The immunology of atopic dermatitis and its reversibility with broad-spectrum and targeted therapies

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Atopic dermatitis (AD), the most common chronic inflammatory skin disease, is driven by both terminal keratinocyte differentiation defects and strong type 2 immune responses. In contrast to chronic plaque-type psoriasis, AD is now understood to be a much more heterogeneous disease, with additional activation of TH22, TH17/IL-23, and TH1 cytokine pathways depending on the subtype of the disease. In this review we discuss our current understanding of the AD immune map in both patients with early-onset and those with chronic disease. Clinical studies with broad and targeted therapeutics have helped to elucidate the contribution of various immune axes to the disease phenotype. Importantly, immune activation extends well beyond lesional AD because nonlesional skin and the blood component harbor AD-specific inflammatory changes. For this reason, future therapeutics will need to focus on a systemic treatment approach, especially in patients with moderate-to-severe disease.

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)

  • D. Thaci et al.

    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

    (2016)
  • J.D. Hamilton et al.

    Dupilumab improves the molecular signature in skin of patients with moderate-to-severe atopic dermatitis

    J Allergy Clin Immunol

    (2014)
  • J.L. Harden et al.

    The immunogenetics of psoriasis: a comprehensive review

    J Autoimmun

    (2015)
  • T. Czarnowicki et al.

    Skin barrier and immune dysregulation in atopic dermatitis: an evolving story with important clinical implications

    J Allergy Clin Immunol Pract

    (2014)
  • M.O. Danso et al.

    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

    (2014)
  • B.E. Kim et al.

    Loricrin and involucrin expression is down-regulated by Th2 cytokines through STAT-6

    Clin Immunol

    (2008)
  • D. Hijnen et al.

    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

    (2004)
  • M.D. Howell et al.

    Cytokine modulation of atopic dermatitis filaggrin skin expression

    J Allergy Clin Immunol

    (2007)
  • T. Nomura et al.

    Advances in atopic dermatitis in 2015

    J Allergy Clin Immunol

    (2016)
  • M.C. Bruggen et al.

    In situ mapping of innate lymphoid cells in human skin: evidence for remarkable differences between normal and inflamed skin

    J Invest Dermatol

    (2016)
  • C.M. Bonefeld et al.

    The role of innate lymphoid cells in healthy and inflamed skin

    Immunol Lett

    (2016)
  • T.Y. Halim et al.

    Group 2 innate lymphoid cells are critical for the initiation of adaptive T helper 2 cell-mediated allergic lung inflammation

    Immunity

    (2014)
  • N. Novak et al.

    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

    (2002)
  • L.S. Chan et al.

    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

    (2001)
  • T. Zheng et al.

    Transgenic expression of interleukin-13 in the skin induces a pruritic dermatitis and skin remodeling

    J Invest Dermatol

    (2009)
  • Q. Hamid et al.

    In vivo expression of IL-12 and IL-13 in atopic dermatitis

    J Allergy Clin Immunol

    (1996)
  • A.M. Brauweiler et al.

    Th2 cytokines increase Staphylococcus aureus alpha toxin-induced keratinocyte death through the signal transducer and activator of transcription 6 (STAT6)

    J Invest Dermatol

    (2014)
  • K.O. Kisich et al.

    Defective killing of Staphylococcus aureus in atopic dermatitis is associated with reduced mobilization of human beta-defensin-3

    J Allergy Clin Immunol

    (2008)
  • M. Niebuhr et al.

    Staphylococcal exotoxins are strong inducers of IL-22: a potential role in atopic dermatitis

    J Allergy Clin Immunol

    (2010)
  • M.D. Howell et al.

    Cytokine milieu of atopic dermatitis skin subverts the innate immune response to vaccinia virus

    Immunity

    (2006)
  • J.K. Gittler et al.

    Progressive activation of T(H)2/T(H)22 cytokines and selective epidermal proteins characterizes acute and chronic atopic dermatitis

    J Allergy Clin Immunol

    (2012)
  • N. Dhingra et al.

    A possible role for IL-17A in establishing Th2 inflammation in murine models of atopic dermatitis

    J Invest Dermatol

    (2014)
  • T. Thepen et al.

    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

    (1996)
  • Y. Tokura

    Extrinsic and intrinsic types of atopic dermatitis

    J Dermatol Sci

    (2010)
  • M.A. McAleer et al.

    The multifunctional role of filaggrin in allergic skin disease

    J Allergy Clin Immunol

    (2013)
  • S. Noda et al.

    The Asian atopic dermatitis phenotype combines features of atopic dermatitis and psoriasis with increased TH17 polarization

    J Allergy Clin Immunol

    (2015)
  • M. Suarez-Farinas et al.

    Intrinsic atopic dermatitis shows similar TH2 and higher TH17 immune activation compared with extrinsic atopic dermatitis

    J Allergy Clin Immunol

    (2013)
  • C. Cole et al.

    Filaggrin-stratified transcriptomic analysis of pediatric skin identifies mechanistic pathways in patients with atopic dermatitis

    J Allergy Clin Immunol

    (2014)
  • D. Malajian et al.

    New pathogenic and therapeutic paradigms in atopic dermatitis

    Cytokine

    (2015)
  • D.J. Margolis et al.

    The persistence of atopic dermatitis and filaggrin (FLG) mutations in a US longitudinal cohort

    J Allergy Clin Immunol

    (2012)
  • E. Berardesca et al.

    Ethnic skin: overview of structure and function

    J Am Acad Dermatol

    (2003)
  • D.J. Margolis et al.

    Filaggrin-2 variation is associated with more persistent atopic dermatitis in African American subjects

    J Allergy Clin Immunol

    (2014)
  • B. Shi et al.

    The skin microbiome is different in pediatric versus adult atopic dermatitis

    J Allergy Clin Immunol

    (2016)
  • M.L. Tang et al.

    Reduced interferon-gamma secretion in neonates and subsequent atopy

    Lancet

    (1994)
  • K. Kaminishi et al.

    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

    (2002)
  • J.M. Hanifin et al.

    A population-based survey of eczema prevalence in the United States

    Dermatitis

    (2007)
  • C. Flohr et al.

    New insights into the epidemiology of childhood atopic dermatitis

    Allergy

    (2014)
  • T. Bieber

    Atopic dermatitis

    Ann Dermatol

    (2010)
  • J.I. Silverberg et al.

    Associations of childhood eczema severity: a US population-based study

    Dermatitis

    (2014)
  • R. Lande et al.

    The antimicrobial peptide LL37 is a T-cell autoantigen in psoriasis

    Nat Commun

    (2014)
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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.

    These authors contributed equally to this work.

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