Staphylococcal phosphatidylglycerol antigens activate human T cells via CD1a.

Expressed on epidermal Langerhans cells, CD1a presents a range of self-lipid antigens found within the skin; however, the extent to which CD1a presents microbial ligands from bacteria colonizing the skin is unclear. Here we identified CD1a-dependent T cell responses to phosphatidylglycerol (PG), a ubiquitous bacterial membrane phospholipid, as well as to lysylPG, a modified PG, present in several Gram-positive bacteria and highly abundant in Staphylococcus aureus. The crystal structure of the CD1a-PG complex showed that the acyl chains were buried within the A'- and F'-pockets of CD1a, while the phosphoglycerol headgroup remained solvent exposed in the F'-portal and was available for T cell receptor contact. Using lysylPG and PG-loaded CD1a tetramers, we identified T cells in peripheral blood and in skin that respond to these lipids in a dose-dependent manner. Tetramer+CD4+ T cell lines secreted type 2 helper T cell cytokines in response to phosphatidylglycerols as well as to co-cultures of CD1a+ dendritic cells and Staphylococcus bacteria. The expansion in patients with atopic dermatitis of CD4+ CD1a-(lysyl)PG tetramer+ T cells suggests a response to lipids made by bacteria associated with atopic dermatitis and provides a link supporting involvement of PG-based lipid-activated T cells in atopic dermatitis pathogenesis.

Primary cicatricial alopecias are characterized by dysregulation of shared gene expression pathways.

The primary forms of cicatricial (scarring) alopecia (PCA) are a group of inflammatory, irreversible hair loss disorders characterized by immune cell infiltrates targeting hair follicles (HFs). Lichen planopilaris (LPP), frontal fibrosing alopecia (FFA), and centrifugal cicatricial alopecia (CCCA) are among the main subtypes of PCAs. The pathogenesis of the different types of PCAs are poorly understood, and current treatment regimens yield inconsistent and unsatisfactory results. We performed high-throughput RNA-sequencing on scalp biopsies of a large cohort PCA patients to develop gene expression-based signatures, trained into machine-learning-based predictive models and pathways associated with dysregulated gene expression. We performed morphological and cytokine analysis to define the immune cell populations found in PCA subtypes. We identified a common PCA gene signature that was shared between LPP, FFA, and CCCA, which revealed a significant over-representation of mast cell (MC) genes, as well as downregulation of cholesterogenic pathways and upregulation of fibrosis and immune signaling genes. Immunohistological analyses revealed an increased presence of MCs in PCAs lesions. Our gene expression analyses revealed common pathways associated with PCAs, with a strong association with MCs. The indistinguishable differences in gene expression profiles and immune cell signatures between LPP, FFA, and CCCA suggest that similar treatment regimens may be effective in treating these irreversible forms of hair loss.

Spin in Abstracts of Systematic Reviews and Meta-analyses of Melanoma Therapies: Cross-sectional Analysis.

BACKGROUND: Spin is defined as the misrepresentation of a study's results, which may lead to misperceptions or misinterpretation of the findings. Spin has previously been found in randomized controlled trials and systematic reviews of acne vulgaris treatments and treatments of various nondermatological conditions. OBJECTIVE: The purpose of this study was to quantify the presence of spin in abstracts of systematic reviews and meta-analyses of melanoma therapies and identify any related secondary characteristics of these articles. METHODS: We used a cross-sectional approach on June 2, 2020, to search the MEDLINE and Embase databases from their inception. To meet inclusion criteria, a study was required to be a systematic review or meta-analysis pertaining to the treatment of melanoma in human subjects, and reported in English. We used the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) definition of systematic reviews and meta-analyses. Data were extracted in a masked, duplicate fashion. We conducted a powered bivariate linear regression and calculated odds ratios for each study characteristic. RESULTS: A total of 200 systematic reviews met the inclusion criteria. We identified spin in 38% (n=76) of the abstracts. The most common type of spin found was type 3 (selective reporting of or overemphasis on efficacy outcomes or analysis favoring the beneficial effect of the experimental intervention), occurring 40 times; the least common was type 2 (title claims or suggests a beneficial effect of the experimental intervention not supported by the findings), which was not present in any included abstracts. We found that abstracts pertaining to pharmacologic interventions were 3.84 times more likely to contain spin. The likelihood of an article containing spin has decreased annually (adjusted odds ratio 0.91, 95% CI 0.84-0.99). No significant correlation between funding source or other study characteristics and the presence of spin was identified. CONCLUSIONS: We have found that spin is fairly common in the abstracts of systematic reviews of melanoma treatments, but the prevalence of spin in these abstracts has been declining from 1992-2020.

Treatment of Toxic Epidermal Necrolysis with Etanercept in a Pediatric Patient.

Toxic epidermal necrolysis is a rare, life-threatening skin disease with no consensus on adjunctive treatment, particularly in pediatric patients. We present the case of a 13-year-old previously healthy patient with drug-associated toxic epidermal necrolysis who experienced significantly shortened length of hospital stay and duration of symptoms compared with published literature when treated with 2 doses of etanercept 50 mg during 5 days.

Punctal Congestion Syndrome: A Reversible, Functional Punctal Stenosis Causing Epiphora in the Setting of Chronic Pretarsal Conjunctivitis.

PURPOSE: To describe a reversible syndrome of epiphora, functional punctal stenosis, and chronic pretarsal conjunctivitis associated with corticosteroid or corticosteroid-antibiotic eyedrop use. METHODS: This is an Institutional Review Board-approved retrospective review of patients diagnosed with epiphora, punctal stenosis, and chronic conjunctivitis by a single surgeon (B.J.W.). These patients were subsequently invited to participate in a prospective study involving allergy skin patch testing for ophthalmic drops, common excipients, and active ingredients. RESULTS: Thirteen patients received a diagnosis of punctal congestion syndrome. The average age was 63 years (range, 41-93) and 69.2% were female. Findings were bilateral in 61.5%. All had used preserved drops in the affected eye(s). Various antecedent diagnoses resulted in treatment with preserved drops. Patients experienced epiphora for an average of 3.8 months (median, 3 months; mode, 3 months; range, 1-8 months) prior to presentation. Two patients had undergone punctoplasty which failed to resolve symptoms. 92.3% of patients had been taking tobramycin-dexamethasone drops, loteprednol drops, or a combination of both prior to presentation. All were taken off preserved drops. 69.2% were also treated with a preservative-free loteprednol etabonate 0.5% ophthalmic ointment taper. All improved. Partial relief of symptoms was achieved by an average of 1.6 months (median, 2 months; mode, 2 months; standard deviation, ±0.7 months) and resolution of symptoms by 2.5 months (median, 2 months; mode, 2 months; standard deviation, ±1.7 months). One patient underwent patch testing with strong positive reactions to formaldehyde and neomycin and a weak positive reaction to gentamicin. CONCLUSIONS: Functional punctal stenosis is associated with topical ophthalmic preparations, especially preserved corticosteroids and antibiotic-corticosteroid combinations. Treatment consists of removal of all preserved eyedrops. Symptoms often improve over several months.

Recapitulating T cell infiltration in 3D psoriatic skin models for patient-specific drug testing.

Drug screening studies for inflammatory skin diseases are currently performed using model systems that only partially recapitulate human diseased skin. Here, we developed a new strategy to incorporate T cells into human 3D skin constructs (HSCs), which enabled us to closely monitor and quantitate T cell responses. We found that the epidermis promotes the activation and infiltration of T cells into the skin, and provides a directional cue for their selective migration towards the epidermis. We established a psoriatic HSC (pHSC) by incorporating polarized Th1/Th17 cells or CCR6+CLA+ T cells derived from psoriasis patients into the constructs. These pHSCs showed a psoriatic epidermal phenotype and characteristic cytokine profiles, and responded to various classes of psoriasis drugs, highlighting the potential utility of our model as a drug screening platform. Taken together, we developed an advanced immunocompetent 3D skin model to investigate epidermal-T cell interactions and to understand the pathophysiology of inflammatory skin diseases in a human-relevant and patient-specific context.

Tofacitinib for the treatment of lichen planopilaris: A case series.

Lichen planopilaris (LPP) is an inflammatory cicatricial alopecia for which many different therapies are attempted with varying success. The Janus kinase (JAK) inhibitor, tofacitinib, has been shown to be effective in treating the noncicatricial alopecia, alopecia areata. As in alopecia areata, upregulation of interferon and JAK signaling may play a role in LPP. We retrospectively reviewed the cases of 10 patients with recalcitrant LPP who were treated with oral tofacitinib. Patients received oral tofacitinib 5 mg twice or three times daily for 2-19 months as either monotherapy or adjunctive therapy to other ongoing treatments including intralesional triamcinolone, hydroxychloroquine, and tacrolimus ointment. Eight patients had clinical improvement in LPP with tofacitinib as either monotherapy (4/10) or adjunctive therapy (4/10). LPP Activity Index (LPPAI) before and after treatment was measured in seven patients and was significantly different (6.22 before treatment, 3.08 after treatment; p value = .0014). Reduction in LPPAI ranged from 30 to 94%. One patient complained of 10 pound (4.5 kg) weight gain after 12 months on tofacitinib. No other adverse effects were reported. Treatment with oral tofacitinib either as monotherapy or adjunctive therapy can lead to measurable improvement in recalcitrant LPP.

JAK Inhibitors for Treatment of Alopecia Areata.

The advancement of genetic and preclinical studies has uncovered the mechanisms involved in the pathogenesis of alopecia areata (AA). The development of targeted therapies using small molecules blocking specific pathways for the treatment of AA is underway. By repurposing Food and Drug Administration-approved small molecule JAK inhibitors as treatments for AA, it has been demonstrated that JAK inhibitors can effectively reverse hair loss in patients with moderate to severe AA. In this review, we summarize and discuss the current preclinical and clinical studies on JAK inhibitors, as well as the prospects of using JAK inhibitors for the treatment of AA.

A kindred with fish eye disease, corneal opacities, marked high-density lipoprotein deficiency, and statin therapy.

A kindred affected with fish eye disease (FED) from Oklahoma is reported. Two probands with corneal opacification had mean levels of high-density lipoprotein (HDL) cholesterol (C), apolipoprotein (apo) A-I, and apoA-I in very large alpha-1 HDL particles that were 9%, 17%, and 5% of normal, whereas their parents and 1 sibling had values that were 61%, 77%, and 72% of normal. The probands had no detectable lipoprotein-X, and had mean low-density lipoprotein cholesterol (LDL-C) and triglyceride levels that were elevated. Their mean lecithin cholesterol acyltransferase (LCAT) activities, cholesterol esterification rates, and free cholesterol levels were 8%, 42%, and 258% of normal, whereas their parents and 1 sibling had values that were 55%, 49%, and 114% of normal. The defect was due to 1 common variant in the LCAT gene in exon 1: c101t causing a proline34leucine substitution and a novel mutation c1177t causing a threonine37methionine substitution, with the former variant being found in the father and 1 sibling, and the latter mutation being found in the mother, and both mutations being present in the 2 probands. FED is distinguished from familial LCAT deficiency (FLD) by the lack of anemia, splenomegaly, and renal insufficiency as well as normal or increased LDL-C. Both FLD and FED cases have marked HDL deficiency and corneal opacification, and FED cases may have premature coronary heart disease in contrast to FLD cases. Therapy, using presently available agents, in FED should be to optimize LDL-C levels, and 1 proband responded well to statin therapy. The investigational use of human recombinant LCAT as an enzyme source is ongoing.