Superantigens are also believed to be involved in the pathogenesis of some viruses, including HIV and COVID.

Physician specialists who normally treat upper and lower respiratory infections, such as Chronic Rhinosinusitis (“CRS”) and Bronchitis, seldom treat these life-threatening immune responses that attack the entire body.  In these cases, patients end up in hospital emergency rooms where serious systemic infections, such as sepsis, scarlet fever, atopic dermatitis, or food poisoning must be treated immediately.  Diagnosis and treatment occur without a complete patient history or knowledge of the cause.

The superantigen or superantigen-like immune responses have also been observed with fungal and viral infections (e.g. HIV, COVID-19, and Long COVID).  The sheer number of COVID patients experienced during the pandemic provided the multiples of cases required to tie COVID to superantigen responses. As a result, there is a growing interest in studying severe inflammatory responses and life-threatening complications related to systemic mold infections and chronic environmental mold exposure.  Many scientists now believe mold spores, debris, and toxins can cause superantigen responses.

Superantigen Response in Perspective

To put this into perspective, the typical immune response to a microbial antigen has a modest immune response.  Typically, 0.0001-0.01% of the body’s T-cells are activated.  In contrast, superantigen exposure can activate up to 30% of the entire body’s T-cell pool.  That calculates to >3,000 times more T-cells and other immune modulators.  The excessive and non-specific immune response to superantigens can cause a range of severe syndromes, including fever, shock, and organ failure. These are life-threatening conditions.  In contrast, the response to a normal antigen is typically more controlled and limited and is designed to eliminate the specific pathogen or foreign substance that is being targeted.  The superantigen response triggers a cytokine storm caused by the rapid response of the adaptive immune system.

Understanding the Immune System

Our bodies have two types of immunity, innate and adaptive.  Our innate immunity (also called cell-mediated) responds immediately to foreign antigens. Innate immunity consists of anatomical barriers to antigens and a cellular response.  Anatomical barriers include skin, mucous generation, stomach acids, bile acids from the liver, tear generation, sweat, and the blood brain barrier.  Internally, our innate immunity also has an immediate cellular response to antigens.

The cell mediated immune response produces eosinophils and cytokines that seek, destroy, and eliminate microbes that enter the body. It is carried out by white blood cells such as leukocytes, monocytes, natural killer cells, and macrophages. Cytokines are the chemical messengers that prevent the spread of infection. They also protect the non-infected cells from infection. There are several types of cytokines including chemokines, interferons, interleukins, and tumor necrosis factors.

Adaptive Immunity takes time for the body to identify antigens and produce antibodies that specifically seek out, destroy, and remember foreign antigens.  This can take weeks or longer to produce the antibodies.

Superantigen Response

A superantigen is a type of antigen that causes excessive and non-specific immune response in the body. Normal antigens stimulate only a small subset of T-cells.  Superantigens can activate an overabundance of T-cells by directly binding to the T-cell receptor (TCR) and the major histocompatibility complex (MHC) class II molecules on antigen-presenting cells (APCs).

The resulting immune response is the release of chemical messengers called cytokines.  Cytokines are very small, non-structural chemical messengers that are secreted by several cells in the body. They function to help regulate the inflammatory and immune responses. Many of the cells that secrete cytokines are white blood cells, such as lymphocytes and monocytes.

A cytokine storm results when the body overproduces T-cells, which then attack the body. Superantigens are responsible for diseases like toxic shock syndrome and necrotizing fasciitis. They are associated with autoimmune diseases and certain types of cancer.

Superantigens in Literature

Over the past 20 years, superantigens or “superantigen-like” proteins have been identified from other microbes, including viruses and fungi.  Superantigen responses are critical concerns amongst physician specialists.  The growing concern is the presence of a life threatening, systemic immune response that attacks the body.  In addition, patients with Chronic Rhinosinusitis (CRS) and other respiratory infections are often recognized to be composed of both fungi and bacterial infection.[3]

Dr. Donald Dennis M.D. FASC first published about this phenomenon in his ENT practice with Chronic Rhinosinusitis Patients in 2003. [4] It is commonly known that refractory infections can be caused by the formation of biofilm, which protects microbes by forming an extracellular matrix cover.  Dr. Dennis provided further information on treating systemic mycotoxicosis resulting from chronic sinusitis. [5]

Fungi may also invade the lungs via direct infection of pulmonary tissue, infection of pulmonary air spaces/lung cavities, or through their ability to trigger an immunological reaction when fungal materials are inhaled. Fungi are thought to serve both as immunogenic antigens and as adjuncts to inflammation through protease activity and are associated with allergic asthma. [6]

“The association of allergic bronchopulmonary aspergillosis, allergic fungal sinusitis, and hypertrophic sinus disease with class II genes of the major histocompatibility complex places the initiation of these inflammatory diseases within the context of antigen presentation and the acquired immune response. Pathological immunomanipulation of this response by local microbial superantigens may be a common mechanism for disease pathogenesis. Future research into the molecular biology of these related conditions may offer insight into the pathogenesis of other chronic inflammatory diseases.” [7]

Mold Mycotoxins

Some molds can produce mycotoxins, which are secondary metabolites that can cause a range of health problems depending on the type and amount of exposure. Mycotoxins are linked to a variety of symptoms, including respiratory problems, skin irritation, headaches, and fatigue.  Mycotoxins are chemical compounds and are not living organisms. (See below).

 

About Superantigens

Superantigens have received a great deal of attention since the discovery of their mechanisms in the late 1980s. Since then, there have been numerous cases and publications about their structure and molecular mechanisms.  However, very little information has been published on their direct role in diseases, other than the obvious food poisoning and toxic shock. Nevertheless, there has been considerable speculation that they are involved in severe immune-related diseases and infections.

Fungal “superantigens” are a specific type of protein produced by some fungi that can activate a large number of T-cells.  This leads to an exaggerated immune response that can result in tissue damage and inflammation. While several superantigens have been documented for bacteria and viruses, the identification of fungal superantigens is still an active area of research, and only a few have been reported so far.

Here are some examples of non-bacterial “superantigens”:

1. Staphylococcal enterotoxin B-like proteins from Aspergillus fumigatus [8] [11](Reported, but not proven)
2. Superantigen-Like effects of Candida albicans polypeptides [9]
3. HIV encoded superantigen [10]
4. Staphylococcal enterotoxin protein from Aspergillus flavus [12] (Superantigen responses reported, but not proven)
5. SARS-CoV-2 to be a superantigen, superantigen-like protein, or a causative agent triggering a superantigenic host response. [13]

It is important to note that the fungi universe is extremely large with most species yet to be isolated or identified. The discovery of new superantigens is in its infancy, is ongoing, and so the list is likely to expand in the future.

Biofilm’s Role in Superantigen Response

Another likely explanation for superantigen responses is the recognition that many respiratory infections are initiated due to the development of biofilms.  Biofilms can form when tissue walls are damaged by foreign antigens. An immediate eosinophil reaction can create additional damage.  Biofilm is the formation of a surface matrix that joins and protects multiple microbes including bacteria and fungi.  It is clearly possible that patients developing fungal or bacterial infections can be impacted by staph or strep endotoxins that cause a superantigen response in a patient.

Conclusions

While more research is needed to explain the specific pathology of superantigen responses, the recognition of cytokine storms has been thoroughly documented in emergency rooms throughout the country.  These unexplainable life threatening infections are common.  Unfortunately, emergency room protocol does not exhaust all diagnostic options when treating a severe infection in an acute setting. Evidence suggests that the historical toxic shock syndrome (TSS) caused by bacterial endotoxins has other potential microbial sources.  The presence of confections and the massive data collected during the COVID pandemic suggest other causes of cytokine storms. In addition, the role of biofilm in serious infections provides an explanation of the intractable nature of these serious infections.

References:

1. Kalland, et. al. Superantigens in Disease, Encyclopedia of Immunology (Second Edition), 1998
2. Schubert, M. “A Superantigen Hypothesis for The Pathogenesis of Chronic Hypertrophic Rhinosinusitis, Allergic Fungal Sinusitis, And Related Disorders.” Annals of Allergy and Asthma Immunology. September 2001.
3. “Prevalence of Fungal and Bacterial Co-Infection in Pulmonary Fungal Infections: A Metagenomic Next Generation Sequencing-Based Study.” Frontiers in Cellular and Infectious Biology. Nov. 1, 2021.
4. Dennis, Donald. “Chronic Sinusitis: Defective T-cells Responding to Superantigen Treated by Reduction of Fungus in the Nose and Air.” Archives of Environmental Health. August 2003
5. Dennis, Donald. et.al. “Surgical and Medical Management of Sinus Mucosal and Systemic Mycotoxicosis.” Journal of Otolaryngology and Reconstructive Surgery. April 24, 2017.
6. Donlan, Rodney, Center of Disease Control, Atlanta, GA. “Biofilms: microbial life on surfaces.” Emerging Infectious Disease. Sept. 8 2002
7. Schubert, M.S. “Allergic Fungal Sinusitis” Clinical Review of Allergy and Immunology. 30, 205-215. 2006.
8. Ickratyh, P. “Aspergillus fumigatus-Specific T Cells in Patients with Chronic Rhinosinusitis.” International Archives Allergy and Immunology. January 18, 2023.
9. Devore-Carter, Denise. “Superantigen-Like Effects of a Candida albicans Polypeptide.” Journal of Infectious Disease. April 1, 2008.
10. Torres, B. “Mechanism of HIV pathogenesis: Role of Superantigen in Disease.” Alcohol Clinical Experimental Research. Aug 22, 1998
11. Dolen, W. “Risk factors for allergic Aspergillus sinusitis” Medical Mycology, Volume 44, Issue Supplement 1, September 2006
12. Rudramurthy, S. “Invasive Aspergillosis by Aspergillus flavus: Epidemiology, Diagnosis, Antifungal Resistance, and Management.” Journal Fungi (Basel). September 5, 2019
13. Bose, P. “Is SARS-CoV-2 a Superantigen?” Lifescience and Medical News. March 29, 2023
14. Saluja, R. et. al. “Role and relevance of mast cells in fungal infections,” Frontiers in Immunology. Front Immunol. June 13, 2012.
15. Shin, H. “Role of Fungal and Bacterial Superantigen in the Pathogenesis of Chronic Rhinosinusitis with Polyps.” Journal of Rhinology. November 30, 2008.
16. Ponikau, J U et. al. « The Diagnosis and Treatment of Chronic Allergic Fungal Sinusitis.” Mayo Clinic Proceedings. September 1999.