Cross-Reaction and Molecular Mimicry
In the CAM approach to dermatology, the environment is considered to play a fundamental diagnostic and therapeutic role. Cross-reactions with foods, chemicals, and infectious agents may be key precipitants or contributors to inflammation which itself may play a role in a range of dermatologic conditions. A mainstay of the CAM approach is to search for the inciting cause of an inflammatory response and once it is identified, to correct the ongoing memory response using natural means. Eliminating foods that exacerbate eczema, or enhancing food breakdown into smaller, less antigenic fragments by supplementing with digestive enzymes, is one example of how CAM acts to remove molecular mimics that stimulate skin inflammation.7
There is individual specificity in antigen recognition,8
exposure history, and the type of tissue response to the resulting inflammatory cascade. It is therefore critical to look for the precipitating stimuli of disease onset for each individual. This concept is widely accepted for contact dermatitis but has not yet been adopted for eczema or psoriasis. At the same time, it is critical to consider the existence of factors that either neutralize or exacerbate the response to suspected or confirmed precipitating stimuli. An exhaustively detailed history is essential to understanding why a patient reacts at certain times and not others.
Just as β-hemolytic Streptococcus
can precipitate guttate psoriasis, molecular mimicry by microorganisms is associated with onset of autoimmune conditions. A corollary possibility that should be considered is that many inflammatory and autoimmune conditions of the skin involve cross-reactive initiation to food antigens, microbes, chemicals or other altered forms of self-antigens. This entire mechanism has been well described in celiac disease,9
a condition closely associated with the dermatologic condition, dermatitis herpetiformis.
Autoimmune attack on tissues depends on a number of factors including recognition, molecular mimicry or identity, attack by lymphocytes with receptors that target a similar autoantigen, and propagation of this response by the phenomenon of bystander activation or epitope spreading.10
Normal mechanisms of tolerance and control by regulatory T cells must also fail for this to occur.
Appearance of autoantibodies in the blood, once considered irrelevant in asymptomatic patients, may well be a warning sign to institute changes to prevent the gradual development of clinical autoimmune disease.
Heavy metals and transition metals lead to autoimmunity because they bind to proteins, replace other metals in metalloproteins, and attach to sulfur groups altering molecular configuration. Crucial biotransformation metalloenzymes are inactivated by displacement. All of these actions affect the tertiary structure of proteins, creating neoantigens and altering function.
Of interest to dermatologists is that increased reactivity to heavy metals has been reported in lupus erythematosis, oral lichen planus, oral burning and itching, eczema, and psoriasis, and Sjögren syndrome.11,12
Urticaria, eczema and other systemic conditions have been found to improve after removal of dental fillings and other treatment to facilitate removal of mercury from the body.8
Drug levels may be affected by foods or medications influencing specific P450
Chemicals targeted by the liver for removal are first chemically converted by P450
isoenzymes in phase I to make them either more soluble or more chemically reactive for coupling to molecules in phase II for transport out via renal excretion. With insufficient transporters, these hyper-reactive drug metabolites, made more chemically reactive by the phase I liver P450
enzymes, may combine with molecules in skin tissue structures to create neoantigens or other molecular informational disturbances. Understanding how insufficient or incomplete biotransformation of accumulated toxic substances could trigger a skin reaction enables one to take a focused history, which includes not only the toxic substances, but also the change in hepatic ability to rid the body of molecular triggers.
Oral ingestion is one of the largest sources of foreign material entering the body. It has been established that large molecules, including horseradish peroxidase with a molecular weight over 1,000,000 daltons can be absorbed intact from the gut.14
Drugs are well known causes of skin eruptions.15
Foods have a variety of effects on skin disorders beyond a role as allergens.16
They can serve as informational molecules to incite eruption, direct or indirect hormonal aggravators, gut permeability modifiers, or influence the ecology of the gut flora. Certain nutrients can overcome the liver's capacity to biotransform harmful antigens and toxic intermediates or aid in hepatic biotransformation. Foods can also have a wide variety of effects partially overlapping those of herbs and pharmaceuticals. Dietary effects on gene expression and individual specific food interaction are now known as neutragenomics.17
Dietary treatment of acne was much more prevalent before the advent of antibiotics. In recent years, food triggers for acne had fallen out of favor and diet was widely assumed to be irrelevant. Recently, however, milk has once again been found to have an etiologic role in this disorder.18
“Food Allergy” Determination and Elimination
In addition to classic immunoglobulin E-mediated allergic response, the term food allergy also includes other types of allergy such as immune complex, delayed, and Toll-like receptor activation. There is also nonallergic sensitivity. Food allergies develop to the many common foods such as wheat, milk, soy, yeast, and corn. Some believe that a hallmark of food allergy is food craving with repetitive eating of the same food each day.19 A 5-day elimination and rechallenge on the sixth day is an effective way to determine if the food under consideration is the cause of the symptoms of concern.
Other symptoms beyond the skin could include digestive upset, nasal stuffiness, fatigue after eating, or even “brain fog.” Brain fog is a popular term for a sense of mental confusion, sluggishness, and slowness that may sometimes include a feeling of unreality or disorientation. Small peptides from casein digestion known as caseomorphins, which can also derive from gluten, rice, bovine albumin, and even spinach, have psychoactive properties.20 Treatment involves elimination, substitution with other foods, and food rotation. Enhancing digestion with digestive enzymes and adding metabolites to enhance the gut permeability barrier (and reduce the impact of leaky gut) helps to prevent sensitization to disease inducing cross-reactive antigens.21,22
Diagnosing food allergy is best initiated by a careful history of the specific foods that preceded a reaction; these include foods consumed a few hours or even few days prior to the reaction. A food and reaction diary helps to reinforce memory and document instances of food consumption and reactions. Elimination and challenge is the gold standard for identifying food allergens. Intradermal testing can be helpful, and is far more useful than scratch tests because the latter detect IgE or immediate allergy only.
Abnormal gut flora, including overgrowth of Candida
sp., parasites, and pathogens can lead to inflammation, which compromises the gut barrier and can lead to “leaky gut.” Numerous studies from Scandinavia establish the importance of probiotic supplementation for reducing by half the incidence of atopy in infants.23,24
Studies on treatment of atopy with probiotics have such mixed results that various summaries and meta-analyses conclude probiotics are of little benefit in the prevention of atopy. Most of these studies are carried out with no insight into the model of Candida
discussed here, so they do not begin to address the synergistic factors necessary to shift gut flora to reduce leaky gut, and cross-reactive attack of Malassezia
in the hair follicles. Furthermore, different strains are used, different prebiotics and fiber loads, or lack of them, to support growth.
EFAs play an essential role in skin health. EFAs are the precursors of the eicosanoids produced when phospholipase cleaves a lipid fragment, arachidonate, from the cell membrane. Arachidonate, a common pathway byproduct from most foods, leads, via cyclooxygenase, to production of the proinflammatory prostaglandin E2(PGE2), or via lipoxygenase to production of proinflammatory leukotrienes.25 Specific ω-6 unsaturated EFAs such as γ linolenic acid, found in borage oil, evening primrose oil, and human breast milk, lead to formation of the anti-inflammatory PGE1. ω-3 unsaturated fatty acids such as those found in fish oils contain eicosapentaenoic acid (EPA), which leads to formation of the anti-inflammatory and anticlotting PGE3. Flaxseed oil has an ω-3-EFA known as α-linolenic acid, which requires two carbon chain elongation to become EPA, requiring activity of the δ-6-desaturase enzyme. That enzyme has cofactor requirements of zinc, magnesium, vitamins C, B3 and B6, and low insulin levels. ω-3 EFAs also play a role in formation of the barrier lipid in the brick and mortar structure of the stratum corneum barrier. Partially hydrogenated oils not only lead to proinflammatory PGE2 formation, but also inhibit the δ6-desaturase, which is crucial for formation of anti-inflammatory γ-linolenic acid.
Shifting the balance toward anti-inflammatory EFAs by removing foods with proinflammatory oils and increasing foods and supplements with anti-inflammatory oils (e.g., cod liver oil) is a strategy useful in most conditions involving inflammation and dry skin. It is especially useful in seborrhea and eczema. Rare problems with excessive fish oil include increased bleeding tendency26 and high-birth weight, postmature babies.27
A number of studies have shown the effectiveness of ω-3-EFAs in psoriasis and other inflammatory and autoimmune diseases.28 EFAs also confer powerful protection from UV exposure and have been used to reduce inflammation and promote wound healing in burn victims.29,30
Mental, Emotional, and Spiritual Issues, and the Skin
It has been observed that an extraordinary emotional stress preceded disease onset in 86% of patients with the autoimmune diseases rheumatoid arthritis and SLE.31
Stress has been observed to affect the immune system of the skin at every level.
Repetitive scratching or other subtle manifestations of inflammation should be addressed in a multidisciplinary way. Treatment of chronic skin disorders requires management of the underlying mental, emotional, and spiritual issues, which are often closely related to the pathophysiologic process itself.
There are numerous approaches to this in complementary medicine. An earlier edition of Fitzpatrick mentioned a patient with lupus who was healed by a curandero, a healer who uses Mayan folk medicine techniques.
Tapping deeply into one's belief systems to release major conflicts and traumas is often effective.
Addressing core conflicts that are so painful that skin rashes become more acceptable diversions is beyond the scope of most dermatologists. Along with the drug therapies often employed by practitioners trained in Western allopathic medicine, there are many techniques drawn from culturally diverse spiritual, healing, and folk medicine practices. These methods include spiritual healing techniques, neuromodulation technique, and many others.