Angiokeratoma-like purpuric palmar nodules following chemotherapy.

We describe a patient with leukemia undergoing chemotherapy who developed painful purpuric nodules of the digits. These findings were concerning for endocarditis (clinically) and angiokeratomas on gross histology. After extensive evaluation, we report the development of painful purpuric nodules as a likely side effect of the patient's therapeutic regimen (hydroxyurea, danorubicin, cytarabine, and methotrexate).

Autoimmune Sequelae Following Rituximab Therapy: A Review of the Literature and Potential Immunologic Mechanisms.

Rituximab is an anti-CD20 antibody used to deplete B lymphocytes in lymphoma and autoimmune disease. Case reports in the literature describe patients who paradoxically develop autoimmune disease in response to rituximab therapy. We review the reports of autoimmune pathology in response to rituximab treatment and the proposed mechanisms of this reaction. These autoimmune diseases manifest in various organ systems, most frequently the skin and lungs, and involve distinct mechanisms of pathogenesis mediated by potential alterations in B and T lymphocytes, innate immune system, and specific environmental factors. Those clinicians utilizing rituximab should be aware of this unusual phenomenon.

Cutting Edge: Resident Memory CD8 T Cells Express High-Affinity TCRs.

Tissue-resident memory T (TRM) cells serve as vanguards of antimicrobial host defense in nonlymphoid tissues, particularly at barrier epithelia and in organs with nonrenewable cell types (e.g., brain). In this study, we asked whether an augmented ability to sense Ag complemented their role as early alarms of pathogen invasion. Using mouse polyomavirus, we show that brain-resident mouse polyomavirus-specific CD8 T cells, unlike memory cells in the spleen, progressively increase binding to MHC class I tetramers and CD8 coreceptor expression. Using the two-dimensional micropipette adhesion-frequency assay, we show that TRM cells in brain, as well as in kidney, express TCRs with up to 20-fold higher affinity than do splenic memory T cells, whereas effector cells express TCRs of similar high affinity in all organs. Together, these data demonstrate that TRM cells retain high TCR affinity, which endows them with the high Ag sensitivity needed for front-line defense against infectious agents.

Progression of relapsing-remitting demyelinating disease does not require increased TCR affinity or epitope spread.

In this study, we investigate the basis of T cell recognition of myelin that governs the progression from acute symptoms into disease remission, relapse, and chronic progression in a secondary progressive model of demyelinating disease. Until now, the frequency and affinity of myelin-reactive CD4 T cells that elicit relapsing-remitting disease have not been quantified. The micropipette adhesion frequency assay was used to obtain a sensitive and physiologically relevant two-dimensional measurement of frequency and TCR affinity for myelin, as the inherent low affinity does not allow the use of specific peptide:MHC-II tetramers for this purpose. We found the highest affinity and frequency of polyclonal myelin oligodendrocyte glycoprotein-reactive cells infiltrate the CNS during acute disease, whereas affinities during remission, relapse, and chronic disease are not significantly different from each other. Frequency analysis revealed that the vast majority of CNS-infiltrating CD4 T cells are myelin oligodendrocyte glycoprotein reactive at all time points, demonstrating epitope spread is not a predominant factor for disease progression. Furthermore, time points at which mice were symptomatic were characterized by an infiltration of Th17 cells in the CNS, whereas symptom remission showed an enrichment of cells producing IFN-γ. Also, the ratio of regulatory T cells to Foxp3(-) CD4 T cells was significantly higher in the CNS at remission than during acute disease. The results of this study indicate that a high frequency of T cells specific for a single myelin Ag, rather than increased TCR affinity or epitope spread, governs the transition from acute symptoms through remission, relapse, and chronic disease states.

CXCL9, CXCL10, and CCL19 synergistically recruit T-lymphocytes to skin in lichen planus.

Lichen planus (LP) is a chronic, debilitating, inflammatory disease of the skin and mucous membranes that affects 1% to 2% of Americans. Its molecular pathogenesis remains poorly understood, and there are no FDA-approved treatments. We performed single cell RNA sequencing on paired blood and skin samples (lesional and non-lesional tissue) from 7 LP patients. We discovered that LP keratinocytes and fibroblasts specifically secrete a combination of CXCL9, CXCL10, and CCL19 cytokines. Using an in vitro migration assay with primary human T cells, we demonstrated that CCL19 in combination with either cytokine synergistically enhanced recruitment of CD8 T cells, more than the sum of individual cytokines. Moreover, exhausted T cells in lesional LP skin secreted CXCL13, which along with CCL19 also enhanced recruitment of T cells, suggesting a feed-forward loop in LP. Finally, LP blood revealed decreased circulating naïve CD8 T cells compared to healthy volunteers, consistent with recruitment to skin. Molecular analysis of LP skin and blood samples increased our understanding of disease pathogenesis and identified CCL19 as a new therapeutic target for treatment.

Recruitment of CXCR4+ type 1 innate lymphoid cells distinguishes sarcoidosis from other skin granulomatous diseases.

Sarcoidosis is a multiorgan granulomatous disease that lacks diagnostic biomarkers and targeted treatments. Using blood and skin from patients with sarcoid and non-sarcoid skin granulomas, we discovered that skin granulomas from different diseases exhibit unique immune cell recruitment and molecular signatures. Sarcoid skin granulomas were specifically enriched for type 1 innate lymphoid cells (ILC1s) and B cells and exhibited molecular programs associated with formation of mature tertiary lymphoid structures (TLSs), including increased CXCL12/CXCR4 signaling. Lung sarcoidosis granulomas also displayed similar immune cell recruitment. Thus, granuloma formation was not a generic molecular response. In addition to tissue-specific effects, patients with sarcoidosis exhibited an 8-fold increase in circulating ILC1s, which correlated with treatment status. Multiple immune cell types induced CXCL12/CXCR4 signaling in sarcoidosis, including Th1 T cells, macrophages, and ILCs. Mechanistically, CXCR4 inhibition reduced sarcoidosis-activated immune cell migration, and targeting CXCR4 or total ILCs attenuated granuloma formation in a noninfectious mouse model. Taken together, our results show that ILC1s are a tissue and circulating biomarker that distinguishes sarcoidosis from other skin granulomatous diseases. Repurposing existing CXCR4 inhibitors may offer a new targeted treatment for this devastating disease.

Granulocyte colony stimulating factor promotes scarless tissue regeneration.

Mammals typically heal with fibrotic scars, and treatments to regenerate human skin and hair without a scar remain elusive. We discovered that mice lacking C-X-C motif chemokine receptor 2 (CXCR2 knockout [KO]) displayed robust and complete tissue regeneration across three different injury models: skin, hair follicle, and cartilage. Remarkably, wild-type mice receiving plasma from CXCR2 KO mice through parabiosis or injections healed wounds scarlessly. A comparison of circulating proteins using multiplex ELISA revealed a 24-fold higher plasma level of granulocyte colony stimulating factor (G-CSF) in CXCR2 KO blood. Local injections of G-CSF into wild-type (WT) mouse wound beds reduced scar formation and increased scarless tissue regeneration. G-CSF directly polarized macrophages into an anti-inflammatory phenotype, and both CXCR2 KO and G-CSF-treated mice recruited more anti-inflammatory macrophages into injured areas. Modulating macrophage activation states at early time points after injury promotes scarless tissue regeneration and may offer a therapeutic approach to improve healing of human skin wounds.

Identification of a neutrophil-specific PIK3R1 mutation facilitates targeted treatment in a patient with Sweet syndrome.

BackgroundAcute febrile neutrophilic dermatosis (Sweet syndrome) is a potentially fatal multiorgan inflammatory disease characterized by fever, leukocytosis, and a rash with a neutrophilic infiltrate. The disease pathophysiology remains elusive, and current dogma suggests that Sweet syndrome is a process of reactivity to an unknown antigen. Corticosteroids and steroid-sparing agents remain frontline therapies, but refractory cases pose a clinical challenge.MethodsA 51-year-old woman with multiorgan Sweet syndrome developed serious corticosteroid-related side effects and was refractory to steroid-sparing agents. Blood counts, liver enzymes, and skin histopathology supported the diagnosis. Whole-genome sequencing, transcriptomic profiling, and cellular assays of the patient's skin and neutrophils were performed.ResultsWe identified elevated IL-1 signaling in lesional Sweet syndrome skin caused by a PIK3R1 gain-of-function mutation specifically found in neutrophils. This mutation increased neutrophil migration toward IL-1ß and neutrophil respiratory burst. Targeted treatment of the patient with an IL-1 receptor 1 antagonist resulted in a dramatic therapeutic response and enabled a tapering off of corticosteroids.ConclusionDysregulated PI3K/AKT signaling is the first signaling pathway linked to Sweet syndrome and suggests that this syndrome may be caused by acquired mutations that modulate neutrophil function. Moreover, integration of molecular data across multiple levels identified a distinct subtype within a heterogeneous disease that resulted in a rational and successful clinical intervention. Future patients will benefit from efforts to identify potential mutations. The ability to directly interrogate the diseased skin allows this method to be generalizable to other inflammatory diseases and demonstrates a potential personalized medicine approach for patients with clinically challenging disease.Funding SourcesBerstein Foundation, NIH, Veterans Affairs (VA) Administration, Moseley Foundation, and H.T. Leung Foundation.

Hand Dermatitis in the Time of COVID-19: A Review of Occupational Irritant Contact Dermatitis.

Occupational contact dermatitis accounts for 95% of all cases of occupational skin disease with irritant contact dermatitis (ICD) constituting 80% to 90% of these cases. Health care workers, hairdressers, and food service workers are typically most affected by occupational ICD of the hands as these occupations require frequent hand hygiene and/or prolonged exposure to water, also known as "wet work." In the context of the current COVID-19 pandemic, frequent hand hygiene has become a global recommendation for all individuals, and new workplace guidelines for hand sanitization and surface sterilization are affecting occupations not previously considered at risk of excessive wet work including grocery or retail workers, postal workers, sanitization workers, and others. In this review, we discuss the etiology and pathogenesis of occupational ICD with additional focus on treatment and interventions that can be made at an institutional and even national level for education and prevention of ICD resulting from frequent hand hygiene.