L’ecosistema cutaneo

nell ’eczema

12 - 14 Settembre 2013

Dr. G. Baviera

TEATRO OPERATIVO

• CUTE: 2.5 m2

• APPARATO RESPIRATORIO: 150 m2

• APPARATO DIGERENTE: 400 m2

Lungo queste superfici ciascuno di noi ospita circa 100 trilioni di batteri che corrispondono all’ 1–3% del peso corporeo

J.I.D. 2012;132:934

La cute è una interfaccia con l’ambiente esterno ma anche un ecosistema composto di diversi

habitats ricchi di tasche, invaginazioni e nicchie specializzate

che ospitano una ampia variabilità di virus, batteri, funghi, acari

CUTE COME ECOSISTEMALe varie regioni cutanee hanno differenti popolazioni microbiche

residenti che riflettono diverse nicchie biologiche.

Le conte coloniche di Batteri Aerobi prelevati da aree umide come le ascelle o le pieghe interdigitali dei piedi possono raggiungere 107 batteri per cm2, mentre le aree asciutte come l’avambraccio o il tronco possono ospitare 102 o meno batteri per cm2 Batteri Anaerobi sono presenti sulla cute con conte coloniche di oltre 107 batteri per cm2

(Leyden J.J. J- Invest Dermatol 1987;88:65s)

DIVERSI FATTORI ESTERNI POSSONO ALTERARE L’ECOSISTEMA CUTANEO

Fattori Ambientali includono temperatura, umidità, salinità, esposizione alla luce

Fattori Individuali includono età, sesso, stato immune, condizioni igieniche, uso di farmaci (antibiotici, steroidi), uso di saponi e cosmetici, permanenza in ambiente ospedaliero, presenza di traumi o ustioni.(Roth RR.- Annu Rev Microbiol 1988;42:441-8)

“If microbes were capable of emotion, they would

celebrate each time an infant was born. At birth, a new

potential host emerges from the protected environment

of the uterus, providing pristine surfaces and body

cavities as sites for microbial colonization.”

G. W. Tanock

Vaginally delivered infants acquired bacterial communities resembling their own mother’s vaginal microbiota. (Lactobacillus, Prevotella)

In C-section babies, the lack of a vaginal exposure leads to first microbial communities resembling the human skin microbiota, with an abundance of Staphylococcus spp, Corynebacterium, Propionibacterium spp

Dominguez-Bello M. G. PNAS 2010;107(26);11971

Gosalbes M.J. CEA 2013;43:198

Two distinct types of microbiota composition can be detected in meconium samples.

Type A - The family Enterobacteriaceae as the most abundant bacterial taxon (58.69%), mainly represented by the Escherichia/Shigella genus (24.68%).Type B – presents Firmicutes, and particularly Lactic Acid Bacteria of the families Leuconostocaceae, Enterococcaceae and Streptococcaceae, with Leuconostoc (25.86%), Enterococcus (16.79%), Lactococcus (14.01%), Staphylococcus (6.75%) or Streptococcus (6.34%) as the most abundant genera

High abundances of Escherichia coli and other enterics have been linked to eczema

A protective role against atopy has been reported for Lactic Acid Bacteria

LOCAL FACTORS INFLUENCING SKIN COLONIZATION

Eccrine glands - Are found on virtually all skin surfaces and continuously bathe the skin surface with their secretion, which is composed mainly of water and salt, but they produce DERMICIDIN.Apocrine glands - located in the axillary vault (armpit), nipple and genitoanal regions, respond to adrenaline by producing milky, viscous, odourless secretions (pheromones )Sebaceous glands - connected to the hair follicle, secrete the sebum. They support the growth of facultative anaerobes such as Propionibacterium acnes which hydrolyses the triglycerides present in sebum, releasing free fatty acids onto the skin contributing to the acidic pH (~5) and they produce LL37, HBD-2

TOPOGRAFIA CUTANEA

MOIST Staphylococcus Corynebacterium

OIL Propionibacterium

DRY Gram- Mixed phyla

Interpersonal variation of the skin microbiome

Skin microbiota from four healthy volunteers (HV1, HV2, HV3, HV4).

Similarities of skin microbial communities are more dependent on the site than the individual

antecubital crease back

nare plantar heel

Fierer N. PNAS 2008;105:17994

% di sequenze per sesso e ore dopo il lavaggio

PRENDERE FIGURE SUPPLEMENTARI – FARE 2-3 DIAPO?

There was a core set of bacterial taxa commonly found on the palm surface Thre is a pronounced intra- and interpersonal variation in bacterial community composition Hands from the same individual shared only 17% of their phylotypes indicating thatthere is an enormous amount of heterogeneity within an individual Only 13% of the bacterial phylotypes on the palm surface are shared between any two individuals Women had significantly higher diversity than men and the palms of women were also found to harbor significantly greater bacterial diversity than those of men Community composition was significantly affected by handedness, time since last hand washing, and an individual’s sex

Verhuls N. O. Plos One 2011;6 (12)e28991

Individuals that are highly attractive to An. gambiae s.s. have a significantly higher abundance, but lower diversity of bacteria on their skin than individuals that are poorly attractive

PA ------ HA

Fierer N. PNAS 2010;107(14):6477

Fingertips of an individual harbor bacterial communities more similar to those found on the keys of that individual’s keyboard than to those communities found on keyboard keys not touched by the individual

Match between bacterial communities on individual keyboards and the fingers of the owners of the keyboards

The collective genomes of our microbial symbionts may be more personally identifying than our own human genomes and the structure of these communities can be used to differentiate objects handled by different individuals, even if those objects have been left untouched for up to 2 weeks at room temperature

Nat. Rev. Immunol. 2009;9:687

Ecosistema cutaneo e immunità

But our skin’s innate immune system is not solely of human origin

Naik S. Science 2012;337:1115

Significant reduction in IFN-g and IL-17A production by ab T cells, and IL-17A by gdlow Tcells, in skin tissue of GF mice relative to SPF mice

The frequency and absolute numbers of cutaneous Foxp3+ Tregs were increased in the absence of commensals

Belkaid in 2012 discovered that mice raised in sterile chambers, lacking bacteria on the skin, in the gut and elsewhere, were unable to fight off the parasite Leishmania major. However, if the germ-free mice were inoculated with Staphylococcus epidermidis at the same time as the L. major infection, they were able to defeat the parasite. S. epidermidis interacts with T cells in the skin to produce inflammatory molecules that are central to the immune response

Phenol-soluble modulins produced by a normal microbial resident of human skin, Staph. epidermidis disrupt artificial

membrane vesicles and selectively kill skin pathogens

Cogen A. L. JID. 2010;130:192

Staphylococcus epidermidis promote innate immunity

Gallo R.L., J. Inv. Derm. 2011;131:1974

Staphylococcus epidermidis acts as a barrier against colonization of potentially pathogenic microbes and against overgrowth of already

present opportunistic pathogens.

Factors contributing to variation in the skin microbiome

DERMATITE ATOPICA

DERMATITE ATOPICA

• Now affects 15-20% (previously about 5%)• 20-40% have an innate genetic filaggrin

mutation– Decrease “Natural Moisturizing Factors”– Increase skin permeability– Increase pH– Increase risks of IgE sensitization

CAN’T KEEP OUT THE MICROBES

The number of children suffering from eczema has tripled in industrialized nations in the past 30 years, suggesting an environmental trigger.

More than 90% of AD patients are colonized with S. aureus on both lesional and non-lesional skin, compared with <5% of healthy individuals

S. aureus on the AD skin can secrete various exotoxins which are superantigens

They may penetrate the skin barrier and contribute to the persistence and exacerbation of allergic skin inflammation

No specific link has been identified between virulence factors expressed by S. aureus and flare-ups in patients with AD

However….

Microbiota cutaneo ed eczema

Grice, E. A. & Segre, J. A. Nature Rev. Microbiol. 9, 244–253 (2011)

Terada M. PNAS 2006;103(23):8816–8821

This raises the intriguing possibility that skin microbial fluctuations modulate the gene–environment interaction on the skin surface, resulting in the episodic exacerbations of AD.

In a mouse model that has reduced skin barrier function (the NC/Nga strain, which is deficient in ceramide production), application of Staphylococcus protein A along with an agitating detergent resulted in a severe AD like phenotype ‑

Nat. Rev. Immunol. 2009;9:687

Mechanisms that promote the increase of S. aureus colonization

• Skin barrier dysfunction• Increased synthesis of the extracellular matrix

adhesins for S. aureus• Reduced skin lipid content• Changes in the skin surface pH values toward

alkalinity• Decreased production of endogenous

antimicrobial peptides.

AD skin

Nomura I. J Immunol 2003; 171:3262-3269

S. Aureus

IL PERCHE’ DI UNA INVASIONE

Normal skin

Kong H. H. Genome Res. 2012;22:850

Shifting Microbiomes in AD

Temporal shifs in the skin microbiome associated with disease flares and treatment in children with atopic dermatitis

Genome Research H. H. Kong, 2012 22: 850

van den Akker. JID 2006;194:814

From 4 known functional GR gene polymorphisms, homozygous presence of haplotype 3 conferred a 68% lower risk of persistent S. aureus nasal carriage, whereas the combination of the haplotype 5 and the haplotype 1 allele was significantly associated with an 80% increased risk of S. aureus nasal carriage

Three human nasal S. aureus carriage patterns can be distinguished: persistent carriage, intermittent carriage, and noncarriage

.

A first positive culture for S aureus at age 6 months was associated with AD prevalence in the first and second years of life aOR, 2.13 and aOR, 2.88, respectively and also with severity (aOR, 3.27). Moreover, frequent colonization in the first year of life (2 times) held a 4.29-fold the risk of moderate to severe AD in the second year of life.

Iwase T. NATURE| Vol 465|20 May 2010

Lew L. C., Journal of Applied Microbiology ISSN 1364-5072

Bioactives from probiotics for dermal health: functions and benefits

Grazie per l’attenzione