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Keratinization, absence of granular layer, and depositation of antibodies
and complement components in the stratum corneum. Most notable is the
hyperproliferation of keratinocytes in the epidermis. These keratinocytes
exhibit an increased mitotic rate and have ten times the turnover rate of
normal keratinocytes. There is also an infiltration of CD4+ T lymphocytes,
monocytes and neutrophils into the epidermis. Recently there has been much
debate over whether psoriasis is mediated by an autoimmune process.
The disease affects roughly two percent of the population in the
United States. It has the greatest prevalence among Scandinavians and
Northern Europeans, where it affects three percent of the population, and
the least prevalence among North American Indians, with just half a
percent being affected. Psoriasis seems to affect both males and females
equally. There are two types of the disease. Type I generally occurs
during adolescence, with an average age of onset of sixteen years for
females and twenty-two years for males. Type II affects people over sixty
years of age.

There are several immunological abnormalities associated with
psoriasis. Early psoriatic changes occur in advancing lesions before the
accumulation of inflammatory cells. These changes are mediated by
activated CD4+ T lymphocytes and can be detected before visible pathology
to the skin occurs. Activated T lymphocytes exhibiting an increase in
HLA-DR and IL-2R can be seen in close proximity to Langerhans cells in the
dermis before lesion formation. Since Langerhans cells are antigen
presenting cells, activation of the T cells may occur by the recognition
of an as-yet unidentified antigen in the context of MHC class II. These
activated T lymphocytes then migrate to the epidermis and activate
epidermal keratinocytes.

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At this point, a cascade of events occurs and appears to become
cyclic after up-regulation of certain cytokines. This cyclic tendency is
probably responsible for the static nature of many psoriatic plaques. An
increase in ICAM-1 and ELAM-1 (endothelial leukocyte adhesion molecule) in
the vascular endothelium underlying the plaque recruits inflammatory cells
to the site of the lesion. Activated T cells produce increased IFN-gamma,
which in turn induces HLA-DR and ICAM-1 expression in keratinocytes. This
increase in ICAM-1 production causes increased retention of activated
T-lymphocytes in the epidermis, localizing them to the site of the lesion.

The IFN-gamma released by activated T-lymphocytes also causes an
up-regulation of keratinocytic cytokines, specifically IL-1, IL-6, IL-8
and TGF-alpha. TGF-alpha, IL-6, and IL-8 are all keratinocyte mitogens, so
their release stimulates the activation of surrounding keratinocytes,
inducing more ICAM-1 expression and causing increased retention of
activated T lymphocytes at the site of the lesion. IL-1 also serves to
increase ICAM-1 expression in keratinocytes. IL-8 (neutrophil activating
factor) mediates migration of monocytes, neutrophils, and CD4+ T-cells
from the vascular endothelium to the epidermis.
There are several indirect lines of evidence that implicate an
autoimmune role in the onset of psoriasis. There is an increased
prevalence of certain HLA haplotypes which have been associated with the
disease. The major haplotype which exhibits this correlation is HLA-Cw6.

Cw6 gives a relative risk of twenty for developing psoriasis, and
eighty-five percent of Type I sufferers are positive for this HLA
haplotype. The correlation isn’t as great for Type II sufferers – fifteen
percent – but is still significant. There is a lesser association with
other HLA haplotypes as well, notably A1, B13, B17, B27, B37, DR7, but
some of these may be due to linkage disequilibrium with Cw6. One study
showed that transgenic rats expressing haplotype B27 develop
psoriasis-like plaques on their tails, strengthening the argument for HLA
correlation. Furthermore, the most common cutaneous manifestation
associated with HLA-B27 is Reiter’s syndrome (keratoderma blenorrhagica),
which shares clinical and histophysiological features with psoriasis.

There is other evidence for a genetic link, as well. Thirty percent
of psoriasis patients have a first degree afflicted relative. Among
sufferers of Type I psoriasis, fifty percent have an afflicted parent (the
same study showed that no Type II patients had an afflicted parent). There
is a seventy-two percent concordance between monozygotic twins, which fits
the pattern of an autoimmune disease, since they are usually
multifactorial. Recently, a study linked some cases of psoriasis to a gene
on the distal end of the long arm of chromosome seventeen. These cases
were not Cw6 associated, indicating that psoriasis susceptability may be
correlated with genetic variation at a genetic locus other than the HLA
locus. A gene involved in the activation of T cells – ILF (interleukin
enhancer binding factor) – was shown (by others) to lie within this region
of chromosome seventeen. ILF binds to purine-rich regions of the IL-2
promoter (along with NFAT), so alterations in this gene could possibly
cause an up-regulation of expression of IL-2, resulting in the
inflammatory cascade and hyperproliferation characteristic of lesional

A study of a murine autoimmune disease involving the skin may give
clues to the possible autoimmune component involved in psoriasis. A murine
epidermal antigen, Skn, is a target for adoptively transferred autoimmune
disease affecting the skin. Murine recipients injected with anti-Skn
splenocytes exhibited histopathologic alterations with psoriasiform
features in their skin lesions, including hyperkeratosis and dermal
infiltration of mononuclear cells and neutrophils.

Another intriguing factor is the efficacy of immunosuppressive
treatments when used for psoriasis. Cyclosporin A (CSA) has been shown to
be very effective in treating psoriasis, but is rarely used due to its
nephrotoxic and hypertensive properties. CSA blocks the formation of a
calcineurin dependent factor (NFAT) essential for transcription of IL-2 in
T cells, and thus can interfere in T cell activation. CSA can also
abrogate Langerhans cell function and is cytostatic for keratinocytes.

Recent work with anti-CD4 antibodies has shown them to be effective as
well. A chimeric human/mouse anti-CD4 monoclonal antibody treatment was
used to treat a sixty-three year old man with severe generalized pustular
psoriasis. The pustular psoriasis dried and disappeared, and the man’s
plaque psoriasis, present since age nineteen, also disappeared. The plaque
psoriasis returned after treatment was stopped, but responded well to
conventional phototherapy.

A high association between Streptococcal infection and psoriasis has
been known for almost fifty years, especially in the case of guttate
psoriasis (a juvenile form), where up to eighty percent of sufferers have
evidence of recent Streptococcal infection. Studies have shown binding of
monoclonal antibodies raised to Streptococcal antigen to products of
keratinocytes. Cytokeratins are quite immunogenic, and if this binding is
due to shared antigens it raises the possibility that memory T cells
specific for Streptococal antigen may activate by recognizing antigens on

There exist a variety of treatments for psoriasis, but no cure. The
most popular treatment is a combination of a topical agent and
phototherapy involving UV light. Coal tar is a major topical agent
prescribed for psoriasis. Many times the tincture includes
corticosteroids, and other times topical corticosteroids are prescribed
alone. Coal tar is usually used in conjunction with UVB phototherapy.

Emollients are also used, such as soft yellow paraffin or aqueous cream
(aquaphor), and these may be effective due to a reversal of the
inflammatory consequences of damage to the stratum corneum. Another
treatment involoves keratolytic agents, such as salicylic acid, which
soften the scaly layers of plaques and ease their removal. These agents
also enhance the efficacy of topical corticosteroids and coal tar by
increasing their absorption.
Phototherapy involves the use of either UVA or UVB light exposure to
affected skin. UVB light inhibits Langerhans cell function and is
cytotoxic for keratinocytes. If the Langerhans cells are indeed causing
the activation of CD4+ T lymphocytes, it makes sense that this type of
therapy would have a beneficial effect. UVA therapy is usually done in
conjunction with methoxalen, a photosensitizing drug. A proposed theory
for the efficacy of this treatment states that there is an intercalation
of methoxalen into DNA forming cross-links between strands that interfere
with DNA synthesis and block cell proliferation. This form of therapy is
also known to have a suppressive effect on cell-mediated immune responses
in the skin, which is an important point because a recent study has shown
that CD8+ lymphocytes also play an important role in the pathogenesis of
this disease.
Several orally administered drugs are also used in the treatment of
psoriasis. Methotrexate, a folic acid antagonist, has been shown to be
effective. It had been proposed that methotrexate may work by causing a
blockage of DNA synthesis, but recent evidence has demonstrated that it
may affect mononuclear cells in skin, blood, and lymphatic tissue, leading
to an immunosuppressive effect. The downside of this treatment is liver
and kidney damage. Etretinate, a retinoic acid derivative, is used in
conjunction with UVA treatments to lower the effective dose of both.

Systemic corticosteroids are also quite effective in treatment of
psoriasis, but many physicians do not prescribe them since the psoriatic
condition may worsen after usage is discontinued. Other, more recent
agents include Cyclosporin A, FK506, anti-CD4 mAb, calcipotriol,
acetazolamide, and tin-protoporphyrin (with UVA).
Psoriasis appears to fit the pattern of an autoimmune disease, or at
least Type I psoriasis fits the pattern. It has its onset around
adolescence, and the onset is gradual rather than sudden. The lesions can
remit and relapse, and the trigger appears to be multifactorial, as can be
demonstrated by the seventy-two percent concordance between identical
twins. The disease remains for the lifetime of the affected person, as
well. The murine experiments identifying the Skn antigen as an autoimmune
target may be a clue indicating that a similar antigen exists in humans,
although this antigen is yet to be identified. The CD4+ T cells are
somehow getting activated and starting the cascade of events which leads
to lesion formation. If this activation is occuring due to a shared
antigen between keratinocytes and Streptococcus, then psoriasis would fit
the definition of an autoimmune disease triggered by molecular mimicry.

However, this correlation is not demonstrated in all sufferers. The high
correlation between HLA-Cw6 and psoriasis also indicates an autoimmune
role in the disease, as does the effectiveness of immunosuppressive
treatments. A recent article speculated that psoriasis may be mediated by
a genetic defect affecting keratinocytes. Langerhans cells are under the
influence of cytokines released by keratinocytes. The Langerhans cells in
the dermis and epidermis are able to process protein antigens with great
efficiency, but are only able to present the antigens to high affinity
memory T cells. Langerhans cells found in nodal regions do not have this
high efficiency of protein processing, but have the ability to activate
both naive and memory T cells. The intraepidermal Langerhans cells in
psoriasis patients look more like intranodal cells than normal
intraepidermal Langerhans cells, giving them the ability to activate naive
T cells. If challenged cutaneously, perhaps these cells can
non-specifically activate naive T cells, leading to the cascade of events
that generates the pathology associated with a psoriatic lesion. Indeed,
psoriatic lesions can occur at the site of local trauma many times
(Koebner’s phenomenon). However, if this genetic defect was the definitive
cause of the disease, then everybody afflicted with this defect would
acquire the psoriatic phenotype. This does not occur – the onset appears
to be multi-factorial. I believe that Type I psoriasis is an autoimmune
disease, but the process mediating its onset is yet to be elucidated. I
supect that there may be a self -antigen present in the epidermis which is
causing an autoimmune reaction. This antigen may be only expressed during
adolescence, hence the onset of disease during this time. It could be that
these sufferers have lost tolerance to this self antigen and have
initiated an autoimmune response to the new challenge. There may be other
genetic defects which can lead to the psoriatic phenotype, but these are
probably distinct from Type I psoriasis, which I believe to be a true
autoimmune disease.


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