8/20/2019 Inflammation in Acne Vulgaris

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INFLAMMATION IN ACNE VULGARIS

 Acne vulgaris is a polymorphic and multifactorial disease

affecting the majority of adolescents and a proportion of

individuals into adulthood. Approximately 30% of

adolescents and 5% of adults with acne require clinical

intervention and in 30% of these patients, significant scarring

has a major impact on their quality of life. The diseaseexhibits non-inflammatory lesions (comedones) which are

believed to be prerequisite for the inflamed lesions, papules,

pustules, nodules, cysts and macules. It is the inflammatory

lesions which are important clinically.

Early investigations focused on the physiology and

immunology of Propionibacterium acnes and its products.

During the latter 1980s two significant publications led to a

change in direction in research into acne. John Leeming

demonstrated, using a follicular isolation technique, that a

proportion of acne lesions were not colonised by P. acnes. W.

J. Cunliffe, using a method for "ageing" acne lesions, showedthat the initial cellular infiltrate was lymphocytic and not

neutrophillic. These studies questioned the conventional

wisdom that P. acnes was the sole aetiological agent of

inflammation in acne. At the same time, research into other

inflammatory dermatoses was focusing on the role of pro-

inflammatory cytokines in cutaneous inflammation. We

developed a working hypothesis that the initial events in acne

inflammation were mediated by keratinocyte-derived

cytokines and that one explanation for the success of

antibiotics used in acne therapy was due to their capacity to

modulate the inflammatory process. We demonstrated that

pro-inflammatory levels of IL-1! bioactivity were present in

the majority of acne comedones and that levels were related

to the total microbial content. This study resulted in the

current hypothesis that leakage of IL-1! from comedones into

the dermal compartment is the initial event in the development

of inflammation in acne.

This study was logically followed by a major clinical

investigation to measure the pro-inflammatory cytokine

content of comedones extracted from patients during oral

tetracycline and minocycline therapy. Paradoxically, the levels

of IL-1 increased significantly during eight weeks of antibiotic

treatment. This was in agreement with previous studies of the

effects of tetracyclines on cytokine production in vitro and was

the first study to demonstrate the effect of tetracyclines on

cytokine levels in vivo. Increased levels of IL-1 in acne

comedones destined to become inflamed may enhance

resolution and promote repair of the damaged follicular

epithelium. These results gave support to the hypothesis that

epidermal IL-1 plays a physiological role in would healing.

This study was awarded the prize for best poster presentation

at the European Society for Dermatological Research in 1991.

Work which progressed logically from the demonstration of

IL-1! in comedones involved an investigation of the capacity

of skin microorganisms to modulate cytokine production by

cultured primary human keratinocytes. These studies failed to

provide direct evidence for a role of P. acnes in modulating

comedonal IL-1! level. Subsequent investigations have

focussed on defining the temporal events occurring during the

development of inflammation in acne lesions using

immunocytochemical techniques. It has been shown that as

early as six hours following visible inflammation the major

cellular infiltrate is CD4 positive T-cells. This infiltrate is

accompanied by increased adhesion molecule expression onkeratinocytes and dermal microvascular endothelial cells. The

pattern is also consistent with a type IV hypersensitivity

pathology. Molecular investigations of the T-cell receptor

usage by D.B. Holland have indicated that the infiltrating T-

cells are oligoclonal, suggesting an antigen specific expansion

of T-cells following non- specific recruitment.

We are currently investigating the role of P. acnes heat shock

proteins (hsp) in acne. The hypothesis is that if P. acnes in

some follicles become stressed, they may express high levels

of heat shock proteins which are highly immunogenic and

stimulate a specific immune response via Langerhans cells in

the follicle wall. This would result in the characteristic CD4+ve

T-cell infiltrate observed. If the T-cells respond to P. acnes 

hsp, they may also cross-react with human hsp. In order to

prevent auto-immune responses, the P. acnes hsp-specific T-

cells may become regulated with time. This theory is

attractive since it offers an explanation for the spontaneous

resolution of inflammatory acne in the continual presence of P.

 acnes. We aim to isolate the T-cells from individual acne

lesions and compare the precursor frequency to P. acnes hsp

with the precursor frequency in peripheral blood in order to

determine the validity of this hypothesis. We will also

investigate the expression of P. acnes hsp in acne lesions

using immunocytochemistry.

Our contribution has been to alter previously held views on the

aetiology of the inflammatory process.

SKIN RESEARCH CENTRE

Skin Research Centre

Research Institute of Molecular and Cellular Biology

Faculty of Biological Sciences

University of Leeds

Leeds LS2 9JT

Phone: +44 (0)113 3435615

e-mail: src@leeds.ac.uk

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