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Psoriasis
Johann E. Gudjonsson & James T. Elder
EPIDEMIOLOGY
Historical Aspects
The earliest descriptions of what appears to represent psoriasis are given at the beginning of medicine in the Corpus Hippocraticum. This work was
edited in Alexandria 100 years after the death of
Hippocrates (460377 bc), who presumably was the
author. Hippocrates used the terms psora and lepra
for conditions that can be recognized as psoriasis.
Later, Celsus (ca. 25 bc) described a form of impetigo that was interpreted by R. Willan (17571812)
as being psoriasis. Willan separated two diseases
as psoriasiform entities, a discoid lepra Graecorum
and a polycyclic confluent psora leprosa, which
later was called psoriasis. In 1841, the Viennese
dermatologist Ferdinand von Hebra (18161880)
unequivocally showed that Willans lepra Graecorum and psora leprosa were one disease that had
caused much confusion because of differences in
the size, distribution, growth, and involution of
lesions.
Genetics of Psoriasis
That psoriasis has a genetic basis has been appreciated for nearly 100 years.8 However, as Gunnar
Lomholt lamented in 1963 in his classic study of
psoriasis in the Faeroe Islands9: That psoriasis is
genetically conditioned is beyond doubt. But when
the mode of inheritance appears to have been almost demonstrated, it again slips out of the fetters
of fixed rules! Over the years, based on some very
large pedigrees and population surveys, singlegene recessive, two-gene recessive, dominant with
reduced penetrance, and polygenic models have
been suggested; recurrence risk analysis strongly
favors the polygenic model.10 Based on population
studies, the risk of psoriasis in an offspring has been
estimated to be 41% if both parents are affected,
14% if one parent is affected, and 6% if one sibling
is affected, compared to 2% when no parent or
sibling is affected.11
The concordance rate for psoriasis in monozygotic
twins ranges from 35% to 73%.1214 This variability,
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Chapter 18:
Psoriasis 21
that the rare variant may actually encode a protective function. Finally, the actual functional variant
may be rare, but carried on a common haplotype
tagged by the observed variant. Fine mapping and
functional studies of psoriasis and other complex
genetic disorders are in their early stages. The outcome of these studies should help to distinguish
between these possibilities.
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M protein serotypes. In contrast, no specific serotype is associated with guttate psoriasis. All M proteins have conserved amino acids with significant
homology to keratins, particularly keratins K16 and
K17.238240 These keratins are strongly upregulated
in psoriasis lesions but are either not expressed in
normal skin or only at low levels at sites of predilection (i.e., elbows, knees, scalp).241 During the transition from guttate to chronic plaque psoriasis, T cells
may recognize the amino acid sequences shared
between M proteins, K16, and K17.230 In support of
this hypothesis, CD8+ T cells taken from HLA-Cw6positive patients respond to peptide sequences
common to K17 and M protein, whereas nonpsoriatic HLA-Cw6-positive controls only respond to M
protein peptides.242 Notably, responsive cells were
enriched tenfold in the skin-homing (CLA+) T-cell
subset.242 Whereas all HLA-C alleles efficiently present peptides derived from streptococcal M proteins
to CD8+ skin-homing memory T cells, HLA-Cw6 may
be particularly efficient at presenting M protein-like
peptides derived from K16 and K17.
Immunological tolerance must be overcome
for the transition from guttate cross-reactivity to
chronic plaque autoreactivity to occur (see Chapter
10). Breakage of tolerance requires high expression
of self-antigen,243 and certainly keratins K16 and K17
fulfill this requirement because they are markedly
overexpressed in the context of regenerative maturation.241,244 However, many other proteins are markedly upregulated in psoriatic lesions compared to
normal skin,245251 and thus are also candidates for
loss of tolerance. Interestingly, many of the most
strongly upregulated genes in psoriasis are located
in the epidermal differentiation complex (PSORS4,
1q21.3), where genetic linkage and association to
psoriasis has been reported.42,43,252 As noted earlier,
T-reg function is markedly decreased in psoriasis.111
T-reg dysfunction may further lower the threshold
for autoreactivity, as depletion of T-regs is associated with at least tenfold expansion253 and activity254
of the CD8+ T-cell population. With tolerance broken, one would expect that those T cells displaying
the highest affinity for self-peptides in the context
of HLA-Cw6 would be preferentially stimulated and
proliferate, leading to the clonal expansion of CD8+
T cells that is observed experimentally.88
Interestingly, HLA-Cw6 homozygotes have a
2.5-fold higher risk of psoriasis relative to heterozygotes, without having more severe disease.255 This
would be the expected outcome if the density of
Chapter 18:
them in the context of HLA Class I on their cell surfaces.262 Known as cross-presentation, this process
is important in host defense because CD8+ T cells,
which are required to kill virus-infected or cancerous cells, only recognize antigen in the context of
HLA Class I, and, in epithelial cells, Class I molecules
can only be loaded with peptides derived from the
intracellular milieu. Many viruses have evolved to
exploit this weakness by learning not to infect DCs.
However, this mechanism carries a risk of autoimmunity, as normal self-proteins are constantly being
cross-presented. To minimize this risk, successful
activation of a cognate CD8+ T cell requires further
support by activated CD4+ T cells, which must also
be specific for the infected/cancerous target cell.
This process is termed cross-priming.263 DCs are
the only APCs able to cross-prime CD8+ T cells.264
CD4+ T-cell support is also necessary for maintaining CD8+ effector T-cell function after cross-priming
takes place.265,266 In the transition from cross-reactivity to autoreactivity, we envision that CD4+ T cells
support the cross-priming of CD8+ T cells capable of
recognizing K16/K17 or other intracellularly derived
peptides in the context of HLA-Cw6 (Fig. 18-3).
Cross-priming would explain the requirement for
CD4+ cells during lesional development observed in
a xenograft model.267
Psoriasis 23
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