YENİ İLAÇ MI GELİYOR?

Ritlecitinib (Pfizer tarafından LITFULO ticari adıyla), yakın zamanda ABD ve Japonya'da şiddetli alopesi areata tedavisi için onaylanan anti-enflamatuar ve immünosupresif bir ilaçtır. İlaç, hepsi oto-immün bozukluklar olarak kabul edilen vitiligo, ülseratif kolit ve Crohn hastalığının tedavisi için test edilmektedir (Blair, 2023).

RITLECITINIB NASIL ÇALIŞIR?

Vitiligo bir oto-immün bozukluktur, yani vücudun bağışıklık sistemi yanlışlıkla kendi hücrelerine - melanositlere (pigment hücreleri) saldırır ve yok eder, bu da beyaz lekelerin oluşmasına neden olur. Bağışıklık sistemi inanılmaz derecede karmaşıktır ve çeşitli yollardan ve sinyal moleküllerinden oluşur. Ritlecitinib bir kinaz inhibitörü olarak kabul edilir, yani bağışıklık sistemindeki belirli proteinler olan kinazların düzgün çalışmasını engeller. Bu da oto-immün hastalıkların gelişimine katkıda bulunduğu düşünülen bağışıklık yollarını bloke ederek, vitiligoda yeniden pigmentasyon veya hastalığın ilerlemesinin durdurulması gibi semptomlarda iyileşme sağlar (Xu ve ark., 2019; Pfizer Inc., 2023).

RITLECITINIB VE VITILIGO - YENI BIR ÇALIŞMA

Vitiligo tedavisinde ritlecitinib'in etkinliğine ilişkin 48 hafta süren faz 2b klinik çalışması Şubat 2023'te yayınlanmıştır (Ezzedine ve ark., 2023). Çalışma, çeşitli dozlarda ritlecitinib alan hasta gruplarını bir plasebo grubu ile karşılaştırmıştır. Çalışma, yüzdeki vitiligo lezyonlarının oranındaki değişiklikleri (Facial-Vitiligo Area Scoring Index, F-VASI) değerlendirmiş ve günde bir kez alınan 50 mg'lık bir tabletin önemli iyileşmelerle sonuçlandığını (24 haftada plaseboya kıyasla F-VASI'de %75'e varan azalma) bulmuştur. Repigmentasyon başlangıç tarihinden 8 hafta sonra başlamış, 28 hafta sonra hızlanmış ve denemenin sona erdiği 48 haftaya kadar gözlenmiştir. Ritlecitinib'in etkinliğini ölçmenin bir başka önemli yolu daha vardı: Hastalardan durumlarının ne kadar değiştiğini hissettiklerini bildirmelerini isteyen 1 maddelik bir anket olan Patient Global Impression of Change-Vitiligo (PGIC-V) skoru. Yanıtlar 'çok iyileşti' ile 'çok kötüleşti' arasında değişmektedir. Tedavi edilen tüm gruplardaki hastalar 'çok iyileşti' veya 'çok iyileşti' gibi anlamlı değişiklikler bildirmişlerdir ve bu tür değişiklikleri bildiren hastaların en yüksek oranı çalışmanın 48. haftasında görülmüştür. Çalışma aynı zamanda ritlecitinib'in güvenliğini de ölçmüş ve öksürük, boğaz ağrısı ve baş ağrısı gibi hafif yan etkileri olan güvenli bir ilaç olduğunu ortaya koymuştur. Yan etkiler muhtemelen ilacın vücudun bağışıklık savunmasını düşürmesi ve enfeksiyonlara daha yatkın hale getirmesi nedeniyle ortaya çıkmıştır. Genel olarak, çalışma ritlecitinib'in aktif non-segmental vitiligo hastaları için etkili ve iyi tolere edilen bir tedavi olduğunu göstermiştir.

ŞİMDİ NE OLACAK?

Ezzedine ve arkadaşları (2023) tarafından yapılan çalışma bir faz 2b çalışmasıydı, yani vitiligoda ritlecitinib'in etkinliğini ve güvenliğini nispeten küçük bir hasta grubunda test etti. Şu anda devam etmekte olan ve tahmini tamamlanma tarihi Haziran 2025 olan bir faz 3 çalışması (NCT05583526; Pfizer, 2023) bulunmaktadır. Bu çalışmanın sonuçlarına bağlı olarak, ritlecitinib vitiligo tedavisi için onaylanabilir.

Reference: https://vitiligosociety.org/vitlife/ritlecitinib-a-new-vitiligo-treatment/

Vitiligolularda Ölüm Riski Daha Düşük!

Kore'de yayınlanan yakın tarihli bir araştırmaya göre, vitiligolu hastalarda ölüm şansı düşük olabilir.

Nüfusa dayalı kohort çalışmasında, bu hastalar arasındaki ölüm riskleri hakkında sınırlı bilgi olduğundan araştırmacılar vitiligonun ölüm oranını araştırdı. Araştırmacılar, ülke çapında bir veri tabanı kullanarak vitiligolu hastaların tüm nedenlere ve nedene özel ölümlerini, vitiligosuz kontrollerle karşılaştırarak araştırdılar.

Çalışmanın yazarları, ulusal bir kohortta vitiligo mortalitesinin araştırılmasının, otoimmün hastalığın yükünün daha iyi anlaşılmasına olanak sağlayacağını ve doğasının daha iyi anlaşılmasına yol açacağını iddia ediyor.

Çalışmaya Kore'de 2002 ile 2019 yılları arasında gözlemlenen vitiligolu toplam 107.424 hasta ve vitiligosuz 537.120 eşleştirilmiş kontrol dahil edildi. Dahil edilen hastaların ortalama yaşı ~48 idi ve %39,61'i erkekti.

Hastaların tıbbi kayıtları kapsamlı bir şekilde analiz edildi ve vitiligosu olan bireylerin çeşitli hastalıklarda ölüm risklerinin önemli ölçüde azaldığını ortaya çıkardı.

Çalışma, bu bulgulardan enfeksiyöz, onkolojik, hematolojik, endokrin, nörolojik, kardiyovasküler, solunum ve böbrek/ürogenital hastalıklarla ilişkili risklerin vitiligo hastalarında belirgin şekilde daha düşük olduğunu ortaya çıkardı.

Önceki çalışmalar, vitiligonun çeşitli otoimmün hastalıklarla birlikte ortaya çıktığını vurgulamış ve bağışıklık aktivasyonu ve düzenlenmesinde yer alan ortak genetik değişikliklere işaret etmiştir. Yazarlar, melanosit yıkımına katkıda bulunanlar olarak spesifik bağışıklık tepkilerinin tanımlandığını paylaştı.

Bu çalışmayı farklı kılan şey, vitiligo'nun özellikle enfeksiyonlar, iltihaplanma ve kanserler söz konusu olduğunda ölüm oranlarına karşı koruyucu bir etki göstermesidir.

Araştırmacılar, hücresel homeostazı düzenleyen bir kendi kendine bozulma süreci olan vitiligodaki otofajinin rolünün de bulgularıyla ilişkili olabileceğini öne sürüyorlar.

Önceki çalışmalar, vitiligo derisinde artan otofaji belirteçlerinin ekspresyonunun, metabolik strese ve dış dejeneratif süreçlere karşı koruyucu bir rol oynayabileceğini öne sürüyor. Ayrıca otofajinin doğuştan gelen bağışıklık sistemini düzenlemesi viral enfeksiyonlara karşı savunma sağlayabilir.

Çalışma aynı zamanda vitiligosu olan hastalarda malignite riskinin azaldığını gösteren önceki araştırmalarla da uyumludur. Aslında vitiligosu olan kişilerde kolon, rektum, yumurtalık ve akciğer kanserleri de dahil olmak üzere iç malignitelerin riski önemli ölçüde azalmıştır. Bulgular vitiligo'nun kanser gelişimine karşı bir tür bağışıklık sağlayabileceğini düşündürmektedir.

Ek olarak, çalışma vitiligo tedavilerinin mortalitenin azaltılmasına katkı sağlamadaki rolünü de değerlendirmektedir. Vitiligo için özel olarak onaylanmış bir ilaç bulunmamakla birlikte, fototerapi gibi tedavilerin sağlık üzerinde daha geniş etkileri olabilir.

Örneğin çalışmalar, fototerapinin bir bileşeni olan ultraviyole B radyasyonunun derinin ötesindeki iç organları etkileyebileceğini, ateroskleroz riskini azaltmak ve kan basıncını iyileştirmek gibi faydalar sağlayabileceğini ileri sürdü.

Ancak çalışmanın, hastalığın ciddiyeti ve vitiligo alt tipleri hakkında bilgi bulunmaması, potansiyel ölçülemeyen faktörler ve farklı popülasyonların gözlemlenmemesi gibi bazı sınırlamaları vardır.

Araştırmanın yazarları, bulguların vitiligo ile ilişkili ölüm risklerine katkıda bulunduğunu ve otoimmün durumların sonuçları hakkındaki önceki inançları çürüttüğüne inanıyor.

Vitiligo hastalarında gözlemlenen beklenmedik koruyucu etkilerin, altta yatan mekanizmaların ve hasta yönetimine yönelik potansiyel sonuçların ortaya çıkarılması için daha fazla araştırmaya açık yollar olduğunu eklediler.

Referans

1. Ju HJ, Kang H, Han JH, Lee JH, Lee S, Bae JM. All-cause and cause-specific mortality among patients with vitiligo: a nationwide population-based study in Korea. J Invest Dermatol. 2023;S0022-202X(23)02481-8. doi:10.1016/j.jid.2023.07.007

Newly Discovered Genes Could Change Vitiligo Treatment

 

A recent study has revealed 135 previously unknown genes that play important roles in regulating melanin production in humans—and that could lead to melanin-modifying drugs for vitiligo and other pigmentation diseases.

The research team was led by Vivek Bajpai, assistant professor in the School of Sustainable Chemical, Biological and Materials Engineering at the University of Oklahoma, with collaborators from Stanford University, where Bajpai did postdoctoral work.

Melanin synthesis is compartmentalized within the melanosome, in specialized pigment cells (melanocytes). The synthesis of melanin within the melanosomes varies, which is why human skin, hair, and eye color vary. Pigmentation-related diseases are associated with disruptions in melanogenesis.

Melanin’s particular physicochemical properties, such as high refractive index, determine its optical properties, the researchers wrote in their article, published in Science on Aug. 11. “We reasoned that an accumulation of melanin within melanosomes would change melanocytes’ light-scattering properties.”

Bajpai developed a novel method to detect and quantify the melanin-producing activity of melanocytes: Passing light through the melanocytes, he could record whether the light was absorbed or scattered by the melanin. “If there are a lot of melanin-producing melanosomes,” he said in a University of Oklahoma press release, “the light will scatter much more than in cells with little melanin.”

The team measured light scattering through flow cytometry, capturing “dynamic shifts” in melanin levels within melanosomes. They used CRISPR-Cas9 technology to genetically engineer cells, and conducted a genome-wide genetic screen, systematically removing more than 20,000 genes from hundreds of millions of melanocytes.

Their screen identified 169 genes, including some that were previously known and 135 new melanin-promoting genes whose deletion was associated with reduced light scattering—in other words, loss of melanin.

The melanin-promoting genes are involved in diverse biological pathways, such as transcription regulation, RNA processing, and endosomal transport, the researchers say. “Consistent with their melanin-promoting role, the expression of the majority of our screen hits is elevated in darkly pigmented, compared with lightly pigmented, human melanocytes. Our analyses revealed that select melanin-promoting genes are associated with skin color variation and show evidence of local adaptation in human populations.”

By focusing on specific previously unidentified candidates, the researchers say, “we implicated a new cargo recycling pathway in melanosome function and identified a transcription factor involved in melanosome maturation. Our work provides a rich resource for further studies of melanogenesis and its relationship with skin color variation and human diseases.”

Their findings are also meaningful to a broad swath of science beyond dermatology. Bajpai’s method of targeting melanin-producing genes could lead to prevention of fungi- and bacteria-related diseases in humans and crops.

Reference: https://www.managedhealthcareexecutive.com/view/newly-discovered-genes-could-change-vitiligo-treatment

Cilt rengiyle ilişkili 135 yeni gen tespit edildi

 

İnsanlara cilt rengini veren pigmentasyonla ilgili 135 yeni gen tanımlandı. ABD'de yapılan araştırmadaki bulguların cilt kanseri ve vitiligo tedavilerinde yeni ilaç ve yol arayışına yön vermesini bekleniyor.

News Medical Life Sciences; Oklahoma Üniversitesi'nden Vivek Bajpai ve Stanford Üniversitesi'nden araştırmacılar tarafından yapılan çalışmada, insanlara cilt rengini veren pigmentasyonla ilişkili 135 yeni gen tanımlandığını yazdı. Araştırmacılar, cilt pigmenti de olarak da tanımlanan melanin üretimini etkileyen, işlevsel olarak farklı 169 gen bulurken bunlardan 135'inin daha önce pigmentasyon ile ilişkili olmadığı tespit edildi.

Araştırmaya göre, yeni keşfedilen KLF6 ve COMMD3 isimli iki genden KLF6 isimli DNA bağlayıcı protein, insanlarda ve hayvanlarda melanin üretimi kaybına yol açarken diğer türlerde ise melanin üretiminde rol oynuyor. COMMD3 ise, melanozomların asitliğini kontrol ederek melanin sentezini düzenliyor.

Cilt kanseri araştırmalarını etkileyecek

Bajpai, çalışmayla ilgili "Melanini neyin düzenlediğini anlayarak daha açık tenli insanları melanomdan veya cilt kanserinden korumaya yardımcı olabiliriz. Bu yeni melanin genlerini hedefleyerek vitiligo ve diğer pigmentasyon hastalıkları için melanin değiştiren ilaçlar da geliştirebiliriz" açıklamasında bulundu. Araştırmacılar, bu tür melanin üreten genleri keşfederek mikroplara ve hastalıklara karşı etkili müdahaleler geliştirebilir. Araştırma, Journal Science  adlı dergide yayımlandı.

Kaynak: Gazete Oksijen

Vitiligo, Causes,Symptoms, and Treatment

 

Vitiligo is a skin disorder in which smooth white areas called macules and patches appear on a person's skin. Generally starts on the hands for arms feet and face. Globally about 1% or so of the population has Vitiligo most people who have. Vitiligo will develop the condition prior to age 40 about half develop it before age 20. Vitiligo I may have a genetic component as the condition 10 Cimarron in families. Vitiligo is sometimes associated with other medical conditions including thyroid dysfunction.There is no way to determine if it'll I will spread or remain confined to one location. Types of Vitiligo do I go can be generalized which is the most common type when macules appear in various places on the body.

Segmental which is restricted to one side of the body or one area such as the hands or face mucosal what's your fax mucous membranes of the mouth and or the genitals. 

Focal which is a rare type in which the macros are in a small area and do not spread in a certain pattern within 1 to 2 years. Tricone which means that there is a white or color lacentre been an area of lighter pigmentation and then an area of normally colored skin.

Symptoms white patches on the skin are the main side of vitiligo these patches are more common in areas where the skin is exposed to the Sun the patches maybe on the hands feet arms face and lips other common areas for white patches are the armpits and groin where the leg meets the body around the mouth eyes nostrils Naval genitals rectal areas.

Causes although the causes of Vitiligo aren't completely understood there are a number of different theories autoimmune disorder the infected person's immune system May develop antibodies that destroyed their on a science genetic factors certain factors that may increase the chance of getting Vitiligo can be inherited.

About 30% of Vitiligo cases run in families neurogenic factors a substance that is toxic to melanocytes may be released at nerve endings in the skin self-destruction a defect in the Milana size causes them to destroy themselves Google are you I may also be triggered by certain events such as physical or emotional stress because none of the explanation seemed to completely account for the condition it's possible that a combination of these factors is responsible for vitiligo.

Diagnosis usually the white patches are easily visible on the skin but Healthcare Providers can use a Wood's lamp which shines ultraviolet or UV light onto the skin to help differentiate from other skin conditions. 

     Treatment repigmentation therapy therapy camouflage therapy surgery counseling prevention since no one knows for certain what causes Vitiligo no one can tell you how to prevent it in general it is smart forever to practice safe sun exposure habits and to take good care of your skin.

Jak Inhibitors

 

Disease where the immune system attacks of pigment cells are melanocytes in the body switch to white spots open and exposed areas such as the face and hands. Patient experienced increased quality of life despite affecting about 25 to 2% of the world's. Population know medications are FDA-approved to repigment in a liger who helped evaluate. 

What's the weather in cream to see if patients maybe were pigmented. About half the patients who received the highest dose of the Medicine Group Higgins 75% or more on the face significant number of patients also repugnant at on the body as well. He should serve as smart as early as 8 weeks after starting treatment. At the top of this medicine was well-tolerated with the table for safety profile it is currently being tested in a phase 3 Program. Hopefully become the first medicine that will be approved to treat vitiligo.

What is Vitiligo

 

Vitiligo likely meaning blemish is a non contagious skin condition that is defined by patches of Discoloration or deep pigmentation. The vitiligo can affect any race or ethnicity. It tends to be more noticeable in people with darker skin Like Canadian fashion model Winnie Harlow. 

Given the effect on a person's appearance, pigment loss can really impact a person's quality of life. Which is made of a single layer of small cuboido to low column stem cells that continually divide and produce new caratinosites They continue to mature is they migrate up through the epidermal layers but the straighten baseley also contains another group of cells Melanosites which secrete the protein pigment or coloring substance called melanin Melanin is actually a broad term that constitutes several types of melanin found in people of differing skin color.

The skin is divided into three layers the epidermis dermis and hypodermis The hypodermist is made of fat and connective tissue that anchors the skin to the underlying muscle Just above is the dermis which contains hair follicles, nerves, and blood vessels and just above that the outer most layer of skin is the epidermis. The epidermis itself has multiple cell layers that are mostly caratinosites which are named for the keratin protein that they're filled with. Keratin is a strong fibers protein that allows caratinocytes to protect themselves from getting destroyed when you rub your hands through the sand at the beach Current assights start their life at the deepest layer of the epidermis called the straight and baseley or basil layer.

These sub types of melanin range in color from black to redish. To reddish yellow and their relative quantity and rate at which their metabolised define a person's skin color When karate sites are exposed to the sun they send a chemical signal to the melanosites which stimulates the melanosites into making more melanin The melanosites move the melanin into small sax called malanosomes and these get taken up by newly formed caratinocytes Which will later metabolize the melanin as they migrate into higher layers of the epidermis melanin then axes in natural sunscreen.

Because it's protein structure dissipates or scatters the UVB light which if left unchecked can damage the DNA in the skin cells inly to skin cancer. Melanice can also be found in the dermis at the base of the hair follicle And in the eye where the help color hair and the iris respectively. There's a loss of melanocytes or the absence of their function. Histologically having less melanin in the epidermis result in white deep pigmented patches these patches are classified by type There's nonsegmental vitiligo which is the more common type that affects any age group. And it occurs at various locations that are mirrored on both sides of the body.

There's also segmental vitiligo which mostly affects children And occurs in segments along a single spinal nerve typically only on one side of the body without crossing the midline The exact cause of melanocyte destruction isn't known But it does seem to be linked to both genetic and environmental triggers. In non-segmental vitilgo there seems to be an autoimmune element where immune cells attack the melanosites. Insegmental vitiligo there seemed to be neural factors. Where nerves released neurochemicals that damage the melanocytes. 

Other causes maybe that the melanosites get damaged by a build up of toxic metabolites Is they make melanin or in other metabolic pathways one interesting observation is called the cubner phenomenon. And that's when Vitiligo develops in skin soon after there's been a trauma like a cut abrasion or burn The main symptom of it a ligo is the irregular round or oval shaped patches of depigmentation appearing within normally pigmented skin The patches can range in size from millimeters to centimeters and can sometimes expand and merge with other patches over time The body hair and the iris may also be depigmented in affected areas Non-segmental vitiligo tends to affect the hands forearms, neck, scalp, feet, and face while segmental vitilgo tends to affect areas of skin near dorsal roots from the spinal cord.

Particularly in the face following the trigeminal nerve. The diagnosis of it a ligo is based on the appearance of D pigmented patches but a skin biopsy can also be done There are two main treatments. When the affected area is small, cosmetic cover up and topical immune suppressants can be applied directly to the skin. When the affected area is large systemic immune suppressant UV photo therapy skin bleaching Skin bleaching and in severe cases skin grafts can all be tried. Whatever the course of therapy sunscreen is recommended to prevent darkening of the skin areas immediately surrounding And contrasting the deep pigmentation areas and to reduce the risk of skin cancer.

Alright it's a quick vitiligo is a non contagious condition where destruction of melanosites and loss of melanin Leads to areas of deep pigmentation on the skin tends to affect the hands Arms, neck, scalp, feet, and face. Well, segmental vitiligo tends to affect the areas of skin near dorsal roots from the spinal cord Particularly in the face following the trigeminal nerve. For small areas, cosmetic cover up and topical immune suppressants can be used Areas systemic immune suppressants UV photo therapy skin bleaching and even skin grafts can be used as well Thanks for watching. If you're interested in a deeper dive on this topic take a look at us most.org where we have flashcards, question Gins and other awesome tools to help you learn medicine.

Vitiligo - Photothreapy

 

It's an autoimmune disease against the pigments within pigmentation. Science so the numbers will be the same for the pigments within then we'll be decreased we should fix all surfaces in the body including the skin and only coastal areas such as the mouth and the inner lining of the genital tract.

What causes the disease to start is still unclear but missions normally start having symptoms but the second or third decade of life because it's an autoimmune disorder is likely to have other autoimmune disorders as well. Keep in mind that fix skin is more prone to sunburns. We have for treatment we can use phototherapy which repigment melanocytes we can use tools to prevent further pigmentation in which layer of the skin do we have melanocytes.

Medical Treatment of Vitiligo

 

Skin discolorations such as vitiligo were known thousands of years ago. White spots caused by vitiligo and other disorders have caused a significant social disgrace throughout history and today for those who have been disfigured due to these pigmentary disorders. Treatments have been desperately sought with only partial success. Recent developments suggest that vitiligo and other pigment disorders may soon be cured.

Leukoderma, white spots ve vitiligo

Perfect, flawless skin color is desired by everyone for its beauty and attractiveness. However, like all biologic systems, pigmentation can be abnormal. There can be dark spots or light spots, both of which are disfiguring. These problems have caused distress to people for millennia. Already in 1500 to 1000 BCE, Indian writers described “kilas” and “palita,” translated as white or yellowish white spots.

The Ebers Papyrus describes people with white spots. In these early writings, the precise condition being described is not known, although leprosy and vitiligo are just two of many possible candidates. There are numerous references to white spots in the Old Testament. Typically these were considered leprosy but it is plausible that much of what was considered to be leprosy was vitiligo or other disorders of skin color.

In the Far East prayers known as Makatominoharai dating from 1200 BCE recognized white skin, possibly vitiligo. In the sixteenth century, Hieronymus Mercurialis6 published his book on diseases of the skin. In it he devotes an entire chapter, entitled “On Leuce and Alphos,” to disorders of abnormal skin color.

He cites early Arabic, Greek, and Latin scholars about white spots and notes that the word “…‘vitiligo’ is a Latin word derived from either ‘vitium’ (blemish) or ‘vitulum’ (small blemish)…” The word vitiligo might have been first used by Celsus. Mercurialis suggests that phlegm accumulating under the skin was the source of leukoderma, a theory that he confirms from the writings of “…divine Plato…that white phlegm has two effects in the body….if it begins to vent through the exterior of the body, it will cause …vitiligo.”

Herodotus in Greece noted white spots on foreigners and suggested they be banished immediately, their having sinned against the sun. In China and Korea, writers discussed white spots and white skin. In Korea vitiligo and other pigmentary disorders, such as nevus depigmentosus or tinea versicolor, were described in Doney Bogam, published in the seventeenth century.

A portrait of Chang-Myeong Song, a high ranking official of the Yi dynasty of Korea, was painted about this time that shows the typical depigmentation of vitiligo. In the seventeenth century, William Byrd described “An Account of a Negro-Boy that is, dappel’d in several places of his Body with White Spots.” The depigmentation began at age 3 years and continued to spread. Byrd conjectures that in time the boy would become all white. The leukoderma was obviously mysterious in origin.

Study skin, color, white spots

Skin color was a mystery until modern times after the invention of the microscope, the techniques of biopsy, and the discovery of histochemical stains. Before the seventeenth century, the origin of skin color was based on myths, folklore, and religious theories. Explanations attempted to explain the origin of dark skin color, not why some skin was very light. Jean Roland in separated the epidermis from the dermis of a black individual.

He was able to observe the upper layer of skin (epidermis) was pigmented, the lower dermal layer not pigmented. He proposed that sunlight and heat caused dark skin, a theory that might explain dark skin at the equator but not why Europeans remained white when traveling to southern climes. Another scientist, Thomas Browne, noted this discrepancy and decided skin color was a genetic trait carried within the sperm.

Theories about the mechanism for production of skin color came and went. Many famous investigators all studied skin color usually in deeply pigmented Ethiopians, often on cadavers but occasionally in living subjects. However, without proper instruments and techniques, the origins of pigmentation remained a mystery. More mysterious back then were the mechanisms for loss of skin color. Benjamin Rush suggested that black skin of Negroes was a form of leprosy and that vitiligo was an indication of spontaneous cure.

Skin Color and Melanin System

 

The skin is a complex organ system capable of going through a wide variety of color changes. Normal skin color arises from a mixture of red, blue, yellow and brown colored pigments. In normal skin, melanin is the main pigment or color determinant, giving a color ranging from very light tan to dark brown or black, depending on the amount of melanin in the epidermis. It can be given a yellow color by carotenoids, red by oxygenated hemoglobin in capillaries, and blue by reduced hemoglobin in dermal venules and pigment in the dermis. Melanin is synthesized by a special cell, melanocyte, which is a dendritic cell located in the basal layer of the epidermis, but some melanocytes higher in the epidermis and a few in the dermis.

The melanin pigment system consists of millions of such melanocytes, each of which is functionally associated with 36 keratinocytes; This cluster of keratinocyte and associated melanocyte is referred to as the "epidermal melanin unit", which appears to be a structural and functional entity. Within each working melanocyte, melanin is synthesized and packaged in special pigment organelles called "melanosomes". The dendritic processes of melanocytes project between keratinocytes so that a single melanocyte supplies melanosomes to 36 keratinocyte groups.

Melanine migrate

These melanosomes migrate centrifugally through the dendritic processes of melanocytes and are then transferred to or captured by keratinocytes. Although the number of active epidermal melanin units per unit area varies considerably in various regions of human skin, the keratinocyte/melanocyte ratio remains constant. The epidermal melanin unit has been suggested to be the functional integrator of the multicellular melanin pigmentation system in humans and animals.

Although skin color can be conceptually thought of as a mixture of the colors red, blue, yellow, and brown above, racial differences in normal skin color and skin color are a function of the number, size, and distribution of melanin-laden organelles.

Melanosomes

It is the melanosomes that are distributed into the keratinocytes that give the skin its color. In the absence of disease, other color contributors play a minor or insignificant role. Therefore, in the absence of melanin, the skin remains essentially white, as in tyrosinase-negative albinism or vitiligo macules. Recent evidence that the movement of keratinocytes within the epidermis is more complex than originally thought is not inconsistent with the concept of the epidermal melanin unit.

Keratinocytes activite

Keratinocytes do not divide randomly in the germinal layer of certain types of human and mouse epidermis. Mitoses can also occur in suprabasilar keratinocytes. According to the epidermal proliferation unit concept, young basal cells divide and move peripherally in the epidermis before final division and formation of regular columns of cornified cells.

Each or several epidermal proliferative units can then be associated with a donor melanocyte. The study of the melanin-producing mechanism should be approached at five scientific levels: macromolecular (visual) - skin viewed as an organ system; multicellular (histological)-epidermal melanin unit; cellular-melanocytes as unicellular glands; subcellular (electron microscopic)- melanosome as a metabolic unit of melanogenesis; and macromolecular (biochemical)-tyrosinase, enzyme and melanoprotein, the end product of melanogenesis.

Types of melanin

 

There are three different types of melanin: eumelanin, pheomelanin, and neuromelanin. Eumelanin is the brown-black pigment of skin and hair and is most responsible for skin color. Phaeomelanin is a red-yellow pigment found in human hair. Neuromelanin is found in neurons of the central nervous system, adrenal medulla, and other areas of the chromaffin system.

Eumelanin

Eumelanin is a high molecular weight polymer whose exact molecular structure has not yet been determined, in part because eumelanin is insoluble in most solvents and resists most chemical changes and degradation.

Observations based on Raper's work with plant tyrosinases and modified by Mason led to the conclusion that melanin is a polymer composed of indole5,6-quinone units. However, the use of labeled antecedents showed that this was an oversimplification.

The ratio, molecular chain length, and molecular weight of the various subunits of eumelanin are still unknown. Blois et al. thinks that melanin is a highly disordered three-dimensional polymer joined by covalent bonds. Melanin has a free radical character associated with the semi-quinonoid form of 5,6-dihydroxyindole, which is highly stabilized by resonance through the conjugated polymer. Can act as a mild free radical quencher and also have some weak acid cation exchange abilities. Skin Melanin has specific absorption peaks at 3 and 6 J.L. only in the infrared region; however, it shows a broad absorption band between 200 and 2400 nm, which is not quite specific.

Phaeomelanin

Phaeomelanins are yellow and red sulfur-containing pigments found in mammalian hair. Unlike eumelanin, pheomelanin is soluble in dilute alkali. Pheomelanins, like eumelanin, are derived from tyrosine via dopaquinone. However, it is the interaction of cysteine ​​with dopaquinone at this level that results in the synthesis of pheomelanin. By adding 1,6 cysteine ​​to dopaquinone, 13-(5-S-cysteinyl-3,4-dehydroxyphenyl)alanine or 2-S-cysteinyldopa is formed. This is further oxidized to form pheomelanin. A minor product of the addition of 1.6 may be 2-S-cysteinyldopa.

Sulfhydryl compounds are involved in in vivo synthesis; indeed, under some experimental conditions, sulfhydryl compounds can induce pigment cells to produce yellow pigment. The interesting genetic control influencing the common pathway of eumelanin and pheomelanin synthesis is mirrored in the agouti mouse, which has only a few subapical pheomelanoms, the rest of which are eumelanogenic. Follicular melanocytes initially produce brown-black eumelanin, temporarily switch to yellow pheomelanin production, and soon revert to the original eumelanin synthesis.

Guinea pig studies have shown that melanosomes in red or yellow follicles are spherical, while those of black follicles are ellipsoidal. Various differences in biochemical behavior were observed between eumelanin and pheomelanin.

It has been shown that more sulfhydryl compounds, including glutathione and cysteine, are more incorporated into pheomelanogenic melanocytes and pheomelanin than eumelanic melanocytes and eumelanin. In the presence of sufficient reduced glutathione in vitro, only melanocytes that synthesize eumelanin in vivo produce pheomelanin. It has been suggested that the agouti band in the agouti mouse is derived from cyclically altered competition patterns by keratinocytes and melanocytes for substrate common to hair growth and melanogenesis.

Therefore, it was suggested that cyclical changes in the type of melanin synthesized might involve histochemical changes, not genetic intervention. Knisely et al. corroborating these findings with yellow (AY/a) samples in similar conditions and cultures of (A/A) agouti skin may be related to such histochemical factors not present in these systems.

Although cysteine ​​is an established substrate for pheomelanogenesis, cysteinyldopa and pheomelanin can be produced by eumelanogenic melanocytes. It has also become clear that there is a third melanocyte pigment called trichochrome, which has dopaquinone as a critical intermediate, such as eumelanin and pheomelanin. The factors that favor one final path over another remain unclear.

Neuromelanin

The trigeminal and dorsal root ganglia, substantia nigra, locus caeruleus, and pigmented nuclei of the basal ganglia contain cytoplasmic organelles containing a brown pigment called "neuromelanin." There seem to be significant differences between eumelanin and neuromelanin.

Since patients with oculocutaneous albinism have a normal amount of neuromelanin, it seems unlikely that neuromelanin is formed by the action of tyrosinase. There are other important differences between melanin and neuromelanin.

Pigment particles of the substantia nigra appear to have a higher electron density than melanosomes, a size of 0.5 to 2.5 f.L, a single limiting membrane, and the longitudinal or diagonal striations typical of eumelanin melanosomes. The presence of labeled tyrosine in the area of ​​pigmented granules in neurons convinced the researchers that tyrosine must be present.

The enzyme that catalyzes the hydroxylation of tyrosine to dopa is probably tyrosine hydroxylase and not the copper-requiring oxidase tyrosinase. Since tyrosine hydroxylase only catabolizes CNS tyrosine, disorders of eumelanin synthesis and CNS abnormalities should not be expected, and neuromelanin disorders (such as Parkinson's disease) should not be expected to have obligatory abnormalities of cutaneous eumelanogenesis.