Comprehensive plasma cytokine and chemokine profiling in prurigo nodularis reveals endotypes in Type 2 inflammation.

Prurigo nodularis (PN) is a chronic inflammatory skin disease that is associated with variability in peripheral blood eosinophil levels and response to T-helper 2 targeted therapies (Th2). Our objective was to determine whether circulating immune profiles with respect to type 2 inflammation differ by race and peripheral blood eosinophil count. Plasma from 56 PN patients and 13 matched healthy controls was assayed for 54 inflammatory biomarkers. We compared biomarker levels between PN and HCs, among PN patients based on absolute eosinophil count, and across racial groups in PN. Eleven biomarkers were elevated in PN versus HCs including interleukin (IL)-12/IL-23p40, tumor necrosis factor-alpha (TNF-α), Thymic stromal lymphopoietin (TSLP), and macrophage-derived chemokine (MDC/CCL22). Additionally, PN patients with AEC > 0.3 K cells/µL had higher Th2 markers (eotaxin, eotaxin-3, TSLP, MCP-4/CCL13), and African American PN patients had lower eosinophils, eotaxin, and eotaxin-3 versus Caucasian and Asian PN patients (p < 0.05 for all). Dupilumab responders had higher AEC (p < 0.01), were more likely to be Caucasian (p = 0.02) or Asian (p = 0.05) compared to African Americans, and more often had a history of atopy (p = 0.08). This study suggests that blood AEC > 0.3 K and Asian and Caucasian races are associated with Th2 skewed circulating immune profiles and response to Th2 targeted therapies.

Single-Cell RNA Sequencing Reveals Dysregulated POSTN+WNT5A+ Fibroblast Subclusters in Prurigo Nodularis.

Prurigo nodularis (PN) is an intensely pruritic, inflammatory skin disease with a poorly understood pathogenesis. We performed single-cell transcriptomic profiling of 28,695 lesional and nonlesional PN cells. Lesional PN has increased dysregulated fibroblasts (FBs) and myofibroblasts. FBs in lesional PN were shifted toward a cancer-associated FB-like phenotype, with POSTN+WNT5A+ cancer-associated FBs increased in PN and similarly so in squamous cell carcinoma. A multicenter cohort study revealed an increased risk of squamous cell carcinoma and cancer-associated FB-associated malignancies (breast and colorectal) in patients with PN. Systemic fibroproliferative diseases (renal sclerosis and idiopathic pulmonary fibrosis) were upregulated in patients with PN. Ligand-receptor analyses demonstrated an FB neuronal axis with FB-derived WNT5A and periostin interactions with neuronal receptors melanoma cell adhesion molecule and ITGAV. These findings identify a pathogenic and targetable POSTN+WNT5A+ FB subpopulation that may predispose cancer-associated FB-associated malignancies in patients with PN.

Management guidelines for pregnant health care workers exposed to infectious dermatoses.

Exanthematous diseases are frequently of infectious origin, posing risks, especially for pregnant health care workers (HCWs) who treat them. The shift from cell-mediated (Th1 cytokine profile) to humoral (Th2 cytokine profile) immunity during pregnancy can influence the mother's susceptibility to infection and lead to complications for both mother and fetus. The potential for vertical transmission must be considered when evaluating the risks for pregnant HCWs treating infected patients because fetal infection can often have devastating consequences. Given the high proportion of women of childbearing age among HCWs, the pregnancy-related risks of exposure to infectious diseases are an important topic in both patient care and occupational health. Contagious patients with cutaneous manifestations often present to dermatology or pediatric clinics, where female providers are particularly prevalent; a growing number of these physicians are female. Unfortunately, the risks of infection for pregnant HCWs are not well defined. To our knowledge, there is limited guidance on safe practices for pregnant HCWs who encounter infectious dermatologic diseases. In this article, we review several infectious exanthems, their transmissibility to pregnant women, the likelihood of vertical transmission, and the potential consequences of infection for the mother and fetus. Additionally, we discuss recommendations with respect to avoidance, contact, and respiratory precautions, as well as the need for treatment after exposure.

Interleukin 9 alterations linked to alzheimer disease in african americans.

OBJECTIVE: Compared to older Caucasians, older African Americans have higher risks of developing Alzheimer disease (AD) and lower cerebrospinal fluid (CSF) tau biomarker levels. It is not known whether tau-related differences begin earlier in life or whether race modifies other AD-related biomarkers such as inflammatory proteins. METHODS: We performed multiplex cytokine analysis in a healthy middle-aged cohort with family history of AD (n = 68) and an older cohort (n = 125) with normal cognition (NC), mild cognitive impairment, or AD dementia. After determining baseline interleukin (IL)-9 level and AD-associated IL-9 change to differ according to race, we performed immunohistochemical analysis for proteins mechanistically linked to IL-9 in brains of African Americans and Caucasians (n = 38), and analyzed postmortem IL-9-related gene expression profiles in the publicly available Mount Sinai cohort (26 African Americans and 180 Caucasians). RESULTS: Compared to Caucasians with NC, African Americans with NC had lower CSF tau, p-Tau181 , and IL-9 levels in both living cohorts. Conversely, AD was only correlated with increased CSF IL-9 levels in African Americans but not Caucasians. Immunohistochemical analysis revealed perivascular, neuronal, and glial cells immunoreactive to IL-9, and quantitative analysis in independent US cohorts showed AD to correlate with molecular changes (upstream differentiation marker and downstream effector cell marker) of IL-9 upregulation only in African Americans but not Caucasians. INTERPRETATION: Baseline and AD-associated IL-9 differences between African Americans and Caucasians point to distinct molecular phenotypes for AD according to ancestry. Genetic and nongenetic factors need to be considered in future AD research involving unique populations. ANN NEUROL 2019;86:407-418.

CSF Cytokines in Aging, Multiple Sclerosis, and Dementia.

Inflammation is a common process involved in aging, multiple sclerosis (MS), and age-related neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD), but there is limited evidence for the effects of aging on inflammation in the central nervous system. We collected cerebrospinal fluid (CSF) from 105 healthy control subjects representing a wide age range (23-86), and analyzed levels of cytokines associated innate immunity (TNF-α) and different T-helper subtypes: interferon-gamma induced protein 10 (IP-10) for Th1, interleukin-10 (IL-10) for Th2, and interleukin 8 (IL-8/CXCL8) for Th17. We show that CSF levels of TNF-α, IP-10, and IL-8 all increased linearly with age, but levels of IL-10 demonstrated a U-shaped relationship with age. We further found greater age-related increases in TNF-α, IL-10, and IL-8 relative to increases in IP-10 levels, consistent with a shift from Th1 to other inflammatory phenotypes. Finally, when we analyzed the same four cytokines in people with neurological disorders, we found that MS and AD, but not PD or dementia with Lewy bodies, further accentuated the age-related shift from Th1- to non-Th1-related cytokines. We propose that CSF cytokine levels represent powerful surrogates of brain inflammation and aging, and some, but not all, neurological disorders accelerate the shift away from Th1 phenotypes.

Automation vs. Experience: Measuring Alzheimer's Beta-Amyloid 1-42 Peptide in the CSF.

Cerebrospinal fluid (CSF) biomarkers can enhance the early and accurate etiologic detection of Alzheimer's disease (AD) even when symptoms are very mild, but are not yet widely available for clinical testing. There are a number of reasons for this, including the need for an experienced operator, the use of instruments mostly reserved for research, and low cost-effectiveness when patient samples do not completely fill each assay plate. Newer technology can overcome some of these issues through automated assays of a single patient sample on existing clinical laboratory platforms, but it is not known how these newer automated assays compare with previous research-based measurements. This is a critical issue in the clinical translation of CSF AD biomarkers because most cohort and clinicopathologic studies have been analyzed on older assays. To determine the correlation of CSF beta-amyloid 1-42 (Aß42) measures derived from the automated chemiluminescent enzyme immunoassay (CLEIA, on Lumipulse® G1200), a bead-based Luminex immunoassay, and a plate-based enzyme-linked immunoassay enzyme-linked immunosorbent assay (ELISA), we analyzed 30 CSF samples weekly on each platforms over 3 weeks. We found that, while CSF Aß42 levels were numerically closer between CLEIA and ELISA measurements, levels differed between all three assays. CLEIA-based measures correlated linearly with the two other assays in the low and intermediate Aß42 concentrations, while there was a linear correlation between Luminex assay and ELISA throughout all concentrations. For repeatability, the average intra-assay coefficient of variation (CV) was 2.0%. For intermediate precision, the inter-assay CV was lower in CLEIA (7.1%) than Luminex (10.7%, p = 0.009) and ELISA (10.8%, p = 0.009), primarily due to improved intermediate precision in the higher CSF Aß42 concentrations. We conclude that the automated CLEIA generated reproducible CSF Aß42 measures with improved intermediate precision over experienced operators using Luminex assays and ELISA, and are highly correlated with the manual Aß42 measures.