Please note: In my book, Rosacea 101, (published in October 2007) in Chapter 3, What Causes Rosacea?, page 18, I mention the UCSD cutting edge research on cathelicidin, an alarmin, that was announced in August 2007. You may want to read more about what causes rosacea since my book is a comprehensive knowledge base for conventional and alternative treatements for rosacea 'newbies' which is a must have for those who want in one book what they should know about rosacea.
Copyright 2010 Brady Barrows
Alarmins are "antimicrobial peptides (AMPs) such as defensins and cathelicidins*, which not only kill microbes but also trigger host-tissue responses, including leukocyte chemotaxis, angiogenesis, expression of extracellular matrix components, and inflammation."** Abnormal levels of cathelicidin LL37*** in the skin have been linked to rosacea. In August 2007 major newspapers across the country said scientists have found the cause of rosacea. For instance the Los Angeles Times, the Washington Post, and Medical News Today all had headlines discussing this subject. Here is the actual abstract from Nature Medicine. Does it claim that the cause of rosacea has really been found?
Richard L. Gallo and colleagues noticed that patients with rosacea had elevated levels of cathelicidin and elevated levels of stratum corneum tryptic enzymes (SCTEs). Cathelicidin antimicrobial protein is an antimicrobial protein found in specific granules of polymorphonuclear leukocytes (PMNs). Stratum Corneum Tryptic Enzyme (SCTE) is part of the the kallikrein family protease. Antibiotics have been used in the past to treat rosacea, but antibiotics may only work because they inhibit some SCTEs.
Begin Abstract
Increased serine protease activity and cathelicidin promotes skin inflammation
in rosacea
Kenshi Yamasaki, Anna Di Nardo, Antonella Bardan, Masamoto Murakami, Takaaki
Ohtake, Alvin Coda1, Robert A Dorschner1, Chrystelle Bonnart, Pascal Descargues, Alain Hovnanian, Vera B Morhenn & Richard L Gallo
Nature Medicine, 5 August 2007 | doi:10.1038/nm1616
Acne rosacea is an inflammatory skin disease that affects 3% of the US population over 30 years of age and is characterized by erythema, papulopustules and telangiectasia1, 2, 3. The etiology of this disorder is unknown, although symptoms are exacerbated by factors that trigger innate immune responses, such as the release of cathelicidin antimicrobial peptides4. Here we show that individuals with rosacea express abnormally high levels of cathelicidin in their facial skin and that the proteolytically processed forms of cathelicidin peptides found in rosacea are different from those present in normal individuals. These cathelicidin peptides are a result of a post-translational processing abnormality associated with an increase in stratum corneum tryptic enzyme (SCTE) in the epidermis. In mice, injection of the cathelicidin peptides found in rosacea, addition of SCTE, and increasing protease activity by targeted deletion of the serine protease inhibitor gene Spink5 each increases inflammation in mouse skin. The role of cathelicidin in enabling SCTE-mediated inflammation is verified in mice with a targeted deletion of Camp, the gene encoding cathelicidin. These findings confirm the role of cathelicidin in skin inflammatory responses and suggest an explanation for the pathogenesis of rosacea by demonstrating that an exacerbated innate immune response can reproduce elements of this disease.
1. Division of Dermatology, University of California, San Diego, and VA San
Diego Health
Care System, 3350 2. La Jolla Village Drive, San Diego, California 92161, USA.
3. Department of Dermatology, Asahikawa Medical College, Asahikawa 078-8510,
Japan.
4. Department of Medicine, Asahikawa Medical College, 2-1-1-1 Midorigacka
Hidashi,
Asahikawa 078-8510, Japan.
5. INSERM, U563, Toulouse F-31000, France.
Université Paul-Sabatier, Toulouse F-31000, France.
6. CHU Toulouse, Department of Genetics, Place du Dr. Baylac, Toulouse F-31000,
France.
--------------------End Abstract
It appears that this team of scientists may be on to something, but as for finding the cause of rosacea, this appears to be a bit premature, but of course, most rosaceans are excited and hopeful about this research.
According to one report by Jen Christensen of WHOI, "skin samples and biopsies from rosacea patients had significantly higher levels of cathelicidin. In addition, the cathelicidin found in rosacea patients was a different form than that found in people without rosacea.
Researchers also found patients had higher levels of an enzyme called stratum corneum tryptic enzyme (SCTE). This enzyme appears to convert the cathelicidin into another peptide that triggers rosacea symptoms.
Dermatologist Richard Gallo, M.D., Ph.D., says the findings explain why tetracycline, a type of antibiotic, reduces symptoms in some patients with rosacea. Tetracycline inhibits the enzymes that convert the cathelicidin into an inflammatory peptide. But it doesn’t work for everyone. In the future, Gallo would like to see the development of medications that specifically target the enzyme or the proteins and prevent the onset of rosacea symptoms." Source
Here is another report on this subject that needs further explanation:
The Epidermal Vitamin D System and Innate Immunity: Some More Light Shed on This Unique Photoendocrine System?
Siegfried Segaert, Thierry Simonart
Department of Dermatology, University Hospital Leuven, Leuven, and
Department of Dermatology, Hôpital Universitaire Erasme, Brussels, Belgium
Dermatology 2008;217:7-11 (DOI: 10.1159/000118506)
Click here for some explanation of the above report.
"Skin biopsies of patients with rosacea and normal controls were compared, and the rosacea samples had elevated cathelicidin based on immunostaining and analysis of cathelicidin mRNA....Rosacea samples had elevated abundance of SCTE compared with normal skin samples, and protease activity was also elevated based on in situ zymography. To ascertain whether the elevated active cathelicidin peptides could contribute to the rosacea symptoms, the most abundant peptides, LL-37 and FA-29, from the rosacea samples were added to cultured human keratinocytes or injected subcutaneously into mice. These rosacea-enriched peptides stimulated interleukin-8 production from the keratinocytes and caused erythema, vascular dilation, neutrophil infiltration, thrombosis, and hemorrhage in the injected skin."
Sci. STKE, 14 August 2007
Vol. 2007, Issue 399, p. tw290
[DOI: 10.1126/stke.3992007tw290]
Hyperactive Antimicrobial Response Produces Rosacea
Nancy R. Gough
Science's STKE, AAAS, Washington, DC 20005, USA
Vitamin D and Cathelicidins
"Current studies have unexpectedly identified vitamin D3 as a major factor for the regulation of cathelicidin expression. This finding may provide new strategies in the management of infectious and inflammatory diseases of the skin by targeting control of the expression and function of cathelicidin and other AMPs."
[Cathelicidins: multifunctional defense molecules of the skin.]
Peric M, Koglin S, Ruzicka T, Schauber J.
Klinik und Poliklinik für Dermatologie und Allergologie, Ludwig-Maximilians-Universität München.
Dtsch Med Wochenschr. 2009 Jan;134(1-2):35-8. Epub 2008 Dec 17.
_____________End Editorial - Brady Barrows
Gallo's theory and resources
*Cathelicidins are small cationic peptides that possess broad-spectrum antimicrobial activity. These gene-encoded 'natural antibiotics' are produced by several mammalian species on epithelial surfaces and within the granules of phagocytic cells. Since their discovery over a decade ago, cathelicidins have been speculated to function within the immune system, contributing to a first line of host defense against an array of microorganisms. Consequently, cathelicidins have captured the interest of basic investigators in the diverse fields of cell biology, immunology, protein chemistry and microbiology. A burgeoning body of experimental research now appears to confirm and extend the biological significance of these fascinating molecules. This article reviews the latest advances in the knowledge of cathelicidin antimicrobial peptides, with particular emphasis on their role in defense against invasive bacterial infection and associations with human disease conditions.
Scand J Infect Dis. 2003;35(9):670-6.
Cathelicidins and innate defense against invasive bacterial
infection.Nizet V, Gallo RL.
Department of Pediatrics, Division of Infectious Diseases University
of California, San Diego, La Jolla 92093, USA
PMID: 14620153 [PubMed - indexed for MEDLINE]
Antimicrobial peptides and the skin immune defense system
Jürgen Schauber, MDa and Richard L. Gallo, MD, PhDb
J Allergy Clin Immunol. 2008 August; 122(2): 261–266.
Published online 2008 April 25. doi: 10.1016/j.jaci.2008.03.027.
This thread has an enormous amount of research on this subject.
** "The term "alarmins" has been used to describe antimicrobial peptides (AMPs) such as defensins and cathelicidins, which not only kill microbes but also trigger host-tissue responses, including leukocyte chemotaxis, angiogenesis, expression of extracellular matrix components, and inflammation. Rosacea, an inflammatory skin disease, exhibits many of these resultant characteristics. Thus, Yamasaki and colleagues recently identified altered levels and post-translational processing of cathelicidin in skin from rosacea patients. When cultured with human keratinocytes, abnormal cathelicidin peptides resulted in erythema and vascular dilatation. Deletion of the cathelicidin gene in a mouse model of skin irritation resulted in significantly less inflammation than in wild-type animals. In addition, increases in the activity of serine proteases that lead to activation of cathelicidin were implicated in inflammatory changes associated with rosacea. Thus, manipulation of antimicrobial peptides and their postsecretory processing may be a focus for the development of effective therapeutic strategies for rosacea."
Editorial
Journal of Investigative Dermatology (2007) 127, 2493. doi:10.1038/sj.jid.5701133
***Autoimmune disease: Skin deep but complex
Nicole Baumgarth1 & Charles L. Bevins
Nature 449, 551-553 (4 October 2007) | doi:10.1038/449551a; Published online 3 October 2007
There is evidence that Vitamin D is "a major regulator of the expression of the cationic antimicrobial peptide cathelicidin."
More info on Vitamin D
