Chapter 18

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,

and the fact that these rates do not approach 100%,

supports a role for environmental factors. Thus, the
mode of inheritance for psoriasis is best described
as multifactorial (i.e., polygenic plus environmental
factors).15 Interestingly, concordance in both monozygotic and dizygotic twins decreases as one moves
closer to the equator.14 Given the beneficial antipsoriatic effects of ultraviolet (UV) light (see Section
Treatment), these data suggest that UV exposure
may be a major environmental factor interacting
with genetic factors in psoriasis.
The search for the involvement of specific genes
in psoriasis began two decades ago with studies of genetic linkage (i.e., the cotransmission of
marker and disease alleles within families). These
studies had the advantage that only a relatively
small number of genetic markers (hundreds) were
needed to scan the genome. However, linkage
studies require collection of large families, which
are not that commonly encountered in practice
and lack power when disease allele frequencies
are high and penetrances are low, as is the case
in polygenic disorders16 (see Chapter 8). Despite
multiple genome-wide linkage studies, only one
locus, termed psoriasis susceptibility 1 (PSORS1),
was consistently confirmed in the linkage era.17
PSORS1 is located in the major histocompatibility
complex (MHC, chromosome 6p21.3), home of the
HLA genes. Multiple HLA alleles have been associated with psoriasis, particularly HLA-B13, HLA-B37,
HLA-B46, HLAB57, HLA-Cw1, HLA-Cw6, HLA-DR7,
and HLA-DQ9.10 Many of these alleles are in linkage
disequilibrium with HLA-Cw6 (i.e., found together
on the same chromosome more often than would
be predicted by chance). Psoriasis is consistently
associated with the Class I, rather than the Class II,
end of extended HLA haplotypes carrying these risk
alleles.1820 HLA-Cw6 has consistently demonstrated
the highest relative risk for psoriasis in Caucasian
populations,10 and remains strongly associated
with psoriasis when found together with several
different HLA-B alleles,21 suggesting that the PSORS1
gene must reside telomeric to HLA-B. HLA-Cw6
is also associated with psoriatic arthritis, with a
tendency for early onset of skin lesions.22 HLA-B27,
HLA-B38, and HLA-B39 are also associated with
psoriatic arthritis even in the absence of HLA-Cw6,23
with HLA-B27 being most strongly associated with
the axial variant (see Chapter 19).
A haplotype containing HLA-Cw1 and HLA-B46,
found only in Southeast Asian populations, is
strongly associated with psoriasis in Thailand and
Japan.18,24,25 In these populations, approximately

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Chapter 18:

Psoriasis

one-third of psoriatics are HLA-Cw6-associated,

one-third are HLA-Cw1-B46-associated, and onethird show no detectable HLA association.18 Unlike
HLA-Cw6, which is associated with early age of onset in Southeast Asian as well as Caucasian psoriatics, the HLA-Cw1-B46 haplotype is equally prevalent
in early- and late-onset psoriatics.18 Although HLACw6 is strongly associated with guttate psoriasis,26
there is no evidence for a similar association with
the HLA-Cw1-B46 haplotype. Interestingly, this haplotype has been associated with other autoimmune
diseases, including myasthenia gravis and Graves
disease.27
Linkage disequilibrium has posed the major
obstacle to confirming or refuting the role of HLACw6 in psoriasis. A particularly strong region of LD
containing ten genes is found just telomeric to HLAC,28,29 and not surprisingly, several of these genes
also display strong associations with psoriasis. By
comparative DNA sequencing of risk versus nonrisk
haplotype haplotypes, we were able to exclude
all structural variants of all these genes with the
exception of HLA-C and CDSN.30 CDSN is an interesting candidate, as its expression is increased in
psoriasis, and it plays an important role in regulating the desquamation of keratinocytes.31 By further
analysis of genetic markers located between HLA-C
and CDSN in Caucasian30 and Chinese32 populations,
CDSN could also be excluded, leaving HLA-Cw6
as the only remaining gene candidate for PSORS1.
However, additional work is needed to rule out the
possibility of regulatory variant(s) in this region that
do not fall within genes. It is also likely that additional psoriasis susceptibility genes remain to be
identified within the MHC, as haplotypes carrying
HLA-Cw6 along with different HLA-B alleles carry
different risks of disease.21 Recent studies have
mapped one of these additional determinants to
the MHC Class IIClass III interface.33,34
Only about 10% of HLA-Cw6 carriers develop
psoriasis, and it has been estimated that PSORS1 accounts for only one-third of the variation in genetic
liability to psoriasis.35 Therefore, it is highly likely
that additional non-MHC genes are also involved. In
addition to PSORS1, linkage studies have reported
18 potential susceptibility loci.17,36 However, many
of these have proven difficult to replicate. After
PSORS1, the second-most consistently replicated
psoriasis susceptibility locus is PSORS2 (17q24q25),37 with four independent studies providing
confirmatory evidence (p < 0.01) in support of

the original report.3841 Other regions of putative

linkage showing some evidence of reproducibility
include PSORS4 (1q21.3),42,43 PSORS5 (3q21),4446
PSORS8 (16q12-q13),47 and PSORS9 (4q28-q31).48,49
It was reported that the PSORS2 locus contributes
to psoriasis by influencing the expression of the
SLC9A3R1, NAT1, and/or RAPTOR genes involved in
immunologic regulation,50 but others have been
unable to confirm these findings.51,52 Reports of
two large families linked to this locus34,37 raise the
possibility that more than one susceptibility gene
may reside at PSORS2one carrying a common
disease allele with low penetrance, and the other
carrying one or more rare alleles with high penetrance. The PSORS4 locus contains the epidermal
differentiation complex (EDC). At least 58 genes
involved in epidermal differentiation reside in
the EDC, including the loricrin, involucrin, filaggrin, small proline-rich region (SPRR), S100, and
late cornified envelope (LCE) genes.53 The PSORS5
locus (3q21) was originally linked to psoriasis in
Swedish families;45 the evidence for replication is
based on two association studies.45,46 The PSORS8
locus overlaps with a known susceptibility gene
for Crohn disease (NOD2/CARD15) and has been
implicated in psoriatic arthritis.47 The PSORS9 locus
was originally identified in a Chinese population,
but also provided some evidence for linkage in four
other genome-wide linkage scans involving largely
Caucasian populations.49
More recently, researchers studying psoriasis
and other complex genetic disorders have turned
to genome-wide association studies (GWAS) to
identify susceptibility genes. In GWAS, disease allele
frequencies are compared in cases and controls,
rather than measuring the transmission of alleles
through pedigrees as is done in linkage studies.
Association is much more powerful than linkage
in the search for common alleles contributing to
polygenic diseases.16 The major disadvantage of
genetic association studies is that their effective
range is short, due to the many generations and
numerous meiotic recombination events between
the initial appearance of an ancient, diseasepredisposing genetic variant and the present
day. Therefore, hundreds of thousands of genetic
markers are required to cover the genome in an
association study.16 Fortunately, recently developed
technologies allow 500,000 to 5,000,000 genetic
markers, called single nucleotide polymorphisms
(SNPs), to be typed at the same time. The identification of these SNPs allowed the development of

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Chapter 18:

the HapMap,54 which provides a dense map of SNP

haplotypes (i.e., the SNP alleles found together on
a single chromosome) from diverse ethnic populations. These resources allow geneticists to infer the
genotypes of SNPs located between experimentally
typed markers, a process called genotype imputation.55 Although the GWAS strategy entails a very
large number of tests and therefore increases the
risk of false-positive results, the ability to confirm
the result in independent replication cohorts addresses this issue. Compounding the problem, it
has become evident that the risk conferred by individual disease alleles is relatively small, meaning
that thousands of cases and thousands of controls
are typically required to carry out a well-powered
GWAS. Fortunately, the prevalence of psoriasis (approximately 2% in Caucasians) is high enough that
assembly of such large collections is feasible. With
the advent of genome-wide association studies
(GWAS), our knowledge of non-MHC genetic determinants of psoriasis susceptibility has advanced
rapidly.56 At least 18 published non-MHC genetic
loci meet strict criteria for genome-wide significance34,5759 (Table 18-1). Of these, four [(1) IL12B, (2)
IL23A, (3) IL23R, (4) TRAF3IP2] map within or near
genes involved in the IL-23/Th17 axis.34,57,60,61 Additional regions of association contain genes whose
products are involved in the control of Th1/Th2 polarization (IL4/IL13),34,63 in regulating NF-B signaling (TNFAIP3, TNIP1, NFKBIA, and FBXL19),34,58,59,61,64 in
MHC Class I antigen processing (ERAP1, PSMA6),59,65
in inflammatory dendritic cell function (NOS2), in
interferon signaling (TYK2, IFIH1, IL28RA),61, 6364 and
in epidermal barrier formation (LCE3B/LCE3C).57,65
A report of increased defensin gene cluster copy
number in psoriasis66 is of interest but remains to
be confirmed. Later in this chapter, these findings
are further examined in the context of the skin
immune system (see Section Psoriasis: Integrating
Genetics and Immunology).
An interesting feature of the GWAS results obtained thus far in psoriasis and other complex
genetic disorders is that the SNP allele conferring
risk of disease is often more common than the
nonrisk in allele not only in cases but also in normal
controls. In some cases, the disease allele may be
ancestral, as is the case for lactose intolerance.
Alternatively, the disease allele may be beneficial in
certain contexts (i.e., defense against pathogens),
as is the case for hemoglobinopathies increasing
resistance to malaria, or at least selectively neutral
with respect to reproduction. It is also possible

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.

Autoantigens and Guttate Flare

What Happens During A Guttate Flare?

During a guttate flare, we speculate that T cells

respond to streptococcal infection by proliferating,
differentiating into an effector/memory phenotype,
and acquiring skin-homing capability. On entering
the skin, these cells encounter a locally activated
dermal environment characterized by capillary dilatation and edema.71,72,74,236 This environment may be
fostered by focal mast cell degranulation and macrophage activation, with release of TNF- leading to
induction of adhesion molecules on the endothelial
cell surface, facilitating entry of T cells into the
dermis. The mechanisms that trigger the activation
of these mast cells and macrophages are presently
unknown. At this point in lesional evolution, epidermal changes are subtle but include an increase
in keratinocyte DNA synthesis, widened extracellular spaces between keratinocytes, and biochemical alterations in the stratum corneum indicative
of altered differentiation, despite a lack of visible
parakeratosis.67 The mechanisms by which these
epidermal changes are evoked remain unknown
but could involve the generation of basement
membrane fenestrations by macrophage-derived
proteases,156,157 allowing permeation of fibronectin
and even cytokine-laden mast cell granules73 into
the epidermal compartment. The former event
stimulates keratinocyte proliferation,219 whereas
the latter could provoke the epidermal spongiosis
characteristic of very early psoriatic lesions.73

What Is (Are) the Psoriasis Autoantigen(s)?

If psoriasis is mediated by antigen-specific T cells,

then what are the T cells reacting against? In guttate psoriasis, streptococcal M protein is a strong
candidate. M proteins are major virulence factors of
group A -hemolytic Streptococci, and more than 80
serotypes are known, reflecting significant variability in protein sequence thought to assist in warding
off host immune responses.237 The autoimmune disorder rheumatic fever is only associated with a few

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Chapter 18:

Psoriasis

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

HLA-Cw6 molecules on the surface of DCs together

with the local concentration of self-antigen determined the probability of exceeding the threshold
for breakage of tolerance, leading to an all-or-none
process of T-cell activation.230 On the other hand,
about half of psoriasis patients are HLA-Cw6 negative, more so in late-onset psoriasis patients lacking
a positive family history.256 A recent study indicates
that similar mechanisms of antigen recognition and
subsequent clonal T-cell expansion are involved in
HLA-Cw6-negative patients, though the process
may be somewhat more efficient in HLA-Cw6-positive patients.257

How Antigen-Specific Is T-Cell Activation in Psoriasis?

Streptococcally induced guttate psoriasis lacks

clonal T-cell receptor gene rearrangements,258 and
clonal T-cell receptor rearrangements are not invariably seen in early psoriatic lesions.259 Indeed, most
dermal and epidermal T cells found in psoriatic lesions are not clonally expanded. Thus, these T cells
may not be directly recognizing antigens at all, instead being bystanders supported by the local cytokine environment. Alternatively, it is also possible
that many different cross-reactive T-cell clones may
recognize self-peptides in the context of HLA-Cw6
with low affinity, without provoking marked expansion. Innate immune mechanisms may also serve to
polyclonally activate existing skin-homing memory
T cells in psoriasis, especially during the presumed
initial infection-related triggering event. Based on
the observation of peptidoglycan (PG)-containing
macrophages in the papillary and perivascular
infiltrates of guttate and chronic plaque psoriasis, it
has been suggested that PG, a major constituent of
the streptococcal cell wall, may function to activate
T cells in psoriasis via a Toll-like receptor (TLR)-mediated and cytokine-dependent mechanism.260 Many
PG-reactive T-cell clones have been recovered from
psoriasis lesions, suggesting that PG may also serve
as a true antigen.260

Cross-Priming in Psoriasis: Why Is It Important?

Along with K16 and K17, most of the proteins that

are strongly overexpressed in psoriatic epidermis
are intracellular proteins expressed by keratinocytes. However, keratinocytes are not effective
APCs for naive or even memory T cells.261 How, then,
could these proteins be effectively processed and
presented to CD8+ T cells to generate persistent
autoreactivity? Antigen-presenting DCs ingest
intracellular proteins from other cells and present

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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

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Psoriasis 23

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Chapter 18:

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