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.

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).

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.

Hypohidrosis as an immune-related adverse event of checkpoint inhibitor therapy.

Background: Immune checkpoint blockade therapies including cytotoxic-T-lymphocyte antigen 4 (CTLA-4) and programmed cell death protein-1 (PD-1) inhibitors have become indispensable tools for treating melanoma and other cancers. An increasing number of diverse cutaneous adverse reactions to immunotherapy have been documented in the literature and have been reported to affect up to 40% of patients treated with targeted therapies. Method & results: Herein, we report a case of a patient with metastatic melanoma treated with checkpoint inhibitor therapy who developed vitiligo, gastritis and hepatitis, all identified as adverse immune events and attributable to his immunotherapy regimen. He subsequently developed acquired idiopathic generalized hypohidrosis with biopsy of lesional skin demonstrating a peri-eccrine lymphocytic infiltrate. Conclusion: These findings suggest this acquired generalized hypohidrosis represents a lymphocyte-mediated adverse immune event related to this patient's checkpoint inhibitor therapy.

Glove-Related Allergic Contact Dermatitis.

Hand dermatitis is a common condition with a lifetime prevalence of 20%. Glove allergic contact dermatitis (ACD) is a very important dermatitis affecting health care workers, hairdressers, cleaning personnel, kitchen workers, craftsmen, construction workers, laboratory workers, and homemakers. Occupationally related cases may be severe and can result in significant disability. Glove ACD is most commonly due to exposure to rubber accelerators, which are compounds that are added to rubber during production to increase strength and durability. Given the known allergic potential of these compounds, glove manufacturing companies have reformulated gloves leading to the introduction of new rubber allergens. In this review, we will discuss risk factors for glove ACD, both common and uncommon allergens in gloves, common contact allergens that permeate gloves, and patch testing to help uncover the inciting allergen(s).

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.

Targeted Therapies: Immunologic Effects and Potential Applications Outside of Cancer.

Two pharmacologic approaches that are currently at the forefront of treating advanced cancer are those that center on disrupting critical growth/survival signaling pathways within tumor cells (commonly referred to as "targeted therapies") and those that center on enhancing the capacity of a patient's immune system to mount an antitumor response (immunotherapy). Maximizing responses to both of these approaches requires an understanding of the oncogenic events present in a given patient's tumor and the nature of the tumor-immune microenvironment. Although these 2 modalities were developed and initially used independently, combination regimens are now being tested in clinical trials, underscoring the need to understand how targeted therapies influence immunologic events. Translational studies and preclinical models have demonstrated that targeted therapies can influence immune cell trafficking, the production of and response to chemokines and cytokines, antigen presentation, and other processes relevant to antitumor immunity and immune homeostasis. Moreover, because these and other effects of targeted therapies occur in nonmalignant cells, targeted therapies are being evaluated for use in applications outside of oncology.

Understanding the Impact of ErbB Activating Events and Signal Transduction on Antigen Processing and Presentation: MHC Expression as a Model.

Advances in molecular pathology have changed the landscape of oncology. The ability to interrogate tissue samples for oncogene amplification, driver mutations, and other molecular alterations provides clinicians with an enormous level of detail about their patient's cancer. In some cases, this information informs treatment decisions, especially those related to targeted anti-cancer therapies. However, in terms of immune-based therapies, it is less clear how to use such information. Likewise, despite studies demonstrating the pivotal role of neoantigens in predicting responsiveness to immune checkpoint blockade, it is not known if the expression of neoantigens impacts the response to targeted therapies despite a growing recognition of their diverse effects on immunity. To realize the promise of 'personalized medicine', it will be important to develop a more integrated understanding of the relationships between oncogenic events and processes governing anti-tumor immunity. One area of investigation to explore such relationships centers on defining how ErbB/HER activation and signal transduction influences antigen processing and presentation.

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.

pH regulating transporters in neurons from various chemosensitive brainstem regions in neonatal rats.

We studied the membrane transporters that mediate intracellular pH (pH(i)) recovery from acidification in brainstem neurons from chemosensitive regions of neonatal rats. Individual neurons within brainstem slices from the retrotrapezoid nucleus (RTN), the nucleus tractus solitarii (NTS), and the locus coeruleus (LC) were studied using a pH-sensitive fluorescent dye and fluorescence imaging microscopy. The rate of pH(i) recovery from an NH(4)Cl-induced acidification was measured, and the effects of inhibitors of various pH-regulating transporters determined. Hypercapnia (15% CO(2)) resulted in a maintained acidification in neurons from all three regions. Recovery in RTN neurons was nearly entirely eliminated by amiloride, an inhibitor of Na(+)/H(+) exchange (NHE). Recovery in RTN neurons was blocked approximately 50% by inhibitors of isoform 1 of NHE (NHE-1) but very little by an inhibitor of NHE-3 or by DIDS (an inhibitor of HCO(3)-dependent transport). In NTS neurons, amiloride blocked over 80% of the recovery, which was also blocked approximately 65% by inhibitors of NHE-1 and 26% blocked by an inhibitor of NHE-3. Recovery in LC neurons, in contrast, was unaffected by amiloride or blockers of NHE isoforms but was dependent on Na(+) and increased by external HCO(3)(-). On the basis of these findings, pH(i) recovery from acidification appears to be largely mediated by NHE-1 in RTN neurons, by NHE-1 and NHE-3 in NTS neurons, and by a Na- and HCO(3)-dependent transporter in LC neurons. Thus, pH(i) recovery is mediated by different pH-regulating transporters in neurons from different chemosensitive regions, but recovery is suppressed by hypercapnia in all of the neurons.