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Immunology of Psoriasis

Cristina Albanesi

CLINICAL AND HISTOLOGICAL FEATURES An association with HLA-B13 was first identified and later with
OF PSORIASIS other class I molecules HLA-B17, HLA-B37, HLA-B57, HLA-Cw6,
and HLA-Cw7, and class II molecules HLA-DR4 and HLA-DR7.
Psoriasis is a common chronic, relapsing immune-mediated Among these, the highest and most consistently reported relative
disease involving skin and small joints of genetically predisposed risk is for HLA-Cw6 haplotype. A significantly higher frequency
individuals. It affects approximately 2% of the general population, of HLA-Cw6 is associated with early-onset (type I) psoriasis
with >50% of patients presenting in the first three decades of compared with late-onset psoriasis (type II). Current data suggest
life. There is a wide spectrum of cutaneous manifestations of that HLA-Cw6 is the susceptibility allele within PSORS1, but
psoriasis. Individual lesions vary from pinpoint to large plaques, no disease-specific mutations have been identified, and variants
or even generalized erythroderma. More specifically, the clinical in regulatory sequences potentially affecting several downstream
spectrum of psoriasis includes the plaque, guttate, small plaque, genes cannot be ruled out. HLA-C might be involved in immune
1
inverse, erythrodermic, and pustular variants. The most common responses at the levels of both antigen presentation and natural
and well-recognized morphological presentation of psoriasis is killer (NK)–cell regulation. Recently, compelling evidence has
that of the plaque type (Fig. 64.1). The disease is characterized emerged for an interaction between the HLA-C and ERAP1
by the formation of demarked erythematous plaques with large (involved in major histocompatibility complex (MHC) class I
3
scaling. The scales are a result of a hyperproliferative epidermis peptide processing) loci in psoriasis. 36763ERAP1 variants only
with premature maturation of keratinocytes and incomplete influenced psoriasis susceptibility in individuals carrying the
cornification, with retention of nuclei in the stratum corneum HLA-C risk allele.
(parakeratosis). The mitotic rate of the basal keratinocytes is Other predisposing polygenes were found in the PSORS2
increased compared with that of normal skin. As a result, the region, on chromosome 17q25. Two distinct regions harboring
epidermis is thickened (acanthosis), with elongated rete ridges susceptibility loci have been identified: the first contains the genes
4
that form finger-like protrusions into the dermis. The granular SLC9A3R1 and NAT9 and the second the gene RAPTOR. The
layer of the epidermis (the starting site of terminal keratinocyte SLC9A3R1 gene encodes a PDZ domain-containing phospho-
differentiation) is strongly reduced or missing. The epidermis protein, implicated in several biological processes occurring in T
is infiltrated by neutrophils and activated CD8 T lymphocytes, cells. NAT9 encodes an N-acetyltransferase involved in MHC class
whereas within the dermis there is an inflammatory infiltrate I antigen-presentation and in immunological processes related
+
composed mainly of CD3 T cells, dendritic cells (DCs), macro- to autoimmune diseases. Additionally, between SLC9A3R1 and
phages, mast cells, and neutrophils. Elongated and dilated blood NAT9 is a polymorphism for the binding site of a transcription
4
vessels in the dermal papillae represent a further histological factor RUNX1 that may affect regulation of the immune synapse.
hallmark of psoriatic skin lesions (Fig. 64.2). 1 Associations with alleles of interleukin (IL)-12, IL-23 receptor
(IL-23R), IL-19/20, and IRF2 have also been described. Interest-
ingly, IL-12 and IL-23R single nucleotide polymorphisms do
IMMUNE-RELATED GENETIC FACTORS not have interactions with HLA-Cw6. Recently, polymorphisms
4
PREDISPOSING TO PSORIASIS have been found in two genes, IL-36RN and CARD14, and to be
4,5
independently associated with psoriasis. For CARD14 (caspase
The genetic basis of psoriasis has long been recognized, since recruitment domain-containing protein 14) gene, many missense
family members of patients with psoriasis are at greater risk of mutations, leading to elevation of CARD14 mRNA in patients,
developing the disease. The concordance rate of psoriasis is were initially found in pediatric patients with a severe clinical
approximately 70% in monozygotic twins and 20% in dizygotic presentation of psoriasis. CARD14 gene mutation protein, in
2
twins, depending on the study and population. The mode of association with an inflammatory stimulus, may induce aberrant
inheritance is complex. It is thought that there is no single disease activation of nuclear factor (NF)-κb, a transcription factor that
gene, but, rather, a complex set of gene variants, resulting in an controls the expression of many genes, including key chemokines
aberrant response to environmental factors. At least nine chro- upregulated in psoriasis, such as chemokine (C-X-C motif) ligand
mosomal loci with statistically significant linkage to psoriasis (CXCL)8 and CC chemokine ligand (CCL)20. Mutations in
have been identified, termed psoriasis susceptibility loci 1 through IL-36RN gene were described in patients with severe pustular
2
9 (PSORS1 through PSORS9). PSORS1 is the major genetic psoriasis. This gene encodes the antiinflammatory protein IL-36Ra,
determinant of psoriasis and is located within the human leu- antagonist of IL-36γ, a cytokine highly produced in psoriatic
kocyte antigen (HLA) complex on chromosome 6p (Chapter 5). lesions and with important proinflammatory function.

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