Lecture 6
A. Compare and contrast the immuno-pathogenesis of psoriasis and atopic dermatitis,
highlighting their key immunological differences.
a. Describe the immunological mechanisms underlying the pathogenesis of psoriasis,
focusing on the role of T cells, cytokines and the keratinocyte response.
b. Explain the immune pathways involved in atopic dermatitis, emphasizing the role
of IgE, Th2 cytokines and the dysfunction of the skin barrier.
c. Compare and contrast the immunological processes between psoriasis and atopic
dermatitis, highlighting similarities and differences in their immune cell
involvement, cytokine profiles, and underlying mechanisms.
d. Discuss specific immunological features unique to each condition that
differentiate psoriasis from atopic dermatitis, contributing to their distinct clinical
presentations and disease courses
Atopic Dermatitis and Psoriasis are inflammatory skin disorders where dysregulation of
immune responses in the skin leads to immuno-pathology and inflammatory disorders. There
are key immunological differences between the two disorders, the main one being that
psoriasis is a Th17 driven disease and AD a Th2-mediated disease. In this essay, we will
compare and contrast the immuno-pathogenesis of psoriasis and AD, highlighting their key
immunological differences.
Psoriasis
Psoriasis is an immune-mediated skin disorder underpinned by genetic susceptibility,
environmental factors and immune dysregulation involving keratinocytes, dendritic cells and
T cells. Clinical manifestations are heterogenous ranging from guttate psoriasis to nail
psoriasis, the most common being plaque psoriasis characterised by bring red plaques due to
KC excessive proliferation and immune cell activation. Arthritis is often associated with
psoriasis, as well as other co-morbidities that affect quality of life, like obesity and
cardiovascular diseases. The immuno-histological features of psoriasis involve parakeratosis
which is the abnormal retention of KC nuclei in the stratum corneum, acanthosis which is the
proliferation of KC and thickening of the dermis and the prominent presence of T cells and
DCs in the dermis and epidermis. KC are the first layer of defence of the skin, sensing
pathogens and commensal microorganisms via their PRRs and producing AMPs and cytokines
to immediately kill pathogens and attract other immune cells. Langerhans’s cells are also key
skin cellular players, they have a tolerogenic and protective role.
Psoriasis etio-pathogenesis is complex, with interactions between genetic predisposition and
environmental factors that trigger a dysregulated immune response in the skin.
Environmental triggers for psoriasis include trauma, infection, drugs and stress like smoking.
GWAS has identified more than 100 loci associated with psoriasis, encompassing genes
related to the skin and mediating many innate and adaptive immune genes that belong to
four major signalling pathways, the type I interferon pathway, the NF-kB signalling pathway,
antigen presentation and the IL-23/17 axis. HLA-C is involved in antigen presentation and
regulation of the immune response, it has the strongest association with psoriasis and confers
the strongest risk with 50% of the UK psoriasis patients carrying the allele. It presents antigens
, to CD8+ T cells and it is suggested that they engage in a pathogenic cross-talk with KC, driving
inflammation in plaque psoriasis. TNF, IL-17 and IL-23 are key mediators of the cellular cross-
talk between KCs, DCs and T cells in the disease such as when they are blocked, they help to
improve the disease.
There is evidence that psoriasis is an immune-mediated disease such as evidence from bone
marrow transplantation cases report clearance of psoriasis following transplant from a
normal donor and vice versa with transplant from a psoriatic donor. Non-lesioned
symptomless skin from psoriatic patient transplanted on immunodeficient mouse showed the
development of fully-fledged psoriasis lesions due to pathogenic tissue resident T cells. As
well, clinically resolved psoriatic lesions contain psoriasis-specific IL-17 producing T cell clones
possibly waiting to be reactivated.
A trigger and genetic predisposition give rise to a stressful environment for KCs which will
release AMPs, self-DNA and self-RNA. These complex with AMP like LL37, breaking down skin
tolerance, LL37:self-RNA activating DCs and LL37:self-DNA activating professional DCs which
will produce INF-alpha favouring the maturation of myeloid DCs and the production of TNF
by KCs. IFN-alpha and TNF are potent DC activators, potentiating their antigen presentation
ability to T cells. Though the auto-antigen in psoriasis is unknown, but speculated to be LL37,
antigen-loaded DCs will travel to skin-running lymph nodes and present the auto-antigen to
T cells, driving T17 differentiation. DCs also release IL-23, IL-6 and TGF-beta to drive the
activation and expansion of IL-17 tissue-resident memory cells in the skin. These T17 cells
release IL-17A, IL-17F, IL-21 and IL-22 causing KC proliferation and release of pro-
inflammatory cytokines (like IL-17c), chemokines (like CXCL8) and AMPs (like S100) leading to
further cell inflammation and infiltration, leading to plaque formation. IL-23 produced in the
skin by macrophages and dermal DCs are critical for T17 expansion and proliferation, also
activating other IL-17 producing cells. Chemokines produced attract more T cells and IL-17
impact cell recruitment and increases AMP production. The pro-inflammatory cytokines
influence KCs production of IL-8 to increase their proliferation. Therefore, IL-17 is a key
cytokine in psoriasis with Th17 and IL-17 producing CD8+ T cells abundantly residing in
lesioned skin. IL-23 is critical for IL-17 producing CD8+ T cell expansion and KC proliferation,
antibodies targeting IL-17 and IL-23 showing dramatic improvement in psoriasis. IL-23
possibly promotes the differentiation of Th17 pathogenic cells, its inhibition may lead to a
more durable response than IL-17 inhibition.
Atopic Dermatitis
AD is a predominantly a Th2-mediated disease in which inherited or acquired barrier
dysfunction and increased susceptibility to environmental factors trigger an aberrant immune
response. It is a type 2 immune response which initiates at the epithelial surface where
alarmins like TLSP, IL-25 and IL-33 activate Th2 and B cells. IL-4 and IL-13 are secreted by the
activated Th2 and Th22 cells, causing atopic diseases. AD is characterised by dry, itchy skin
with poorly defined red lesions with blistering and crusting early on, leading to scaling,
fissuring and thickening at later stages. It is often associated with other atopic disorders like
asthma and food allergy. The lesions in AD show an immune infiltrate of mostly CD4 T cells
and various DC subsets like Langerhans’s cells. Alarmins trigger epithelial barrier disruption,
activating inflammatory epidermal DCs and initiating Th2 response. Activated Th2 cells
