Udey, Mark C.

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COMMENTARY
In This Issue: Progress Towards A More Complete Understanding
of Two Important Immune Diseases Involving Skin
Mark C. Udey
National Cancer Institute, NIH, Bethesda, Maryland, USA
Two articles in this issue of the JID piqued my interest because
the ¢ndings have implications regarding two important dermato-
logic diseases. One disease (systemic sclerosis) is uncommon but
particularly important because it is often devastating and our
treatments are largely ine¡ective.The second disease (latex hyper-
sensitivity) is much more common, running the gamut from a
minor inconvenience to a life-threatening condition.
Sato and coworkers (p. 542) report in this issue of the JID that
antibodies reactive with a matrix metalloproteinase are com-
monly found in patients with systemic sclerosis (SSc), and suggest
that these antibodies may play a role in disease pathogenesis.
Classi¢ed as an autoimmune disease because of the high fre-
quency with which autoantibodies are detected and the not infre-
quent occurrence of sclerosis in patients with mixed connective
tissue disease, the pathogenesis of SSc has been attributed to in-
trinsic abnormalities of ¢broblasts, alterations of cytokine/growth
factor production that impact in ¢broblasts and/or vascular
abnormalities. Ultimately, the ¢nal common pathway is inap-
propriate accumulation of extracellular matrix (ECM) compo-
nents (especially collagen); a result that could re£ect increased
production of ECM, decreased degradation or both. Matrix me-
talloproteinases (MMPs) play a critical role in ECM degradation,
and MMP-1 is essential for the initiation of degradation of the
¢brillar collagens (collagens type I, II and III).
Serum was obtained from 57 Japanese patients with SSc, and
autoantibodies were assessed by ELISA, Western blotting,
immuno£uorescence or immunoprecipitation. Controls included
patients with active systemic lupus erythematosus (SLE), derma-
tomyositis (DM) and normal individuals. Anti-MMP-1 IgG
autoantibodies were detected in 75% of patients with di¡use
SSc, 15% of patients with limited SSc, 5% of patients with SLE
or DM and 3% of normals. Interestingly, there was a direct cor-
relation between SSc severity (indicated by the extent of skin
sclerosis, presence of vascular abnormalities as quanti¢ed using a
pulsivity index and/or pulmonary abnormalities such as reduced
di¡using capacity for carbon monoxide) and the levels of
anti-MMP-1 antibodies in serum. The particular relevance of
anti-MMP-1 antibodies to disease pathogenesis is suggested by
the observation that SSc sera with IgG anti-MMP-1 antibodies
(by ELISA and Western blotting) inhibited the activity of
MMP-1 in vitro, whereas normal sera and SSc sera that contained
autoantibodies other than anti-MMP-1 did not.
Extension of these ¢ndings to other SSc patient populations
will be important. It will be interesting to determine if sera from
SSc patients also contain autoantibodies reactive with other
MMPs or TIMPs (tissue inhibitiors of metalloproteinases). If con-
¢rmed, the results reported in this paper suggest a pathogenic role
of IgG anti-MMP autoantibodies in SSc, providing a surrogate
marker for disease activity that may be easier to quantify and fol-
low serially than cutaneous sclerosis, and suggesting autoantibody
production as a relevant therapeutic target. In light of this, im-
proved, rational therapies for SSc may be on the horizon.
Good animal models of human diseases are invaluable. Indeed,
lack of a mouse model that recapitulates essential features of SSc
has limited progress in this disease to a signi¢cant degree. In this
issue of the JID, Lehto and colleagues (p. 633) describe a new
mouse model of contact sensitivity to natural rubber latex
(NRL)-derived proteins, ¢lling an important gap.
Latex hypersensitivity that results in hand dermatitis is a rela-
tively common disorder and a signi¢cant occupational health
problem. Although most individuals who are a¥icted with this
disease can control their symptoms by avoiding exposures to
latex (usually in gloves), rare individuals are exquisitely sensitive,
necessitating more stringent measures. Although contact sensitivity
to highly reactive chemicals (e.g., trinitrochlorobenzene) has been
extensively studied in mice, studies of contact hypersensitivity
reactions to proteins in mice have been less frequent.
This model incorporates several features that are likely to be
important in the pathogenesis of latex hypersensitivity in
humans. Induction of a dermatitis manifested by epidermal and
dermal thickening and characterized by the dermal accumulation
of eosinophils and degranulated mast cells required prior disrup-
tion of the cutaneous barrier by tape stripping (injury) and
chronic application of an aqueous extract of NRL proteins under
hydrating conditions. Assessment of cytokine production in NRL
protein-sensitized skin revealed accumulation of Th2 cytokine
(IL-4) mRNA. In addition, epicutaneous application of NRL
protein in the absence of adjuvant led to increased levels of total
serum IgE and NRL-reactive IgE as well. Intraperitoneal admin-
istration of NRL protein in alum did not cause an increase in ser-
um IgE and led to production of NRL-reactive IgG2a rather than
IgE antibodies. Interestingly, the antibodies induced by epicuta-
neous and intraperitoneal sensitization also di¡ered with regard
to reactivity with two major NRL antigens. These results indicate
that epicutaneous immunization with protein antigens induces an
immune response with a striking Th2 bias and that route of ad-
ministration can also in£uence immunogenicity.
The availability of this model system should facilitate
additional studies of latex contact hypersensitivity. Conceivably,
latex-containing products could be evaluated with regard to
immunogenicity. The contribution of injury and hydration to
sensitization can also be systematically explored. Finally, the
e⁄cacy of novel topical and systemic therapies that might be
predicted to have e⁄cacy in humans can be carefully tested.
Although I have focused on two papers that deal with immune-
mediated diseases, the content of this issue is wide-ranging, re£ect-
ing the diversity of interests represented in the JID readership.
Interested readers will ¢nd articles that additionally explore the
‘‘re-discovered’’ hair follicle. Studies of lipid metabolism and bar-
rier function are included. New insights into mechanisms of apop-
tosis that are operative in epithelial cells are described, and medical
genetics continues to be prominently represented. Finally, a treat-
ment that may promote tolerance induction in the setting of gene
therapy is described (see the Commentary by JonathanVogel).
0022-202X/03/$15.00  Copyrightr 2003 by The Society for Investigative Dermatology, Inc.


In This Issue: Progress Towards A More Complete Understanding of Two Important Immune Diseases Involving Skin 

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In This Issue: Progress Towards A More Complete Understanding of Two Important Immune Diseases Involving Skin

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