Expression of Antimicrobial Peptides: DISCUSSION

19 Jan

AD is multifactorial, polygenetic skin disorder and is commonly viewed as immunologic in patho­genesis. Examination of skin biopsy samples from patients with AD has shown that S. aureus grows in colonies in the upper layers of the epidermis between keratinocyres. This suggests that an exponential increase in S. aureus could results from failure of the innate immune defense system. Naturally occurring AMPs are a critical component of this innate immune system. Among numerous AMPs, LL-37 and hBD-2 are the major classes of peptides in human skin. hBD-2 and LL-37 in human are normally produced by keratinocytes in response to inflammatory stimuli such as bacteria, viruses, and fungi. In fact, S. aureus can be isolated from skin lesions of most patients with AD. The mechanisms leading to increased S. aureus colonization in atopic dermatitis are unknown until now. A number of processes could contribute to increase in S. aureus colonization. These include disruption of skin barrier function from scratching, exposure of inflamed underlying skin from scrat­ching, loss of certain innate antibacterial activities from changes in lipid composition or hBD levels.

Both patients with AD and psoriasis have altered skin barrier function, but patients who are psoriatic are more resistant to skin infections than healthy individuals. About 30 percent of patients with atopic dermatitis have bacterial or viral infections of the skin, as compared with only 7 percent of patients with psoriasis/,b. ThatO s why both LL-37 and hBD-2 have been known to be decreased significantly in acute and chronic lesions of AD compared to psoriasis. In psoriatic skin, keratino- cytes were increased in number and differentiated accelerativingly, thus, the epidermis became thicken­ing. So, quantitatively, abundant antimicrobial peptides are expressed in the psoriatic epidermis. However, in AD, why the expressions of AMPs decreased are still unknown, a deficiency in the expressions of AMPs may account for the suscep­tibility of AD patients to skin infection, such as S. aureus. The inability to increased AMPs may be caused by suppression by TH2 cytokines that are elevated in AD. In vitro, keratinocytes in culture could be shown to lose the ability to increase hBD-2 expression when exposed to IL-4 or IL-13. Enhanced TH2 cell activity is a hallmark of acute AD. Increased production of IL-4, IL-5 and IL-13 by TH2 cells, in turn, inhibit TH1 cytokine production, including generation of interferon- gamma and IL-18, which are two beneficial antimicrobial mediators. IL-4, IL-13 have also direct inhibitory effects for AMPs expression.
levitra plus

In the addition, Elias et al suggested that the changes of stratum corneum pH due to disruption of permeability barrier function increased the activity of SP which could degrade AMPs. There is a reduction in ceramides in the epidermis of patients with AD, with an abnormal expression of sphingo­myelin deacylase. This enzyme hydrolyzes sphingo­myelin to yield sphingosylphosphorylcholine rather than ceramide. Insufficiency of ceramides in the stratum corneum is an etiologic factor in atopic dry skin. Dry skin is a feature of AD with increased TEWL, which is a reflection of impaired barrier function of stratum corneum. Several studies have shown a significant increase in basal TEWL, even in clinically uninvolved skin in AD. The low levels of ceramide makes skin surface pH altered toward to alkalinity. As a result of alkalinized or neutral skin surface pH, recovery of permeability barrier may be delayed and activity of SP are increased, thus amounts of AMPs may decrease by SP. According to Elias et al, the substitution of a ceramide-dominant barrier repair formulation for standard, nonphysiologic lipid-based emollients and moisturizers is beneficial not only for the uninvolved ‘dry’ skin in AD but also for the inflammatory skin in recalcitrant AD patients. It implicated that emollients are helpful in not only skin hydration but also ceasing to cytokine cascade leading to inflammation through normalization of permeability barrier function.As our results were shown, TEWL levels were increased both involved and uninvolved sites compared to normal control, which these were more significantly decreased in involved sites. These find­ing showed that the permeability barrier were disrupted in both involved and uninvolved sites in AD, obviously more significant in involved sites. In RT-PCR analyses of AMP mRNA expressions, the expression levels of hBD-2 and LL-37 mRNA were down-regulated in both uninvolved and involved sites compared to healthy donor, more decreased in involved sites. These tendency were also confirmed by Western blot and IHC. These results suggested that AMPs expressions were downregulated in AD, even in uninvolved sites and more decreased in involve sites. For comparing relationship between the expression of AMPs and permeability barrier function, we calculated the subtraction values of TEWL levels and AMPs expressions between involved and uninvolved sites, respectively. We supposed that these subtraction values could reflect a contribution for decreasing AMPs expressions according to disrupted degrees of permeability barrier. And we also expected that the subtraction values of expressed AMPs would be in inverse proportion with severity as measured TEWL levels. It implicated that permeability barrier function have a role in modulation the expression of AMPs . In other words, more significant permeability barrier disrupted, less the AMPs expressed in AD. canadian antibiotics

In conclusion, we were able to conclude there was in proportion between TEWL levels and the permeability barrier disruption. Thus, our results demonstrated that AMPs barrier may co-localize to permeability barrier. The co-localization of the permeability and antimicrobial peptide barrier had demonstrated by the translocation of hBD-2 from the endoplasmic reticulum to epidermal lamellar body (LB) following IL-la stimulation. These find­ings showed in agreement with our results. Although our results have a statistical limitation because patient group were only 7, however, we believe that it is first results about relationship between skin barrier function and AMPs. It should be necessary to carry out further studies that after restoration of skin barrier function through using a ceramide dominant emollients on atopy skin, how the expression of AMPs changes.