Sunday, April 18, 2021

Vitiligo—Knowing the Basics

Figure 1.  Blaschko's lines (source: ScienceDirect.com)

Vitiligo is a disorder that causes the presence of pale patchy areas of depigmented skin on the face, hands and wrists; these patches are initially small, but often grow and change in shape.[1]  Genetic and environmental factors are important in the pathogenesis of vitiligo. There are many therapies for vitiligo, the most used are local steroids and ultraviolet light.


Segmental Vitiligo (SV) vs Nonsegmental Vitiligo 


Vitiligo results from autoimmune destruction of melanocytes,[21]  with elevated prevalence of other autoimmune diseases in patients with vitiligo and their relatives.[22] Vitiligo pathogenesis involves innate immune responses triggered by damage-associated molecular patterns (DAMPs) released by damaged melanocytes, causing downstream adaptive immune activation that drives melanocyte destruction by autoreactive cytotoxic T lymphocytes.[23] 

Vitiligo have the following characteristics:
  • Melanocytes in vitiligo patients are more susceptible to oxidative damage than melanocytes from unaffected individuals 
    • Which is due to an inherited inability to manage stressors from normal cellular processes, or exposure to environmental chemicals
    • Chemicals such as monobenzone and other phenols commonly found in commercial products (including rubber, leather products, cosmetic dyes, etc.) are well known to both induce and exacerbate vitiligo 
    • In addition to the very specific effect of phenols in melanocytes through interaction with tyrosinase, cellular stress results from oxygen and/or nutrient imbalances, chemical or physical agents, infection, inflammation, and misfolded proteins.
  • Innate immunity plays an important role too (melanocyte stress → innate immunity → adaptive immunity)[31]
    • While cellular stress in melanocytes provides a reasonable explanation for how vitiligo is induced, it cannot completely account for the disease, since stressed melanocytes remain viable. 
  • Tyrosinase is an enzyme that catalyzes melanin biosynthesis, and it is a major autoantigen that is implicated in generalized vitiligo.  
  • Critical cytokines in pathogenesis
    • Cytokine interleukin-1beta (IL-1β) is expressed at high levels in patients with vitiligo
    • IFN-γ is identified as a critical cytokine in pathogenesis[24,25]
  • Tregs are reported to be dysregulated in patients with vitiligo[26-29]
    • Disease is exacerbated in their absence, suggesting a possible role for T regulatory (Treg) suppression
    • Although there is no clear consensus on specific abnormalities (i.e. decreased numbers, skin homing defects, or functional defects)[24]
  • The deficiency of TSLP gene expression produces the dominance of the Th1 immune response, which is involved in vitiligo development.
    • TSLP gene encodes thymic stromal lymphopoietin that induces naive CD4+ T cells to produce cytokines that induce a T helper (Th)2 response [IL-4, IL-5, IL-13, tumor necrosis factor (TNF)-α] and inhibit production of Th1cytokines [IL-10, interferon (IFN)-γ].[7]

The disorder is classified in two categories:
  • Nonsegmental vitiligo
    • Bilateral and symmetrical distribution of depigmented macules.
    • Genetic studies concern mainly patients with NSV.  
      • Up to now, about 36 NSV susceptibility loci have been identified: 90% encode immunoregulatory proteins; 10% encode melanocyte proteins. 
  • Segmental vitiligo
Figure 2.  Interferon-mediated antiviral responses and diseases (Source: [18])


CXCL10


It has been recently reported that the serum and/or the tissue CXCL10 expressions are increased in organ specific autoimmune diseases, which include vitiligo. Determination of high level of CXCL10 in peripheral liquids is a marker of host immune response, especially of a Th1 orientated immune response.
A critical role for CXCL10 in both the progression and maintenance of vitiligo was identified and thereby support inhibiting CXCL10 (e.g. by administering CXCL10 neutralizing antibodies) as a targeted treatment strategy.[8-10]
More importantly, a recent study reports that both human vitiligo and a mouse model of vitiligo reflect an IFN-γ-specific Th1 immune response in the skin that involves the IFN-γ-dependent chemokines CXCL9, 10, and 11:[8]
Melanocyte-specific CD8+ T cells expressed CXCR3 (the common receptor for CXCL9, CXCL10 and CXCL11, unlike healthy controls.
In a mice study, autoreactive T cells express CXCR3, similarly to what observed in humans with disease.
In inflamed tissues recruited Th1 lymphocytes are responsible for enhanced IFN-γ and TNF-α production, which in turn stimulate CXCL10 secretion from a variety of cells, therefore creating an amplification feedback loop.[11]
CXCL10 is secreted by several cell types in response to IFN-γ. These cell types include monocytes, endothelial cells and fibroblasts.[12] CXCL10 has been attributed to several roles, such as chemoattraction for monocytes/macrophages, T cells, NK cells, and dendritic cells, promotion of T cell adhesion to endothelial cells, antitumor activity, and inhibition of bone marrow colony formation and angiogenesis.[13-14]

Simvastatin—a Potential Treatment Option


On the base of the results obtained from an important study,[8] it was evaluated the effect of inhibition of IFN-γ in vitiligo. STAT1 activation is required for IFN-γ signaling and recent studies revealed that simvastatin, an FDA-approved cholesterol-lowering medication, inhibited STAT1 activation in vitro.[15] Therefore, it was hypothesized that simvastatin may be an effective treatment for vitiligo.

In fact, simvastatin both prevented and reversed depigmentation in the mouse model of vitiligo, and reduced the number of infiltrating autoreactive CD8+ T cells in the skin. Treatment of melanocyte-specific, CD8+ T cells in vitro decreased proliferation and IFN-γ production, suggesting additional effects of simvastatin directly on T cells. Based on these data, it has been suggested that simvastatin may be a safe, targeted treatment option for patients with vitiligo.[15] However, the clinical trial finished in 2016 and the result was not ideal as the author explained in his review article:
Vitiligo Simvastatin Clinical Trial Results

References

  1. Taïeb A, Picardo M. Clinical practice. Vitiligo. N Engl J Med 2009;360:160-9.
  2. The role of the Th1 chemokine CXCL10 in vitiligo
  3. World Vitiligo Day: 10 Effective Home Remedies To Treat Vitiligo
  4. Are You Th1 or Th2 Dominant?
  5. Blaschko lines and other patterns of cutaneous mosaicism
  6. Jin Y, Birlea SA, Fain PR, et al. Variant of TYR and autoimmunity susceptibility loci in generalized vitiligo. N Engl J Med 2010;362:1686-97.
  7. Soumelis V, Reche PA, Kanzler H, et al. Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat Immunol 2002;3:673-80.
  8. Rashighi M, Agarwal P, Richmond JM, et al. CXCL10 is critical for the progression and maintenance of depigmentation in a mouse model of vitiligo. Sci Transl Med 2014;6:223ra23.
  9. Zhang S, Liu S, Yu N, et al. RNA released from necrotic keratinocytes upregulates intercellular adhesion molecule-1 expression in melanocytes. Arch Dermatol Res 2011;303:771-6.
  10. Harris JE, Harris TH, Weninger W, et al. A mouse model of vitiligo with focused epidermal depigmentation requires IFN-γ for autoreactive CD8+ T-cell accumulation in the skin. J Invest Dermatol 2012;132:1869-76.
  11. Antonelli A, Ferrari SM, Giuggioli D, et al. Chemokine (C-X-C motif) ligand (CXCL)10 in autoimmune diseases. Autoimmun Rev 2014;13:272-80.
  12. Luster AD, Unkeless JC, Ravetch JV (1985). "Gamma-interferon transcriptionally regulates an early-response gene containing homology to platelet proteins". Nature. 315 (6021): 672–6.
  13. Dufour JH, Dziejman M, Liu MT, Leung JH, Lane TE, Luster AD (April 2002). "IFN-gamma-inducible protein 10 (IP-10; CXCL10)-deficient mice reveal a role for IP-10 in effector T cell generation and trafficking". Journal of Immunology. 168 (7): 3195–204.
  14. Angiolillo AL, Sgadari C, Taub DD, Liao F, Farber JM, Maheshwari S, et al. (July 1995). "Human interferon-inducible protein 10 is a potent inhibitor of angiogenesis in vivo". The Journal of Experimental Medicine. 182 (1): 155–62.
  15. Agarwal P, Rashighi M, Essien KI, et al. Simvastatin Prevents and Reverses Depigmentation in a Mouse Model of Vitiligo. J Invest Dermatol 2015;135:1080-8.
  16. N-Acetylglucosamine Inhibits T-helper 1 (Th1)/T-helper 17 (Th17) Cell Responses and Treats Experimental Autoimmune Encephalomyelitis
  17. Association of a Marker of N-Acetylglucosamine With Progressive Multiple Sclerosis and Neurodegeneration
  18. Regulation of RIG-I-like receptor-mediated signaling: interaction between host and viral factors
  19. Jin, Y. et al. Genome-wide association analyses identify 13 new susceptibility loci for generalized vitiligo. Nat. Genet. 44, 676–680 (2012).
  20. Jin, Y., Andersen, G. H. L., Santorico, S. A. & Spritz, R. A. Multiple Functional Variants of IFIH1, a Gene Involved in Triggering Innate Immune Responses, Protect against Vitiligo. J. Invest. Dermatol 137, 522–524 (2017).
  21. Picardo M. Taïeb A. Vitiligo. Springer, Heidelberg & New York2010
  22. Alkhateeb A., Fain P.R., Thody A., Bennett D.C., Spritz R.A. Epidemiology of vitiligo and associated autoimmune diseases in Caucasian probands and their families.Pigment Cell Res. 2003; 16: 208-214.
  23. Richmond J.M., Frisoli M.L., Harris J.E. Innate immune mechanisms in vitiligo: danger from within.Curr Opin Immunol. 2013; 25: 676-682.
  24. Gregg RK, Nichols L, Chen Y, Lu B, Engelhard VH. Mechanisms of spatial and temporal development of autoimmune vitiligo in tyrosinase-specific TCR transgenic mice. J Immunol. 2010;184:1909–1917.
  25. Harris JE, Harris TH, Weninger W, Wherry EJ, Hunter CA, Turka LA. A mouse model of vitiligo with focused epidermal depigmentation requires IFN-gamma for autoreactive CD8(+) T-cell accumulation in the skin. J Invest Dermatol. 2012;132:1869–1876.
  26. Klarquist J, Denman CJ, Hernandez C, Wainwright DA, Strickland FM, Overbeck A, Mehrotra S, Nishimura MI, Le Poole IC. Reduced skin homing by functional Treg in vitiligo. Pigment Cell Melanoma Res. 2010;23:276–286.
  27. Tu CX, Jin WW, Lin M, Wang ZH, Man MQ. Levels of TGF-beta(1) in serum and culture supernatants of CD4(+)CD25 (+) T cells from patients with non-segmental vitiligo. Arch Dermatol Res. 2011;303:685–689. 
  28. Lili Y, Yi W, Ji Y, Yue S, Weimin S, Ming L. Global activation of CD8+ cytotoxic T lymphocytes correlates with an impairment in regulatory T cells in patients with generalized vitiligo. PLoS One. 2012;7:e37513. 
  29. Zhou L, Li K, Shi YL, Hamzavi I, Gao TW, Henderson M, Huggins RH, Agbai O, Mahmoud B, Mi X, et al. Systemic analyses of immunophenotypes of peripheral T cells in non-segmental vitiligo: implication of defective natural killer T cells. Pigment Cell Melanoma Res. 2012;25:602–611.
  30. N-ACETYL GLUCOSAMINE
  31. Shi F, Kong BW, Song JJ, Lee JY, Dienglewicz RL, Erf GF. Understanding mechanisms of vitiligo development in Smyth line of chickens by transcriptomic microarray analysis of evolving autoimmune lesions. BMC Immunol. 2012;13:18.
  32. Phenol
    • Phenol derivatives have been used in the preparation of cosmetics including sunscreens,hair colorings, skin lightening preparations, as well as in skin toners/exfoliators. However, due to safety concerns, phenol is banned from use in cosmetic products in the European Union and Canada.
  33. Damage-Associated Molecular Patterns in Inflammatory Diseases
  34. Oral Gliadin-Protected Superoxide Dismutase in Addition to Phototherapy for Treating Non-segmental Vitiligo: A 24-Week Prospective Randomized Placebo-Controlled Study
Posted by at
Labels: , , , , , , , , ,

No comments:

Post a Comment

Subscribe to: Post Comments (Atom)