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SnapshotDx Quiz: December 2020

  • Alexander Herbst
    Affiliations
    Dr Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami L. Miller School of Medicine, Miami, Florida, USA
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  • Mariya Miteva
    Correspondence
    Correspondence: Mariya Miteva, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, 1600 Northwest 10th Avenue, RMSB 2023A, Miami, Florida 33136, USA.
    Affiliations
    Dr Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami L. Miller School of Medicine, Miami, Florida, USA
    Search for articles by this author

      What is your Diagnosis?

      Figure thumbnail gr1
      Figure 1
      Images courtesy of Mariya Miteva, Dr Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami
      Figure thumbnail gr2
      Figure 1
      Images courtesy of Mariya Miteva, Dr Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami
      Editorial note: Welcome to the Journal of Investigative Dermatology (JID) SnapshotDx Quiz. In this monthly online-only quiz, the first question (“What is your diagnosis?”) relates to the clinical image shown, while additional questions concern the findings reported in the JID article by
      • Gadsbøll A.Ø.
      • Jee M.H.
      • Funch A.B.
      • Alhede M.
      • Mraz V.
      • Weber J.F.
      • et al.
      Pathogenic CD8+ epidermis-resident memory T cells displace dendritic epidermal T cells in allergic dermatitis.
      (https://doi.org/10.1016/j.jid.2019.07.722).
      Detailed answers and a list of relevant references are available following the Quiz Questions below.

      Quiz Questions

      • 1.
        What is your diagnosis on the basis of the clinical and histologic findings?
        • a.
          Mycosis fungoides
        • b.
          Tinea manuum
        • c.
          Urticaria
        • d.
          Allergic contact dermatitis (ACD)
        • e.
          Fixed drug eruption
      • 2.
        Which of the following answers is TRUE?
        • a.
          Among γδ and αβ T cells, only the latter are found in human epidermis.
        • b.
          Histopathology reliably distinguishes ACD from irritant contact dermatitis and atopic dermatitis.
        • c.
          Exposure of the skin to contact allergen induces the accumulation of allergen-specific CD8+CD69+CD103+ T cells in the skin.
        • d.
          In humans, Vδ1 T cells (the major subset of γδ T cells) possess dendritic shape as in rodents.
        • e.
          CD4+CCR10+ memory T cells disappear from the dermis after the clinical resolution of ACD.
      • 3.
        Which of the following answers is FALSE according to the article by
        • Gadsbøll A.Ø.
        • Jee M.H.
        • Funch A.B.
        • Alhede M.
        • Mraz V.
        • Weber J.F.
        • et al.
        Pathogenic CD8+ epidermis-resident memory T cells displace dendritic epidermal T cells in allergic dermatitis.
        • a.
          Exposure to allergens leads to the generation of CD8+ epidermal resident memory T (TRM) cells (skin TRM cells).
        • b.
          Dendritic epidermal T cells (DETCs) are not required for the generation of CD8+ epidermal TRM cells after exposing the skin to an allergen.
        • c.
          Expansion of the CD8+ epidermal TRM cell population after allergen re-exposure is mediated solely by local proliferation in the epidermis and not by recruitment from the circulation.
        • d.
          CD8+ epidermal TRM cells have a higher respiratory capacity than DETCs.
        • e.
          The magnitude of the cutaneous hypersensitivity reaction and the frequency of CD8+ epidermal TRM cells directly correlate with the dose of the allergen.
      See the following pages for detailed answers

      Detailed Answers

      • 1.
        What is your diagnosis on the basis of the clinical and histologic findings?
      • CORRECT ANSWER: d. Allergic contact dermatitis (ACD).
      • The image shows a patient with ACD. ACD is a disease typified by a localized eruption secondary to a delayed-type hypersensitivity reaction (
        • Rashid R.S.
        • Shim T.N.
        Contact dermatitis.
        ). Occupational exposures are frequent, with nearly 40% of patients having positive patch testing that identifies a relevant occupational contactant (
        • DeKoven J.G.
        • Warshaw E.M.
        • Zug K.A.
        • Maibach H.I.
        • Belsito D.V.
        • Sasseville D.
        • et al.
        North American contact dermatitis group patch test results: 2015-2016.
        ). Acutely, ACD is characterized by pruritus localized to a well-demarcated area of erythema, often with vesiculation. Over time, this may give way to a lichenified or fissured dermatitis (
        • Murphey P.B.
        • Hooten J.N.
        • Atwater A.R.
        • Gossman W.
        Allergic contact dermatitis.
        ). Histology of ACD typically demonstrates a spongiotic dermatitis (including eosinophilic spongiosis as noted on the image) with an associated superficial lymphocytic perivascular infiltrate. These features are shared with irritant contact dermatitis (ICD) as well as atopic dermatitis (AD), and histology does not reliably differentiate these entities. Specific findings suggestive of ACD, including increased deep dermal infiltrate, absence of papillary dermal edema, reduced CD34 expression, and increased CD3+ T cells relative to ICD and AD, did not reach statistical significance. Between these three histologically similar conditions, only increased eosinophils in AD relative to ICD and ACD was found to be significant (
        • Frings V.G.
        • Böer-Auer A.
        • Breuer K.
        Histomorphology and immunophenotype of eczematous skin lesions revisited-skin biopsies are not reliable in differentiating allergic contact dermatitis, irritant contact dermatitis, and atopic dermatitis.
        ).
        • Discussion of incorrect answers:
        • a.
          Mycosis fungoides: Cutaneous T-cell lymphoma (CTCL) is a non-Hodgkin lymphoma with infiltration of the skin by malignant T lymphocytes. Mycosis fungoides (MF) is the most common form of CTCL, accounting for 55% of the cases (
          • Trautinger F.
          • Eder J.
          • Assaf C.
          • Bagot M.
          • Cozzio A.
          • Dummer R.
          • et al.
          European Organisation for Research and Treatment of Cancer consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome - update 2017.
          ). The incidence of CTCL is approximately 6.4 per million persons, with improvements in diagnosis likely accounting for reports of increased incidence (
          • Phyo Z.H.
          • Shanbhag S.
          • Rozati S.
          Update on Biology of cutaneous T-cell lymphoma.
          ). Many clinical and histopathologic features of MF are nonspecific, resulting in a median time from onset of symptoms to diagnosis of between 3 and 4 years. In addition to consistent clinical and histopathologic features, the diagnosis of MF can be supported by demonstrating clonality of T cells between lesions at different sites as well as the loss of pan T-cell antigens such as CD2, CD5, and CD7 in the malignant lymphocytes (
          • Wilcox R.A.
          Cutaneous T-cell lymphoma: 2016 update on diagnosis, risk-stratification, and management.
          ). Skin-directed therapies for MF include topical corticosteroids, topical mechlorethamine, topical bexarotene, UV phototherapy, and radiation therapies. Systemic therapies, which are often combined with skin-directed therapies, include retinoids, IFN-α, methotrexate, chemotherapies, immunotherapies, and extracorporeal photopheresis (
          • Trautinger F.
          • Eder J.
          • Assaf C.
          • Bagot M.
          • Cozzio A.
          • Dummer R.
          • et al.
          European Organisation for Research and Treatment of Cancer consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome - update 2017.
          ).
        • b.
          Tinea manuum: Tinea manuum is a common superficial fungal infection of the hands, most commonly caused by dermatophytes from the genera Epidermophyton, Trichophyton, and Microsporum. Tinea infections are among the most common infections worldwide. When affecting the palmar hands, the infection takes on a dry, scaling appearance. This typically presents solely on the dominant hand in combination with bilateral tinea pedis on the one hand, two-foot syndrome; however, bilateral palmar infection is possible (
          • Moriarty B.
          • Hay R.
          • Morris-Jones R.
          The diagnosis and management of tinea.
          ). The most commonly implicated dermatophytes in the United States are Trichophyton rubrum, T. mentagrophytes, and T. tonsurans, and tinea infections occur in up to 70% of adults (
          • Drake L.A.
          • Dinehart S.M.
          • Farmer E.R.
          • Goltz R.W.
          • Graham G.F.
          • Hardinsky M.K.
          • et al.
          Guidelines of care for superficial mycotic infections of the skin: tinea corporis, tinea cruris, tinea facei, tinea manuum, and tinea pedis. Guidelines/Outcomes Committee. American Academy of Dermatology.
          ). With appropriate history and clinical examination findings, diagnosis can be verified with potassium hydroxide preparation or fungal culture. Treatment may be a topical application of imidazoles, allylamines, or ciclopirox olamine; however, systemic therapy with antifungals can be used in inflammatory or widespread cases (
          • Drake L.A.
          • Dinehart S.M.
          • Farmer E.R.
          • Goltz R.W.
          • Graham G.F.
          • Hardinsky M.K.
          • et al.
          Guidelines of care for superficial mycotic infections of the skin: tinea corporis, tinea cruris, tinea facei, tinea manuum, and tinea pedis. Guidelines/Outcomes Committee. American Academy of Dermatology.
          ).
        • c.
          Urticaria: Urticaria presents with pruritic wheals with or without angioedema and can be divided into acute and chronic forms with a delineation of a 6-week duration. Chronic urticaria can further be divided into spontaneous and inducible types. Inducible types may be secondary to triggers, including exposure to temperature changes, pressure, vibration, UV radiation, and contact with water (
          • Kudryavtseva A.V.
          • Neskorodova K.A.
          • Staubach P.
          Urticaria in children and adolescents: an updated review of the pathogenesis and management.
          ). Acute urticaria is idiopathic in the majority of cases. When triggers are identified, the most common are infections, drug reactions, and food allergies. In noninducible cases of chronic urticaria, up to 30% of cases have associated autoantibodies to the high-affinity IgE receptor FCεRIα or IgA. Histopathologic findings of urticaria include upper dermal edema with mild perivascular and interstitial mixed inflammation (
          • Antia C.
          • Baquerizo K.
          • Korman A.
          • Bernstein J.A.
          • Alikhan A.
          Urticaria: a comprehensive review: epidemiology, diagnosis, and work-up.
          ). Second-generation antihistamines are first line for the treatment of chronic urticaria, and data do not support the superiority of an individual agent relative to another. The dosing required to treat chronic urticaria is commonly greater than the approved doses, with most cases requiring two to four times the recommended doses (
          • Antia C.
          • Baquerizo K.
          • Korman A.
          • Alikhan A.
          • Bernstein J.A.
          Urticaria: a comprehensive review: treatment of chronic urticaria, special populations, and disease outcomes.
          ).
        • e.
          Fixed drug eruption: Fixed drug eruption (FDE) is a cutaneous drug eruption that presents with dusky red to brown patches on the skin and mucosa. The patches recur at the same sites during recurrences owing to resident populations of intraepidermal memory CD8+ T lymphocytes. The most common offending medications are antibiotics and nonsteroidal anti-inflammatory drugs. Similar to Stevens‒Johnson syndrome and toxic epidermal necrolysis, cytotoxic Fas, Fas-ligand, perforin, and granzyme B play an important role in FDE. In contrast to the image in this question stem, the histopathology of FDE typically demonstrates apoptotic keratinocytes, vacuolar interface change, pigment incontinence, and a superficial perivascular inflammatory infiltrate with the presence of eosinophils (
          • Cho Y.T.
          • Lin J.W.
          • Chen Y.C.
          • Chang C.Y.
          • Hsiao C.H.
          • Chung W.H.
          • et al.
          Generalized bullous fixed drug eruption is distinct from Stevens-Johnson syndrome/toxic epidermal necrolysis by immunohistopathological features.
          ).
      • 2.
        Which of the following answers is TRUE?
      • CORRECT ANSWER: c. Exposure of the skin to contact allergen induces the accumulation of allergen-specific CD8+CD69+CD103+ T cells in the skin.
      • CD8+CD69+CD103+ resident memory T (TRM) cells in the skin are directly involved in the production of the rapid hypersensitivity reaction that occurs on exposure to a previously encountered contactant (
        • Gadsbøll A.Ø.
        • Jee M.H.
        • Funch A.B.
        • Alhede M.
        • Mraz V.
        • Weber J.F.
        • et al.
        Pathogenic CD8+ epidermis-resident memory T cells displace dendritic epidermal T cells in allergic dermatitis.
        ).
        • Gamradt P.
        • Laoubi L.
        • Nosbaum A.
        • Mutez V.
        • Lenief V.
        • Grande S.
        • et al.
        Inhibitory checkpoint receptors control CD8+ resident memory T cells to prevent skin allergy.
        demonstrated that circulating effector T cells involved in the early acute hypersensitivity reaction give way to these TRM cells, which can persist in the skin for several weeks. Subsequent re-exposure produces the expansion of this cell population and also by the influx of circulating CD8+ T cells.
        • Gadsbøll A.Ø.
        • Jee M.H.
        • Funch A.B.
        • Alhede M.
        • Mraz V.
        • Weber J.F.
        • et al.
        Pathogenic CD8+ epidermis-resident memory T cells displace dendritic epidermal T cells in allergic dermatitis.
        demonstrated further that the TRM cells displace dendritic epidermal T cells (DETCs) and that the magnitude of the hypersensitivity reaction correlated with both the frequency of CD8+ TRM cells and the dose of the allergen.
        • Discussion of incorrect answers:
        • a.
          Among γδ and αβ T cells, only the latter are found in human epidermis: This statement is false because both γδ and αβ T cells are found within the human epidermis (
          • Gadsbøll A.Ø.
          • Jee M.H.
          • Funch A.B.
          • Alhede M.
          • Mraz V.
          • Weber J.F.
          • et al.
          Pathogenic CD8+ epidermis-resident memory T cells displace dendritic epidermal T cells in allergic dermatitis.
          ). These resident T-cell populations may function in immune surveillance in the skin and participate in skin homeostasis through the production of insulin-like GF-1, and their dysfunction may play a role in the chronicity of nonhealing wounds (
          • Toulon A.
          • Breton L.
          • Taylor K.R.
          • Tenenhaus M.
          • Bhavsar D.
          • Lanigan C.
          • et al.
          A role for human skin-resident T cells in wound healing.
          ).
        • b.
          Histopathology reliably distinguishes ACD from irritant contact dermatitis and atopic dermatitis: This statement is false because there is considerable overlap between histopathologic features of ACD, ICD, and AD. All three of these conditions commonly demonstrate a spongiotic dermatitis with superficial perivascular lymphocytic infiltrates.
          • Frings V.G.
          • Böer-Auer A.
          • Breuer K.
          Histomorphology and immunophenotype of eczematous skin lesions revisited-skin biopsies are not reliable in differentiating allergic contact dermatitis, irritant contact dermatitis, and atopic dermatitis.
          performed a retrospective analysis of the histologic and immunohistochemistry findings from 35 biopsy specimens from 28 patients. With the exception of an increased presence of eosinophils in biopsies from AD, there were no significant differences in routine histology or immunophenotyping among these disorders (
          • Frings V.G.
          • Böer-Auer A.
          • Breuer K.
          Histomorphology and immunophenotype of eczematous skin lesions revisited-skin biopsies are not reliable in differentiating allergic contact dermatitis, irritant contact dermatitis, and atopic dermatitis.
          ).
        • d.
          In humans, Vδ1 T cells (the major subset of γδ T cells) possess dendritic shape as in rodents: This statement is false. Although Vδ1 T cells do account for the major subset of γδ T cells in human skin, they do not have the specific dendritic shape as seen in rodent DETCs (
          • Sutoh Y.
          • Mohamed R.H.
          • Kasahara M.
          Origin and evolution of dendritic epidermal T cells.
          ). In rodents, the development of these cells is dependent on Skint1 gene expression. Humans express a SKINT1L gene, in which inactivating mutations are thought to be responsible for this lack of a discrete dendritic shape. Interestingly, chimpanzees demonstrate similar nonfunctional Skint1l expression and DETC morphology to humans, but Old World monkeys possess functional Skint1 sequences and a population of dendritic-shaped γδ T cells. These findings suggest that the functionality of this gene, which plays a major role in the phenotype of these resident T cells, was lost in a hominoid ancestor (
          • Mohamed R.H.
          • Sutoh Y.
          • Itoh Y.
          • Otsuka N.
          • Miyatake Y.
          • Ogasawara K.
          • et al.
          The SKINT1-like gene is inactivated in hominoids but not in all primate species: implications for the origin of dendritic epidermal T cells.
          ).
        • e.
          CD4+CCR10+ memory T cells disappear from the dermis after clinical resolution of ACD: This is false. By treating skin with oxazolone to produce ACD,
          • Wang X.
          • Fujita M.
          • Prado R.
          • Tousson A.
          • Hsu H.C.
          • Schottelius A.
          • et al.
          Visualizing CD4 T-cell migration into inflamed skin and its inhibition by CCR4/CCR10 blockades using in vivo imaging model.
          demonstrated that CCR4 and CCR10 are upregulated on CD4+ T lymphocytes in lymph nodes, which leads to the recruitment of these cells to the skin affected by ACD. After the clinical resolution of the ACD, however, these cells persist in the skin and may mediate the accelerated inflammatory responses seen after repeated exposures to contactants. This is in contrast to ICD, in which these cells were not detected after clinical resolution. Taken together, the findings suggest that the presence of CD4+CCR10+ T cells is likely allergen mediated (
          • Moed H.
          • Boorsma D.M.
          • Tensen C.P.
          • Flier J.
          • Jonker M.J.
          • Stoof T.J.
          • et al.
          Increased CCL27-CCR10 expression in allergic contact dermatitis: implications for local skin memory.
          ).
      • 3.
        Which of the following answers is FALSE according to the article by
        • Gadsbøll A.Ø.
        • Jee M.H.
        • Funch A.B.
        • Alhede M.
        • Mraz V.
        • Weber J.F.
        • et al.
        Pathogenic CD8+ epidermis-resident memory T cells displace dendritic epidermal T cells in allergic dermatitis.
        ?
      • CORRECT ANSWER: c. Expansion of the CD8+ epidermal TRM cell population after allergen re-exposure is mediated solely by local proliferation in the epidermis and not by recruitment from the circulation.
      • This choice is FALSE. According to the article by
        • Gadsbøll A.Ø.
        • Jee M.H.
        • Funch A.B.
        • Alhede M.
        • Mraz V.
        • Weber J.F.
        • et al.
        Pathogenic CD8+ epidermis-resident memory T cells displace dendritic epidermal T cells in allergic dermatitis.
        , the expansion of CD8+ TRM population occurs both by local proliferation and by an influx of CD8+ T cells from circulation. In this article, mice were exposed to dinitrofluorobenzene (DNFB) allergen. The change in the number of CD8+ TRM cells was monitored. In a portion of mice, however, FTY720 was administered. FTY720, also known as fingolimod, is an immunomodulator, with the applications as a treatment for multiple sclerosis and as an anticancer therapy. FTY720 sequesters T cells to lymphoid tissues through the antagonism of sphingosine-1-phosphate 1 receptor (
        • White C.
        • Alshaker H.
        • Cooper C.
        • Winkler M.
        • Pchejetski D.
        The emerging role of FTY720 (fingolimod) in Cancer treatment.
        ). This sequestration prevented their recruitment to the skin. In this subset of mice, a significant reduction of CD8+ TRM cells was noted after exposure to DNFB compared with the subset of those without lymphocyte sequestration. They demonstrated that approximately 40% of the TRM expansion is due to the recruitment of CD8+ cells from circulation (
        • Gadsbøll A.Ø.
        • Jee M.H.
        • Funch A.B.
        • Alhede M.
        • Mraz V.
        • Weber J.F.
        • et al.
        Pathogenic CD8+ epidermis-resident memory T cells displace dendritic epidermal T cells in allergic dermatitis.
        ).
        • Discussion of incorrect answers:
        • a.
          Exposure to allergens leads to the generation of CD8+ epidermal resident memory T (TRM) cells (skin TRM cells): This is true. On exposure to an allergen, allergen-specific CD8+CD69+CD103+ TRM cells accumulate in the skin and then mediate the hypersensitivity reactions that occur on exposure to the allergen. This article compared the composition of epidermal T-cell populations in control mice with that of mice sensitized to the experimental allergen, DNFB. In the control group, the majority of T cells in the epidermis were Vγ3+CD69+CD103+ DETCs. In these control mice, CD4+ and CD8+ cells were rare. In the experimental group, however, allergen exposure resulted in an increased presence of CD8+CD69+CD103+ TRM cells to account for 60% of the total epidermal T-cell population. CD4+CD69+ T cells also increased to a lesser degree (
          • Gadsbøll A.Ø.
          • Jee M.H.
          • Funch A.B.
          • Alhede M.
          • Mraz V.
          • Weber J.F.
          • et al.
          Pathogenic CD8+ epidermis-resident memory T cells displace dendritic epidermal T cells in allergic dermatitis.
          ).
        • b.
          Dendritic epidermal T cells (DETCs) are not required for the generation of CD8+ epidermal TRM cells after exposing the skin to an allergen: This is true. In this article, an experimental mouse model without the expression of TCRδ and therefore without DETCs was evaluated. After the exposure of these mice to DNFB allergen, a major population of TRM cells was still produced. Therefore, these TRM cells are generated independently of DETCs (
          • Gadsbøll A.Ø.
          • Jee M.H.
          • Funch A.B.
          • Alhede M.
          • Mraz V.
          • Weber J.F.
          • et al.
          Pathogenic CD8+ epidermis-resident memory T cells displace dendritic epidermal T cells in allergic dermatitis.
          ).
        • d.
          CD8+ epidermal TRM cells have a higher respiratory capacity than DETCs: After exposure to allergen, the DETC population decreases in the epidermis as the TRM population increases.
          • Gadsbøll A.Ø.
          • Jee M.H.
          • Funch A.B.
          • Alhede M.
          • Mraz V.
          • Weber J.F.
          • et al.
          Pathogenic CD8+ epidermis-resident memory T cells displace dendritic epidermal T cells in allergic dermatitis.
          determined the bioenergetics profiles of the epidermal T-cell populations by looking at the basal oxygen consumption rate and extracellular acidification rate. These were significantly increased in TRM cells compared with those of DTECs, possibly accounting for a survival advantage and resultant persistence within the epidermis of CD8+ TRM cells compared with that of DTECs (
          • Gadsbøll A.Ø.
          • Jee M.H.
          • Funch A.B.
          • Alhede M.
          • Mraz V.
          • Weber J.F.
          • et al.
          Pathogenic CD8+ epidermis-resident memory T cells displace dendritic epidermal T cells in allergic dermatitis.
          ).
        • e.
          The magnitude of the cutaneous hypersensitivity reaction and the frequency of CD8+ epidermal TRM cells directly correlates with the dose of the allergen:
          • Gadsbøll A.Ø.
          • Jee M.H.
          • Funch A.B.
          • Alhede M.
          • Mraz V.
          • Weber J.F.
          • et al.
          Pathogenic CD8+ epidermis-resident memory T cells displace dendritic epidermal T cells in allergic dermatitis.
          exposed mice to DNFB and measured ear thickness at several time points. Ear thickness was used to determine the magnitude of the contact hypersensitivity (CHS) reaction. Ear thickness and therefore the magnitude of CHS reaction was proportional to the number of CD8+ TRM cells, the number of exposures to an experimental allergen, and the dose of that allergen (
          • Gadsbøll A.Ø.
          • Jee M.H.
          • Funch A.B.
          • Alhede M.
          • Mraz V.
          • Weber J.F.
          • et al.
          Pathogenic CD8+ epidermis-resident memory T cells displace dendritic epidermal T cells in allergic dermatitis.
          ).

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