Journal of Allergy and Clinical Immunology
The immunology of atopic dermatitis and its reversibility with broad-spectrum and targeted therapies
Section snippets
The emerging immune map of AD
Similar to psoriasis, which is centered around a TH17/IL-23 axis, AD has been associated with activation of T-cell subsets.27 Although AD seems to be unanimously characterized by a strong activation of TH2 immune responses in lesional and even nonlesional skin,20 the TH22, TH17/IL-23, and TH1 cytokine pathways likely play a role in the disease, particularly in some AD subtypes.8
In acute lesions AD onset is characterized by profound increases of TH2 levels (IL-4, IL-5, IL-13, IL-31, and CCL18)
AD shows phenotypic variations
Several AD subtypes have been described with considerable variations (Fig 1).8, 75 These are based on IgE levels (intrinsic vs extrinsic AD),76 FLG mutation status, race, and age.3, 29, 77, 78, 79
Mutations in the FLG gene, leading to deficiency in FLG, have been associated with AD that is more severe and persistent than with its wild-type counterpart. This includes a higher degree of immune dysregulation with type 1 interferon–mediated stress responses and higher IL-1 cytokine levels and higher
Pediatric versus adult AD: Different immune phenotypes on a common TH2 background
Despite the fact that AD usually starts early in childhood, most AD studies have only investigated adult patients. However, there are some clinical clues for differences between early pediatric and adult AD, such as lesions on extensor surfaces in infants, whereas adults typically show flexor involvement.3 Furthermore, the skin microbiome differs in patients with pediatric versus adult AD.94 Most studies in children with AD are limited to studies of peripheral blood,80, 95, 96, 97, 98, 99, 100,
AD as a systemic disease
Often, AD begins during early infancy or childhood, and adults usually have longstanding disease for decades.121, 122 Circulating skin-homing T cells marked by cutaneous lymphocyte antigen (CLA) in patients with severe AD show significant increases in levels of activation markers and polar cytokines, even compared with those seen in patients with psoriasis, when compared with levels in healthy subjects.123 Significant increases in B-cell counts in blood are also seen in patients with AD but not
Targeted therapies as milestones in understanding pathogenesis
Because of the advent of new targeted therapeutics (Fig 2, A), our knowledge in key disease pathways is rapidly expanding. Ongoing or recently published controlled trials are summarized in Table I.
IgE, levels of which are profoundly increased in 80% of patients with extrinsic disease, has long been regarded as key in the development of eczema.145 Thus far, 2 randomized controlled studies did not show clinical effects of the IgE blocker omalizumab,146, 147 suggesting that increased IgE levels
Outlook
Currently, clinical trials with targeted therapeutics have become key in the advancement of understanding the pathophysiology of this debilitating skin disease. Both successful treatment approaches and failing therapies have profoundly increased our understanding of AD and will help shape future therapies, hopefully at a similar successful pace as seen for psoriasis in the last 15 years.
References (174)
- et al.
Atopic dermatitis
Lancet
(2016) - et al.
Cellular and molecular immunologic mechanisms in patients with atopic dermatitis
J Allergy Clin Immunol
(2016) - et al.
Alefacept (lymphocyte function-associated molecule 3/IgG fusion protein) treatment for atopic eczema
J Allergy Clin Immunol
(2008) - et al.
Efalizumab therapy for atopic dermatitis causes marked increases in circulating effector memory CD4+ T cells that express cutaneous lymphocyte antigen
J Invest Dermatol
(2008) - et al.
Cyclosporine in patients with atopic dermatitis modulates activated inflammatory pathways and reverses epidermal pathology
J Allergy Clin Immunol
(2014) - et al.
Lessons learned from mice and man: mimicking human allergy through mouse models
Clin Immunol
(2014) - et al.
The translational revolution and use of biologics in patients with inflammatory skin diseases
J Allergy Clin Immunol
(2015) - et al.
Deciphering the complexities of atopic dermatitis: shifting paradigms in treatment approaches
J Allergy Clin Immunol
(2014) - et al.
A mild topical steroid leads to progressive anti-inflammatory effects in the skin of patients with moderate-to-severe atopic dermatitis
J Allergy Clin Immunol
(2016) - et al.
Residual genomic signature of atopic dermatitis despite clinical resolution with narrow-band UVB
J Allergy Clin Immunol
(2013)
Efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments: a randomised, placebo-controlled, dose-ranging phase 2b trial
Lancet
Dupilumab improves the molecular signature in skin of patients with moderate-to-severe atopic dermatitis
J Allergy Clin Immunol
The immunogenetics of psoriasis: a comprehensive review
J Autoimmun
Skin barrier and immune dysregulation in atopic dermatitis: an evolving story with important clinical implications
J Allergy Clin Immunol Pract
TNF-alpha and Th2 cytokines induce atopic dermatitis-like features on epidermal differentiation proteins and stratum corneum lipids in human skin equivalents
J Invest Dermatol
Loricrin and involucrin expression is down-regulated by Th2 cytokines through STAT-6
Clin Immunol
Serum thymus and activation-regulated chemokine (TARC) and cutaneous T cell- attracting chemokine (CTACK) levels in allergic diseases: TARC and CTACK are disease-specific markers for atopic dermatitis
J Allergy Clin Immunol
Cytokine modulation of atopic dermatitis filaggrin skin expression
J Allergy Clin Immunol
Advances in atopic dermatitis in 2015
J Allergy Clin Immunol
In situ mapping of innate lymphoid cells in human skin: evidence for remarkable differences between normal and inflamed skin
J Invest Dermatol
The role of innate lymphoid cells in healthy and inflamed skin
Immunol Lett
Group 2 innate lymphoid cells are critical for the initiation of adaptive T helper 2 cell-mediated allergic lung inflammation
Immunity
Dichotomic nature of atopic dermatitis reflected by combined analysis of monocyte immunophenotyping and single nucleotide polymorphisms of the interleukin-4/interleukin-13 receptor gene: the dichotomy of extrinsic and intrinsic atopic dermatitis
J Invest Dermatol
Expression of interleukin-4 in the epidermis of transgenic mice results in a pruritic inflammatory skin disease: an experimental animal model to study atopic dermatitis
J Invest Dermatol
Transgenic expression of interleukin-13 in the skin induces a pruritic dermatitis and skin remodeling
J Invest Dermatol
In vivo expression of IL-12 and IL-13 in atopic dermatitis
J Allergy Clin Immunol
Th2 cytokines increase Staphylococcus aureus alpha toxin-induced keratinocyte death through the signal transducer and activator of transcription 6 (STAT6)
J Invest Dermatol
Defective killing of Staphylococcus aureus in atopic dermatitis is associated with reduced mobilization of human beta-defensin-3
J Allergy Clin Immunol
Staphylococcal exotoxins are strong inducers of IL-22: a potential role in atopic dermatitis
J Allergy Clin Immunol
Cytokine milieu of atopic dermatitis skin subverts the innate immune response to vaccinia virus
Immunity
Progressive activation of T(H)2/T(H)22 cytokines and selective epidermal proteins characterizes acute and chronic atopic dermatitis
J Allergy Clin Immunol
A possible role for IL-17A in establishing Th2 inflammation in murine models of atopic dermatitis
J Invest Dermatol
Biphasic response against aeroallergen in atopic dermatitis showing a switch from an initial TH2 response to a TH1 response in situ: an immunocytochemical study
J Allergy Clin Immunol
Extrinsic and intrinsic types of atopic dermatitis
J Dermatol Sci
The multifunctional role of filaggrin in allergic skin disease
J Allergy Clin Immunol
The Asian atopic dermatitis phenotype combines features of atopic dermatitis and psoriasis with increased TH17 polarization
J Allergy Clin Immunol
Intrinsic atopic dermatitis shows similar TH2 and higher TH17 immune activation compared with extrinsic atopic dermatitis
J Allergy Clin Immunol
Filaggrin-stratified transcriptomic analysis of pediatric skin identifies mechanistic pathways in patients with atopic dermatitis
J Allergy Clin Immunol
New pathogenic and therapeutic paradigms in atopic dermatitis
Cytokine
The persistence of atopic dermatitis and filaggrin (FLG) mutations in a US longitudinal cohort
J Allergy Clin Immunol
Ethnic skin: overview of structure and function
J Am Acad Dermatol
Filaggrin-2 variation is associated with more persistent atopic dermatitis in African American subjects
J Allergy Clin Immunol
The skin microbiome is different in pediatric versus adult atopic dermatitis
J Allergy Clin Immunol
Reduced interferon-gamma secretion in neonates and subsequent atopy
Lancet
Flow cytometric analysis of IL-4, IL-13 and IFN-gamma expression in peripheral blood mononuclear cells and detection of circulating IL-13 in patients with atopic dermatitis provide evidence for the involvement of type 2 cytokines in the disease
J Dermatol Sci
A population-based survey of eczema prevalence in the United States
Dermatitis
New insights into the epidemiology of childhood atopic dermatitis
Allergy
Atopic dermatitis
Ann Dermatol
Associations of childhood eczema severity: a US population-based study
Dermatitis
The antimicrobial peptide LL37 is a T-cell autoantigen in psoriasis
Nat Commun
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P.M.B. was supported in part by grant no. UL1TR001866 from the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH) Clinical and Translational Science Award (CTSA) Program.
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These authors contributed equally to this work.