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Background: Autoimmune blistering diseases (AIBDs) are severe dermatologic disorders known for their debilitating physical impact. Recent research has reported that AIBDs lead to psychosocial impairment, including depression and anxiety. Missing from the extant literature is an examination of the impact of AIBDs on body image and related psychological constructs., Objectives: The current study seeks to characterize the psychological and social consequences of AIBD diagnosis, with particular attention to body image dissatisfaction., Methods: We conducted a survey study of adults with AIBDs. The survey was open from February 2023 to March 2023. Validated self-report questionnaires assessed depressive symptomatology, body image disturbance and quality of life. Demographic information and self-reported psychiatric history before and after AIBD diagnosis were collected via self-report. Participants were 451 adults with AIBDs, recruited through the International Pemphigus and Pemphigoid Foundation newsletters, email distribution lists and social media., Results: Participants reported increased incidence of psychiatric disorders following AIBD diagnosis. Participants reported high levels of depressive symptomatology and impairments to quality of life compared to other patient groups. The sample reported extremely high levels of body image disturbance, more so than other patients with disfiguring diseases or injury. Correlation analyses revealed significant relationships between body image variables and quality of life, even after controlling for depression., Conclusions: Current treatment guidelines for AIBDs focus primarily on the management of disease flares and the consequences of immunosuppression, without consideration of the psychosocial consequences of the disease. The current study underscores the need for mental health support for patients with AIBDs., (© 2024 European Academy of Dermatology and Venereology.)

Competing Interests: Conflicts of interest the authors declare no conflicts of interest.

Introduction: Alloimmune responses against platelet antigens, which dominantly target the major histocompatibility complex (MHC), can cause adverse reactions to subsequent platelet transfusions, platelet refractoriness, or rejection of future transplants. Platelet transfusion recipients include individuals experiencing severe bacterial or viral infections, and how their underlying health modulates platelet alloimmunity is not well understood., Methods: This study investigated the effect of underlying inflammation on platelet alloimmunization by modelling viral-like inflammation with polyinosinic-polycytidylic acid (poly(I:C)) or gram-negative bacterial infection with lipopolysaccharide (LPS), hypothesizing that underlying inflammation enhances alloimmunization. Mice were pretreated with poly(I:C), LPS, or nothing, then transfused with non-leukoreduced or leukoreduced platelets. Alloantibodies and allogeneic MHC-specific B cell (allo-B cell) responses were evaluated two weeks later. Rare populations of allo-B cells were identified using MHC tetramers., Results: Relative to platelet transfusion alone, prior exposure to poly(I:C) increased the alloantibody response to allogeneic platelet transfusion whereas prior exposure to LPS diminished responses. Prior exposure to poly(I:C) had equivalent, if not moderately diminished, allo-B cell responses relative to platelet transfusion alone and exhibited more robust allo-B cell memory development. Conversely, prior exposure to LPS resulted in diminished allo-B cell frequency, activation, antigen experience, and germinal center formation and altered memory B cell responses., Discussion: In conclusion, not all inflammatory environments enhance bystander responses and prior inflammation mediated by LPS on gram-negative bacteria may in fact curtail platelet alloimmunization., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Tran, Muench, Gaillard, Darst, Tomayko and Jackman.)

Introduction: Alloimmunization is common following platelet transfusion and can result in negative outcomes for recipients such as refractoriness to subsequent transfusions and rejection of transplants. Healthy people do not receive blood transfusions, and the diseases and therapies that result in a need to transfuse have significant impacts on the immunological environment to which these alloantigens are introduced. Ablative chemotherapies are common among platelet recipients and have potent immunological effects. In this study, we modeled the impact of chemotherapy on the alloresponse to platelet transfusion. As chemotherapies are generally regarded as immunosuppressive, we hypothesized that that they would result in a diminished alloresponse., Methods: Mice were given a combination chemotherapeutic treatment of cytarabine and doxorubicin followed by transfusion of allogeneic platelets, and compared to controls given no treatment, chemotherapy alone, or transfusion alone. Alloantibody responses were measured 2 weeks after transfusion, and cellular responses and growth factors were monitored over time., Results: Contrary to our hypothesis, we found that chemotherapy led to increased alloantibody responses to allogeneic platelet transfusion. This enhanced response was antigen-specific and was associated with increased CD4 + and CD8 + T cell responses. Chemotherapy led to rapid lymphocyte depletion followed by reconstitution, non-specific activation of transitional B cells with the highest levels of activation in the least mature subsets, and increased serum levels of B cell activating factor (BAFF)., Conclusion: These data suggest that ablative chemotherapy can increase the risk of alloimmunization and, if confirmed clinically, that additional measures to protect these patient populations may be warranted., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Jackman, Darst, Gaillard, Tran, Tomayko and Muench.)

Ticks are hematophagous arthropods that use a complex mixture of salivary proteins to evade host defenses while taking a blood meal. Little is known about the immunological and physiological consequences of tick feeding on humans. Here, we performed the first bulk and single-nucleus RNA sequencing (snRNA-seq) of skin and blood of four persons presenting with naturally acquired, attached Ixodes scapularis ticks. Pathways and individual genes associated with innate and adaptive immunity were identified based on bulk RNA sequencing, including interleukin-17 signaling and platelet activation pathways at the site of tick attachment or in peripheral blood. snRNA-seq further revealed that the Hippo signaling, cell adhesion, and axon guidance pathways were involved in the response to an I. scapularis bite in humans. Features of the host response in these individuals also overlapped with that of laboratory guinea pigs exposed to I. scapularis and which acquired resistance to ticks. These findings offer novel insights for the development of new biomarkers for I. scapularis exposure and anti-tick vaccines for human use., Competing Interests: The authors declare no conflict of interest.

How to develop highly informative serology assays to evaluate the quality of immune protection against coronavirus disease-19 (COVID-19) has been a global pursuit over the past years. Here, a microfluidic high-plex immuno-serolomic assay is developed to simultaneously measure50 plasma or serum samples for50 soluble markers including 35proteins, 11 anti-spike/receptor binding domian (RBD) IgG antibodies spanningmajor variants, and controls. This assay demonstrates the quintuplicate test in a single run with high throughput, low sample volume, high reproducibilityand accuracy. It is applied to the measurement of 1012 blood samples including in-depth analysis of sera from 127 patients and 21 healthy donors over multiple time points, either with acute COVID infection or vaccination. The protein analysis reveals distinct immune mediator modules that exhibit a reduced degree of diversity in protein-protein cooperation in patients with hematologic malignancies or receiving B cell depletion therapy. Serological analysis identifies that COVID-infected patients with hematologic malignancies display impaired anti-RBD antibody response despite high level of anti-spike IgG, which can be associated with limited clonotype diversity and functional deficiency in B cells. These findings underscore the importance to individualize immunization strategies for these high-risk patients and provide an informative tool to monitor their responses at the systems level., (© 2023 The Authors. Small Methods published by Wiley-VCH GmbH.)

Competing Interests: Conflicts of interest the authors declare they have no conflicts of interest.

BACKGROUNDWhile B cell depletion is associated with attenuated antibody responses to SARS-CoV-2 mRNA vaccination, responses vary among individuals. Thus, elucidating the factors that affect immune responses after repeated vaccination is an important clinical need.METHODSWe evaluated the quality and magnitude of the T cell, B cell, antibody, and cytokine responses to a third dose of BNT162b2 or mRNA-1273 mRNA vaccine in patients with B cell depletion.RESULTSIn contrast with control individuals (n = 10), most patients on anti-CD20 therapy (n = 48) did not demonstrate an increase in spike-specific B cells or antibodies after a third dose of vaccine. A third vaccine elicited significantly increased frequencies of spike-specific non-naive T cells. A small subset of B cell-depleted individuals effectively produced spike-specific antibodies, and logistic regression models identified time since last anti-CD20 treatment and lower cumulative exposure to anti-CD20 mAbs as predictors of those having a serologic response. B cell-depleted patients who mounted an antibody response to 3 vaccine doses had persistent humoral immunity 6 months later.CONCLUSIONThese results demonstrate that serial vaccination strategies can be effective for a subset of B cell-depleted patients.FUNDINGThe NIH (R25 NS079193, P01 AI073748, U24 AI11867, R01 AI22220, UM 1HG009390, P01 AI039671, P50 CA121974, R01 CA227473, U01CA260507, 75N93019C00065, K24 AG042489), NIH HIPC Consortium (U19 AI089992), the National Multiple Sclerosis Society (CA 1061-A-18, RG-1802-30153), the Nancy Taylor Foundation for Chronic Diseases, Erase MS, and the Claude D. Pepper Older Americans Independence Center at Yale (P30 AG21342).

Pemphigus is a debilitating autoimmune blistering disorder mediated by IgG autoantibodies to desmosomal cadherins that requires novel steroid-sparing therapies. In this phase 1b/2 trial reported by Werth et al. (2021), the FcRn inhibitor ALXN1840 induced rapid and sustained clinical improvement in patients with chronic, active, refractory pemphigus. FcRn inhibition is a promising new approach to the treatment of pemphigus and other autoantibody-mediated autoimmune disorders., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Immunological memory is a composite of lasting antibody titers maintained by plasma cells in conjunction with memory T and B cells. Memory B cells are a critical reservoir for plasma cell generation in the secondary response. Identification of memory B cells requires that they be distinguished from naïve, activated, and germinal center precursors and from plasma cells. Memory B cells are heterogeneous in isotype usage, immunoglobulin mutational content, and phenotypic marker expression. Phenotypic subsets of memory B cells are defined by PD-L2, CD80, and CD73 expression in mice, by CD27 and FCRL4 expression in humans and by T-bet in both mice and humans. These subsets display marked functional heterogeneity, including the ability to rapidly differentiate into plasma cells versus seed germinal centers in the secondary response. Memory B cells are located in the spleen, blood, other lymphoid organs, and barrier tissues, and recent evidence indicates that some memory B cells may be dedicated tissue-resident populations. Open questions about memory B cell longevity, renewal and progenitor-successor relationships with plasma cells are discussed., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

In response to T-dependent Ag, germinal centers (GC) generate bone marrow-resident plasma cells (BMPC) and memory B cells (MBC). In this study, we demonstrate that the bone morphogenetic protein receptor 1A (BMPR1A) signaling pathway, which regulates differentiation and self-renewal in multiple stem cell populations, regulates GC dynamics and resultant establishment of BMPC and MBC. Expression studies using quantitative PCR and novel Bmpr1a IRES.EGFP reporter mice demonstrated that Bmpr1a expression is upregulated among GC B cells (GCBC) and subsets of MBC, bone marrow plasmablasts, and BMPC. In immunized mice carrying B cell-targeted Bmpr1a gene deletions, the GC response was initially diminished. Subsequently, the GCBC compartment recovered in size, concurrent with accumulation of GCBC that carried unmodified rather than deleted Bmpr1a alleles. Similarly, the resulting class-switched MBC and BMPC carried retained non-recombined alleles. Despite the strong selective pressure for "leaky" B cells that retained Bmpr1a , there was a permanent marked reduction in switched bone marrow Ab-forming cells (plasmablasts + plasma cells), BMPC, MBC, and Ag-specific serum IgM in mice carrying B cell-targeted Bmpr1a gene deletions. These findings demonstrate a novel role for BMPR1A in the modulation of the B cell response and in the establishment of long-term memory., (Copyright © 2021 The Authors.)

Antibodies are key components of the skin immune barrier, and antibodies directed toward skin structures can result in disease. Wilson et al. (2019) show that healthy skin is a niche for antibody secreting plasma cells and plasmablasts, and that inflammation and immunization increase their numbers. This work advances our understanding of skin associated B and plasma cells in health and disease., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: There is increasing recognition of distinct inflammatory eruptions associated with checkpoint inhibitors. A better understanding of their severity, therapeutic response, and impact on cancer treatment is needed., Objective: To analyze the different rashes associated with immunotherapy referred to our institution's oncodermatology clinic and inpatient consultative service and to evaluate their therapeutic response and impact on immunotherapy., Methods: We retrospectively reviewed the medical records of patients referred to the oncodermatology clinic or inpatient dermatology service during 2016-2018 at Yale-New Haven Hospital for eruptions that developed during immunotherapy., Results: In total, 98 patients (51 men, 47 women) treated with checkpoint inhibitors developed 103 inflammatory eruptions, with a range of mean latency of 0.2-17.7 months. A minority of patients (25/103; 24.3%) required immunotherapy interruption; most of these cases involved immunobullous (7/8; 87.5%), lichenoid (8/26; 30.8%), maculopapular (6/18; 33.3%), and Stevens-Johnson syndrome-like (2/2, 100%) reactions. Only 3 of 16 (18.8%) patients who had their immunotherapy interrupted had a grade 2 or 3 flare on rechallenge. Most reactions (93/103; 90.3%) responded to dermatologic therapy or immunotherapy interruption., Limitations: This was a retrospective study from a single tertiary care center., Conclusion: A variety of inflammatory reactions might occur from immunotherapy with differing degrees of severity. While most rashes responded to topical treatment, immunobullous and exfoliative presentations frequently interrupted immunotherapy. Increased awareness and early recognition could reduce the need for unnecessary immunotherapy interruption., (Copyright © 2018 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

In many ways, memory B cells represent the ultimate outcome of humoral immunity. Many of these cells express exceptionally high affinity antigen-specific B cell receptors for antigen, and these cells are a critical source of the long-lived plasma cells that secrete protective serum antibodies to protect against secondary exposure to pathogens and other life-threatening antigens. Evidence is now emerging that not all memory B cells are created via the same cellular pathways and molecular events. Similarly, it is becoming clear that different memory B cells can take on different functions, with some producing IgM rather than IgG antibodies upon reactivation, and others preferentially producing plasma cells rather than additional waves of memory B cells. With this review, we discuss the conceptual ides and early studies surrounding early work on B cell memory, then discuss the many pathways and functional attributes of subpopulations of memory B cells and current approaches to characterize these cells directly., (Copyright © 2019. Published by Elsevier Ltd.)

Background: Bullous disorders associated with anti-programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) therapy are increasingly reported and may pose distinct therapeutic challenges. Their frequency and impact on cancer therapy are not well established., Objective: To evaluate the clinical and histopathologic findings, frequency, and impact on cancer therapy of bullous eruptions due to anti-PD-1/PD-L1 therapy., Methods: We retrospectively reviewed the medical records of patients evaluated by the oncodermatology clinic and consultative service of Yale New Haven Hospital from 2016 to 2018., Results: We identified 9 of 853 patients who developed bullous eruptions (∼1%) that were treated with an-PD-1/PD-L1 therapy at our institution during the study period: 7 presented with bullous pemphigoid, 1 presented with bullous lichenoid dermatitis, and 1 presented with linear IgA bullous dermatosis in the context of vancomycin therapy. In all, 8 patients required systemic steroids, 5 required maintenance therapy, and 8 required interruption of immunotherapy. All 9 patients had an initial positive tumor response or stable disease, but 4 went on to develop disease progression., Limitations: This was a retrospective study from a single tertiary care center., Conclusions: Bullous disorders developed in approximately 1% of patients treated with anti-PD-1/PD-L1 therapy at our institution and frequently resulted in interruption of immune therapy and management with systemic corticosteroids and occasionally steroid-sparing agents., (Copyright © 2018 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Bullous systemic lupus erythematosus (BSLE) is a rare subepidermal blistering disorder characterized by an acute vesiculobullous eruption in a subset of individuals with systemic lupus erythematosus. BSLE most commonly affects young women and only rarely affects children. Herein we report a rare case of BSLE in a 6-year-old boy., (© 2017 Wiley Periodicals, Inc.)