Increased levels of oxidative stress within the melanocytes can lead to their damage and death. Oxidative stress results from an imbalance between the production of reactive oxygen species (ROS) and the body’s ability to detoxify these reactive intermediates or repair the resulting damage. Melanocytes in vitiligo patients are particularly susceptible to oxidative stress due to the intrinsic properties of melanin synthesis. Some theories suggest a neurogenic component, where substances released from nerve endings may be toxic to melanocytes or alter their environment in a way that leads to their destruction. Melanocytorrhagy is a hypothesis that vitiligo may be caused by the detachment and subsequent loss of melanocytes from the epidermal basal layer. Factors contributing to melanocytorrhagy include genetic predispositions and environmental triggers. Ultraviolet radiation, chemical exposure such as phenolic compounds, and physical trauma known as Koebner phenomenon can trigger or exacerbate vitiligo in genetically predisposed individuals.
These factors interplay in a complex manner to initiate and propagate the depigmentation characteristic of vitiligo. Despite significant advancements in understanding the pathophysiology of vitiligo, many aspects remain unclear, and ongoing research aims to elucidate these mechanisms further to develop more effective treatments.
The enzymatic process involved in the pathogenesis of vitiligo is complex and involves the imbalance between the production of melanin by melanocytes and the destruction of these cells due to various factors, including oxidative stress. There are many enzymes that play crucial roles in both the synthesis of melanin and the generation of reactive oxygen species (ROS) that lead to melanocyte damage. Melanin synthesis, also known as melanogenesis, occurs within the melanocytes and is catalysed by several enzymes. Tyrosinase is the most critical enzyme in melanogenesis. It catalyses the first two steps in the melanin synthesis pathway, including the conversion of tyrosine to DOPA (dihydroxyphenylalanine) and then to dopaquinone. Tyrosinase activity is a major determinant of the melanin production rate. Enzyme Tyrosinase-related protein 1 or TRP-1 catalyses the oxidation of 5,6-dihydroxyindole-2-carboxylic acid (DHICA) to indole-5,6-quinone-2-carboxylic acid, a step in the eumelanin synthesis pathway. Tyrosinase-related protein 2 or TRP-2 / DOPA chrome tautomerase is involved in the conversion of dopachrome into 5,6-dihydroxyindole-2-carboxylic acid (DHICA), another step in the eumelanin production pathway.
The balance between ROS production and antioxidant defence mechanisms is crucial for maintaining cellular health. In vitiligo, an imbalance leads to oxidative stress, which can damage melanocytes. NADPH oxidase is an enzyme complex that plays a role in generating ROS. Increased activity of NADPH oxidase has been observed in vitiligo, contributing to the oxidative stress in the skin. Superoxide Dismutase (SOD) is an enzyme that converts superoxide radicals into hydrogen peroxide, which is less damaging. Variations in the activity of SOD and other antioxidant enzymes can influence the extent of oxidative damage. Catalase enzyme breaks down hydrogen peroxide into water and oxygen. Reduced activity of catalase in the epidermis of vitiligo patients has been noted, leading to higher levels of hydrogen peroxide and oxidative stress. Enzyme Glutathione Peroxidase reduces hydrogen peroxide to water, using glutathione as a substrate. Changes in the activity of this enzyme can also contribute to the oxidative stress observed in vitiligo. The increased oxidative stress in vitiligo leads to the damage and eventual death of melanocytes, contributing to the depigmentation seen in this condition. The specific triggers that start this enzymatic and oxidative cascade are still being researched, with genetics, environmental factors, and the immune system all playing potential roles.
In the context of vitiligo, the dysfunction or alteration in the activity of enzymes involved in melanogenesis and the body’s antioxidant defence mechanisms plays a significant role in the pathophysiology of the disease. Several factors can affect or deactivate these enzymes, leading to melanocyte damage or death and subsequent depigmentation. Mutations or polymorphisms in the genes encoding tyrosinase and other melanogenic enzymes can affect their function, stability, or expression levels, leading to altered melanin production. In vitiligo, autoantibodies against tyrosinase and other melanocyte antigens can impair enzyme function directly or lead to the destruction of melanocytes. High levels of reactive oxygen species (ROS) can oxidatively modify enzymes like tyrosinase, affecting their activity. Oxidative stress can also disrupt the organelles within melanocytes, such as the endoplasmic reticulum, where tyrosinase is processed and matured, leading to decreased enzyme activity.
Excessive ROS can overwhelm the antioxidant defence mechanisms, leading to oxidative damage to these enzymes themselves, reducing their activity and efficiency. In vitiligo, there is often a reported decrease in the expression of antioxidant enzymes. This reduction could be due to genetic factors, epigenetic modifications, or a direct result of increased oxidative stress. Certain chemicals, such as those found in environmental pollutants or cosmetics, can inhibit the activity of antioxidant enzymes, further exacerbating oxidative stress. Alterations in the microenvironment of the skin, such as pH and ionic composition, can affect enzyme activities. For instance, high levels of hydrogen peroxide in vitiligo patients can alter the skin’s pH, affecting enzyme functioning. Certain micronutrients, like copper and zinc, act as cofactors for melanogenic and antioxidant enzymes. Deficiencies in these nutrients can impair enzyme activity.
In vitiligo, the deactivation or altered function of these enzymes contributes to the reduced melanin production and increased melanocyte vulnerability to oxidative damage. This imbalance between oxidative stress and antioxidant defence, along with impaired melanin synthesis, ultimately leads to the characteristic depigmentation of the skin seen in vitiligo. Strategies aimed at reducing oxidative stress, enhancing antioxidant defence mechanisms, and possibly correcting enzyme activities are among the therapeutic approaches being explored for vitiligo management.
The off-target effects of antibodies generated against infectious agents can contribute to the pathogenesis of so-called autoimmune diseases, including vitiligo, through a process known as molecular mimicry and bystander activation. In the context of vitiligo, where the immune system attacks melanocytes leading to depigmentation, such off-target effects can exacerbate or trigger the condition.
Molecular mimicry occurs when antibodies or T-cells generated against infectious agents recognize similar epitopes or antigenic determinants on self-antigens. This similarity can lead to an immune response where the immune system inadvertently targets the body’s own cells. If a pathogen shares epitope similarities with proteins found in melanocytes such as tyrosinase, TRP-1, or TRP-2, antibodies generated against the pathogen might cross-react with these melanocyte proteins. This can lead to melanocyte destruction and, consequently, vitiligo.
Bystander activation occurs when inflammation induced by an infectious agent leads to the activation of self-reactive T cells. Inflammatory cytokines and the local release of antigens from tissue damaged by infection can activate T cells that, while not specific to the pathogen, attack self-antigens. An infectious event that leads to local skin inflammation might activate self-reactive T cells against melanocytes. This could be further facilitated by the release of melanocyte antigens in the inflamed environment, contributing to the autoimmune attack on these cells.
Some studies have suggested links between vitiligo and previous infections, hinting at the possible role of molecular mimicry and bystander activation. For example, there have been observations of vitiligo onset following viral infections, which could trigger autoimmunity against melanocytes through the mechanisms described. Additionally, the presence of autoantibodies against melanocyte-specific antigens in vitiligo patients supports the idea that the immune system’s targeting of melanocytes may, in part, be due to cross-reactivity or an overly aggressive immune response initiated by an infection.
Understanding the role of off-target effects and cross-reactivity of antibodies in the pathogenesis of vitiligo is crucial for identifying potential triggers of the disease. It suggests that managing infections and reducing inflammation could be strategies to prevent or mitigate the onset or progression of vitiligo in susceptible individuals. It also highlights the complexity of autoimmune diseases, where the immune system’s response to external pathogens can inadvertently lead to self-tissue damage. This understanding can guide research towards more targeted treatments that can distinguish between pathogenic and self-antigens, potentially reducing the risk of autoimmunity. T of molecular mimicry and bystander activation provides a plausible link between infections and the development of autoimmune conditions like vitiligo.
The autoimmune hypothesis suggests that vitiligo is caused, at least in part, by an autoimmune response where the body’s immune system mistakenly targets and destroys melanocytes, the cells responsible for producing melanin pigment. Vitiligo often co-occurs with other autoimmune diseases such as autoimmune thyroid disease, rheumatoid arthritis, and type 1 diabetes, suggesting a common autoimmune mechanism. Autoantibodies targeting melanocytes or their components have been found in the serum of some vitiligo patients. These include antibodies against melanocyte-specific proteins such as tyrosinase, tyrosinase-related protein 1 (TRP-1), and Pmel17/gp100. The presence of these autoantibodies supports the idea of an autoimmune response against melanocytes. Autoantibodies may directly bind to melanocytes, leading to their damage or death through complement activation or antibody-dependent cellular cytotoxicity (ADCC). By targeting specific melanocyte proteins, autoantibodies could interfere with the normal functioning of these cells, potentially affecting melanin production and leading to pigment loss. The binding of autoantibodies to melanocytes might also trigger an inflammatory response, attracting immune cells such as T cells, which could contribute to melanocyte destruction. While the detection of autoantibodies in vitiligo patients supports the autoimmune hypothesis, not all patients have detectable levels of these antibodies, and their presence is not exclusive to individuals with vitiligo. This suggests that while autoimmunity plays a role in vitiligo, it is likely part of a multifactorial pathogenesis involving genetic, environmental, and possibly other immune-related factors. Understanding the autoimmune aspects of vitiligo is crucial for developing targeted therapies that can modulate the immune response, restore pigment, or prevent further pigment loss.
From MIT point of view, therapeutics of vitiligo should aim at removing the molecular inhibitions in various enzymatic pathways and biomolecular processes caused by diverse kinds of exogenous or endogenous chemical molecules and enzyme inhibitors involved in the pathogenesis. Molecular imprints of pathogenic molecules, antibodies, drug molecules and biological ligands prepared through the process of homeopathic potentization could be used for this purpose. Molecular imprints are nanocavities or molecular voids created in water-ethanol azeotropic matrices through a host- guest interaction involved in potentization somewhat similar to what is done in the process of molecular imprinting in polymers. These nanocavities with three-dimensional conformation of template molecules engraved into it can act as artificial binding pockets for pathogenic molecules having conformational affinity, thereby deactivating them and removing the biomolecular inhibitions they have produced.
As discussed above, tyrosinase is the most critical enzyme in melanogenesis or melanin synthesis. Various environmental factors, chemical substances, endogenous ligands and phytochemicals are found to inhibit tyrosine’s. Arbutin, a phytochemical contained in Uva Ursi, Arbutus Andrachne, Gaultheria, Kalmia Latiflora, etc acts as a tyrosinase inhibitor. Molecular imprints of arbutin can act as artificial ligand binds for any molecule that has functional groups capable binding to the binding sites of tyrosine molecules, and can protect the enzyme from the attack of endogenous or exogenous molecules that may inhibit tyrosine activity. Potentized forms of homeopathic drug substances such as Uva Ursi, Arbutus Andrachne, Gaultheria, Kalmia Latiflora, Arbutin etc contains molecular imprints of arbutin, and as such, could work as remedies for vitiligo arising from tyrosinase inhibition. Ellagic Acid, a photochemical present in pomegranates, strawberries, raspberries, and walnuts, inhibits tyrosinase directly and has been shown to prevent the formation of melanin by interrupting the transfer of melanosomes to keratinocytes. As such, molecular imprints contained in homeopathic potentized forms of Granatum (Pomegranate), Juglans regia (Walnut), Fragaria Vesca (Strawberry) etc in 30c potency could be incorporated in the prescription for vitiligo. Licorice Extract (Glabridin), derived from the root of the licorice plant (Glycyrrhiza glabra), inhibits tyrosinase activity and has anti-inflammatory properties, reducing UV-induced pigmentation. These drugs in 30c potency could be used. Vitamin C (Ascorbic Acid), found in citrus fruits, bell peppers, and kale, reduces melanin synthesis by reducing dopaquinone back to dopa, and by inhibiting the enzyme dopachrome tautomerase. Mulberry Extract, derived from the roots or leaves of mulberry plants, contains compounds that inhibit tyrosinase activity, thereby reducing melanin production. Soybean extract contains active components like genistein and daidzein, which can Inhibit melanin synthesis by acting on various points in the melanogenesis pathway, including the inhibition of tyrosinase activity. Green tea extract contains polyphenols, particularly epigallocatechin gallate (EGCG), which has been shown to inhibit tyrosinase, thereby reducing melanin synthesis. Kojic Acid, derived from various fungi and a byproduct of certain fermentation processes, such as the production of sake, inhibits tyrosinase by chelating the copper ions necessary for its enzymatic activity.
Some studies have suggested a higher prevalence of vitiligo among patients with history of Hepatitis C Virus (HCV), potentially due to autoimmune reactions triggered by the virus. Human Immunodeficiency Virus (HIV), which affects the immune system, has been associated with various autoimmune phenomena, including vitiligo, possibly due to immune dysregulation. Cases of vitiligo following herpes simplex virus infections have been reported, which might be related to local immune responses and inflammation triggering depigmentation. Helicobacter pylori, known for causing stomach ulcers, has been suggested to play a role in some autoimmune diseases and has been linked with the presence of vitiligo in some studies, potentially through systemic inflammation or molecular mimicry. There is some evidence to suggest that infection by Staphylococcus aureus, especially in areas prone to atopic dermatitis, could be linked to the development of vitiligo, possibly through changes in the skin microbiome and immune activation.
Environmental chemicals can impact melanogenesis by inhibiting the enzymes involved in the production of melanin, and create conditions like vitiligo. Certain chemicals, such as those found in environmental pollutants or cosmetics, can inhibit the activity of antioxidant enzymes, further exacerbating oxidative stress. Mercury found in some skin-lightening creams and traditional medicines inhibits the melanogenesis process, though their exact mechanism of action on specific enzymes isn’t fully clear. They are thought to nonspecifically inhibit enzymes by binding to sulfhydryl groups. Triclosan, previously used in antibacterial soaps and other personal care products, though its use has declined due to regulatory restrictions, has been shown to inhibit tyrosinase in vitro, which could potentially affect melanogenesis with prolonged exposure. The inhibitory effects of these chemicals on melanogenesis can lead to cosmetic and medical concerns, including unwanted skin lightening or the exacerbation of conditions like vitiligo. Hydroquinone is a skin-lightening agent used in the cosmetic industry and in dermatology for the treatment of hyperpigmentation and discoloration disorders. It’s considered one of the most effective tyrosinase inhibitors, which means it can reduce the production of melanin, the pigment responsible for skin color. Hydroquinone works by inhibiting the enzymatic oxidation of tyrosine and phenol oxidases, which are crucial steps in the melanin synthesis pathway. Certain micronutrients, like copper and zinc, act as cofactors for melanogenic and antioxidant enzymes. Deficiencies in these nutrients can impair enzyme activity.
MIT HOMEOPATHY APPROACH TO VITILIGO
MIT or Molecular Imprints Therapeutics refers to a scientific hypothesis that proposes a rational model for biological mechanism of homeopathic therapeutics.
According to MIT hypothesis, potentization involves a process of ‘molecular imprinting’, where in the conformational details of individual drug molecules are ‘imprinted or engraved as hydrogen- bonded three dimensional nano-cavities into a supra-molecular matrix of water and ethyl alcohol, through a process of molecular level ‘host-guest’ interactions. These ‘molecular imprints’ are the active principles of post-avogadro dilutions used as homeopathic drugs. Due to ‘conformational affinity’, molecular imprints can act as ‘artificial key holes or ligand binds’ for the specific drug molecules used for imprinting, and for all pathogenic molecules having functional groups ‘similar’ to those drug molecules. When used as therapeutic agents, molecular imprints selectively bind to the pathogenic molecules having conformational affinity and deactivate them, thereby relieving the biological molecules from the inhibitions or blocks caused by pathogenic molecules.
According to MIT hypothesis, this is the biological mechanism of high dilution therapeutics involved in homeopathic cure. According to MIT hypothesis, ‘Similia Similibus Curentur’ means, diseases expressed through a particular group of symptoms could be cured by ‘molecular imprints’ forms of drug substances, which in ‘molecular’ or crude forms could produce ‘similar’ groups of symptoms in healthy individuals. ‘Similarity’ of drug symptoms and diseaes indicates ‘similarity’ of pathological molecular inhibitions caused by drug molecules and pathogenic molecules, which in turn indicates conformational ‘similarity’ of functional groups of drug molecules and pathogenic molecules. Since molecular imprints of ‘similar’ molecules can bind to ‘similar ligand molecules by conformational affinity, they can act as the therapeutics agents when applied as indicated by ‘similarity of symptoms. Nobody in the whole history could so far propose a hypothesis about homeopathy as scientific, rational and perfect as MIT explaining the molecular process involed in potentization, and the biological mechanism involved in ‘similiasimilibus- curentur, in a way fitting well to modern scientific knowledge system.
If symptoms expressed in a particular disease condition as well as symptoms produced in a healthy individual by a particular drug substance were similar, it means the disease-causing molecules and the drug molecules could bind to same biological targets and produce similar molecular errors, which in turn means both of them have similar functional groups or molecular conformations. This phenomenon of competitive relationship between similar chemical molecules in binding to similar biological targets scientifically explains the fundamental homeopathic principle Similia Similibus Curentur.
Practically, MIT or Molecular Imprints Therapeutics is all about identifying the specific target-ligand ‘key-lock’ mechanism involved in the molecular pathology of the particular disease, procuring the samples of concerned ligand molecules or molecules that can mimic as the ligands by conformational similarity, preparing their molecular imprints through a process of homeopathic potentization upto 30c potency, and using that preparation as therapeutic agent.
Since individual molecular imprints contained in drugs potentized above avogadro limit cannot interact each other or interfere in the normal interactions between biological molecules and their natural ligands, and since they can act only as artificial binding sites for specific pathogentic molecules having conformational affinity, there cannot by any adverse effects or reduction in medicinal effects even if we mix two or more potentized drugs together, or prescribe them simultaneously- they will work.
Based on the discussions above, potentized homeopathy preparations such as Mercurius 30, Triclosan 30, Hydroquinone 30, Kojic Acid 30, Green tea extract or Epigallocatechin gallate (EGCG) 30, Soybean extract or Genistein 30, Vitamin C or Ascorbic Acid 30, Licorice Extract or Glabridin 30, Ellagic Acid 30,, Arbutin 30, Tyrosine 30, Uva Ursi, Arbutus Andrachne, Gaultheria, Kalmia Latiflora, Hepatitis C Virus 30, Helicobacter pylori 30, Sulphur 30, Staphylococcin, Cuprum Met 30, Zincum Met 30 etc can be used as therapeutic agents to provide the diverse types of molecular imprints required for removing the diverse types of probable molecular inhibitions in a condition of VITILIGO. These drugs could be used as single drugs, or as combinations o multiple drugs selected on the basis of the pathophysilogical studies of individual cases.
REDEFINING HOMEOPATHY 