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Objectives: Adult T-cell leukemia/lymphoma (ATLL) is a rare aggressive T-cell leukemia/lymphoma associated with human T lymphotropic virus type 1 infection. The patients might present with skin rash before, at, or after the diagnosis. The dermatopathologic finding might be diagnostically very challenging., Methods: We retrospectively identified 110 patients with ATLL at a single institution in a 19-year period, with 19 patients having skin biopsies. Clinical, dermatopathologic, immunophenotypic, and molecular findings were studied., Results: The cohort included 13 skin-first (5 acute, 5 lymphomatous, 2 chronic, 1 smoldering), 6 skin-second (4 acute, 1 lymphomatous, 1 smoldering), and 91 patients without skin biopsy. Some nonphotoprotected areas of body such as the forearm and lower lip were also seen. Skin manifestations included papular (5), erythroderma (1), nodulotumoral (3), plaques (1), patches (1), and a combination of skin rashes (2). Histopathologic findings included large pleomorphic cells, angiocentrism, epidermal infiltration with large Pautrier-like microabscesses, and folliculotropism. Fifteen (78.9%) cases showed CD4+/CD7-/CD25+. Next-generation sequencing study was conducted on 5 patients using either blood or bone marrow samples, revealing multiple genetic mutations across multiple signaling pathways., Conclusions: Pleomorphic large, atypical cells with CD4+/CD25+/CD7- immunophenotype from a non-"bathing trunk" location, especially in a patient from endemic regions, raise suspicion for ATLL. T-cell receptor gene rearrangement is almost always positive, and the neoplasm usually demonstrates multiple mutations by next-generation sequencing study., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Diaphragmatic dysfunction is often underdiagnosed as clinical presentation is non-specific and reference values for normal diaphragmatic excursion are inadequate. The rationale of this study is to provide a normal reference value of diaphragmatic excursion and thickness in Malaysia's paediatric population using M-mode sonography, as no previous local data are available to our knowledge., Materials and Methods: A total of 119 healthy infants and children fulfilling our inclusion and exclusion criteria were recruited. They were divided into three groups according to age - 0-2 years old in group 1; 2-6 years old in group 2; 6- 12 years old in group 3. Sonography B-mode was used to assess bilateral diaphragmatic thickness and M-mode to assess diaphragmatic excursion during quiet spontaneous respiration., Results: In our paediatric population, the normal right and left diaphragmatic thickness were 2.0 mm ± 0.5 and 2.0 mm ± 0.5 for group 1; 2.5 mm ± 0.8 and 2.4 mm ± 0.6 for group 2; 2.7 mm ± 0.7 and 2.5 mm ± 0.5 for group 3, respectively. The normal right and left diaphragmatic excursion were 7.7 mm ± 2.5 and 7.3 mm ± 2.6 for group 1; 11.5 mm ± 3.8 and 10.6 mm ± 3.8 for group 2; 13.8 mm ± 3.9 and 12.9 mm ± 3.3 for group 3, respectively (data presented in mean ± standard deviation). There were no significant differences between two genders for each group. Significant positive correlation between age, weight, height, and body surface area with bilateral diaphragmatic thickness and excursion were detected in all studied population. The percentage difference between excursions of both hemidiaphragm was below 40%., Conclusions: M-mode sonography is the modality of choice for diaphragmatic kinetics especially in paediatric population. This study provides normal sonographic reference value of diaphragmatic excursion and thickness in the Malaysian paediatric population as well as percentile curves for right diaphragmatic excursion plotted against body weight. The availability of this data will aid in the diagnosis of diaphragmatic dysfunction and hence immediate intervention for better recovery.

Competing Interests: Conflicts of interest: All authors declare that the research was conducted in the absence of any commercial or financial relationships. The authors report no conflicts of interest for this work.

Cryptosporidium can cause severe diarrhea and morbidity, but many infections are asymptomatic. Here, we studied the immune response to a commensal strain of Cryptosporidium tyzzeri (Ct-STL) serendipitously discovered when conventional type 1 dendritic cell (cDC1)-deficient mice developed cryptosporidiosis. Ct-STL was vertically transmitted without negative health effects in wild-type mice. Yet, Ct-STL provoked profound changes in the intestinal immune system, including induction of an IFN-γ-producing Th1 response. TCR sequencing coupled with in vitro and in vivo analysis of common Th1 TCRs revealed that Ct-STL elicited a dominant antigen-specific Th1 response. In contrast, deficiency in cDC1s skewed the Ct-STL CD4 T cell response toward Th17 and regulatory T cells. Although Ct-STL predominantly colonized the small intestine, colon Th1 responses were enhanced and associated with protection against Citrobacter rodentium infection and exacerbation of dextran sodium sulfate and anti-IL10R-triggered colitis. Thus, Ct-STL represents a commensal pathobiont that elicits Th1-mediated intestinal homeostasis that may reflect asymptomatic human Cryptosporidium infection., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Generation of tolerogenic peripheral regulatory T (pTreg) cells is commonly thought to involve CD103 + gut dendritic cells (DCs), yet their role in commensal-reactive pTreg development is unclear. Using two Helicobacter - specific T cell receptor (TCR) transgenic mouse lines, we found that both CD103 + and CD103 - migratory, but not resident, DCs from the colon-draining mesenteric lymph node presented Helicobacter antigens to T cells ex vivo. Loss of most CD103 + migratory DCs in vivo using murine genetic models did not affect the frequency of Helicobacter-specific pTreg cell generation or induce compensatory tolerogenic changes in the remaining CD103 - DCs. By contrast, activation in a Th1-promoting niche in vivo blocked Helicobacter-specific pTreg generation. Thus, these data suggest a model where DC-mediated effector T cell differentiation is 'dominant', necessitating that all DC subsets presenting antigen are permissive for pTreg cell induction to maintain gut tolerance., Competing Interests: ER, JY, SY, KN, HW, TA, JC, VD, DK, RG, KM, CH No competing interests declared

Itch is an evolutionarily conserved sensation that facilitates expulsion of pathogens and noxious stimuli from the skin. However, in organ failure, cancer, and chronic inflammatory disorders such as atopic dermatitis (AD), itch becomes chronic, intractable, and debilitating. In addition to chronic itch, patients often experience intense acute itch exacerbations. Recent discoveries have unearthed the neuroimmune circuitry of itch, leading to the development of anti-itch treatments. However, mechanisms underlying acute itch exacerbations remain overlooked. Herein, we identify that a large proportion of patients with AD harbor allergen-specific immunoglobulin E (IgE) and exhibit a propensity for acute itch flares. In mice, while allergen-provoked acute itch is mediated by the mast cell-histamine axis in steady state, AD-associated inflammation renders this pathway dispensable. Instead, a previously unrecognized basophil-leukotriene (LT) axis emerges as critical for acute itch flares. By probing fundamental itch mechanisms, our study highlights a basophil-neuronal circuit that may underlie a variety of neuroimmune processes., Competing Interests: Declaration of interests B.S.K. has served as a consultant for AbbVie, ABRAX Japan, Almirall, AstraZeneca, Cara Therapeutics, Daewoong Pharmaceutical, Incyte, LEO Pharma, Lilly, Maruho, Menlo Therapeutics, OM Pharma, Pfizer, and Third Rock Ventures. He has also participated on the advisory board for Almirall, Boehringer Ingelheim, Cara Therapeutics, Kiniksa Pharmaceuticals, Menlo Therapeutics, Regeneron Pharmaceuticals, Sanofi Genzyme, and Trevi Therapeutics. He is stockholder of Locus Biosciences. All other authors declare that they have no relevant conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Homeostatic mucosal immune responses are fine-tuned by naturally evolved interactions with native microbes, and integrating these relationships into experimental models can provide new insights into human diseases. Here, we leverage a murine-adapted airway microbe, Bordetella pseudohinzii (Bph), to investigate how chronic colonization impacts mucosal immunity and the development of allergic airway inflammation (AAI). Colonization with Bph induces the differentiation of interleukin-17A (IL-17A)-secreting T-helper cells that aid in controlling bacterial abundance. Bph colonization protects from AAI and is associated with increased production of secretory leukocyte protease inhibitor (SLPI), an antimicrobial peptide with anti-inflammatory properties. These findings are additionally supported by clinical data showing that higher levels of upper respiratory SLPI correlate both with greater asthma control and the presence of Haemophilus, a bacterial genus associated with AAI. We propose that SLPI could be used as a biomarker of beneficial host-commensal relationships in the airway., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Stress is a known trigger for flares of inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS); however, this process is not well understood. Here, we find that restraint stress in mice leads to signs of diarrhea, fecal dysbiosis, and a barrier defect via the opening of goblet-cell associated passages. Notably, stress increases host immunity to gut bacteria as assessed by immunoglobulin A (IgA)-bound gut bacteria. Stress-induced microbial changes are necessary and sufficient to elicit these effects. Moreover, similar to mice, many diarrhea-predominant IBS (IBS-D) patients from two cohorts display increased antibacterial immunity as assessed by IgA-bound fecal bacteria. This antibacterial IgA response in IBS-D correlates with somatic symptom severity and was distinct from healthy controls or IBD patients. These findings suggest that stress may play an important role in patients with IgA-associated IBS-D by disrupting the intestinal microbial community that alters gastrointestinal function and host immunity to commensal bacteria., Competing Interests: DECLARATION OF INTERESTS The authors declare no competing interests. D.K. serves as Senior Scientific Advisor to Diversigen, a company involved in the commercialization of microbiome analysis. Diversigen is now a wholly owned subsidiary of OraSure. P.C.K. is on the advisory board of Novome Biotechnologies and is an ad hoc consultant for Pendulum Therapeutics, IP Group, and Otsuka Pharmaceuticals. These interests have been reviewed and managed by the respective institutions in accordance with their conflict-of-interest policies.

The gastrointestinal tract hosts the largest collection of commensal microbes in the body. Infections at this site can cause significant perturbations in the microbiota, known as dysbiosis, that facilitate the expansion of pathobionts, and can elicit inappropriate immune responses that impair the intestinal barrier function. Dysbiosis typically occurs during intestinal infection with Toxoplasma gondii . Host resistance to T. gondii depends on a potent Th1 response. In addition, a Th17 response is also elicited. How Th17 cells contribute to the host response to T. gondii remains unclear. Here we show that class I-restricted T cell-associated molecule (CRTAM) expression on T cells is required for an optimal IL-17 production during T. gondii infection. Moreover, that the lack of IL-17, results in increased immunopathology caused by an impaired antimicrobial peptide production and bacterial translocation from the intestinal lumen to the mesenteric lymph nodes and spleen.

Glioblastoma is a highly lethal brain cancer that frequently recurs in proximity to the original resection cavity. We explored the use of oncolytic virus therapy against glioblastoma with Zika virus (ZIKV), a flavivirus that induces cell death and differentiation of neural precursor cells in the developing fetus. ZIKV preferentially infected and killed glioblastoma stem cells (GSCs) relative to differentiated tumor progeny or normal neuronal cells. The effects against GSCs were not a general property of neurotropic flaviviruses, as West Nile virus indiscriminately killed both tumor and normal neural cells. ZIKV potently depleted patient-derived GSCs grown in culture and in organoids. Moreover, mice with glioblastoma survived substantially longer and at greater rates when the tumor was inoculated with a mouse-adapted strain of ZIKV. Our results suggest that ZIKV is an oncolytic virus that can preferentially target GSCs; thus, genetically modified strains that further optimize safety could have therapeutic efficacy for adult glioblastoma patients., (© 2017 Zhu et al.)

The small intestine contains CD4 + CD8αα + double-positive intraepithelial lymphocytes (DP IELs), which originate from intestinal CD4 + T cells through down-regulation of the transcription factor Thpok and have regulatory functions. DP IELs are absent in germ-free mice, which suggests that their differentiation depends on microbial factors. We found that DP IEL numbers in mice varied in different vivaria, correlating with the presence of Lactobacillus reuteri This species induced DP IELs in germ-free mice and conventionally-raised mice lacking these cells. L. reuteri did not shape the DP-IEL-TCR (TCR, T cell receptor) repertoire but generated indole derivatives of tryptophan that activated the aryl-hydrocarbon receptor in CD4 + T cells, allowing Thpok down-regulation and differentiation into DP IELs. Thus, L. reuteri , together with a tryptophan-rich diet, can reprogram intraepithelial CD4 + T cells into immunoregulatory T cells., (Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Specific gut commensal bacteria improve host health by eliciting mutualistic regulatory T (T reg ) cell responses. However, the bacteria that induce effector T (T eff ) cells during inflammation are unclear. We addressed this by analyzing bacterial-reactive T cell receptor (TCR) transgenic cells and TCR repertoires in a murine colitis model. Unexpectedly, we found that mucosal-associated Helicobacter species triggered both T reg cell responses during homeostasis and T eff cell responses during colitis, as suggested by an increased overlap between the T eff /T reg TCR repertoires with colitis. Four of six T reg TCRs tested recognized mucosal-associated Helicobacter species in vitro and in vivo. By contrast, the marked expansion of luminal Bacteroides species seen during colitis did not trigger a commensurate T eff cell response. Unlike other T reg cell-inducing bacteria, Helicobacter species are known pathobionts and cause disease in immunodeficient mice. Thus, our study suggests a model in which mucosal bacteria elicit context-dependent T reg or T eff cell responses to facilitate intestinal tolerance or inflammation., (Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Commensal bacteria shape the colonic regulatory T (Treg) cell population required for intestinal tolerance. However, little is known about this process. Here, we use the transfer of naive commensal-reactive transgenic T cells expressing colonic Treg T cell receptors (TCRs) to study peripheral Treg (pTreg) cell development in normal hosts. We found that T cells were activated primarily in the distal mesenteric lymph node. Treg cell induction was rapid, generating >40% Foxp3(+) cells 1 week after transfer. Contrary to prior reports, Foxp3(+) cells underwent the most cell divisions, demonstrating that pTreg cell generation can be the dominant outcome from naive T cell activation. Moreover, Notch2-dependent, but not Batf3-dependent, dendritic cells were involved in Treg cell selection. Finally, neither deletion of the conserved nucleotide sequence 1 (CNS1) region in Foxp3 nor blockade of TGF-β (transforming growth factor-β)-receptor signaling completely abrogated Foxp3 induction. Thus, these data show that pTreg cell selection to commensal bacteria is rapid, is robust, and may be specified by TGF-β-independent signals., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Trillions of commensal bacteria cohabit our bodies to mutual benefit. In the past several years, it has become clear that the adaptive immune system is not ignorant of intestinal commensal bacteria, but is constantly interacting with them. For T cells, the response to commensal bacteria does not appear uniform, as certain commensal bacterial species appear to trigger effector T cells to reject and control them, whereas other species elicit Foxp3(+) regulatory T (Treg) cells to accept and be tolerant of them. Here, we review our current knowledge of T cell differentiation in response to commensal bacteria, and how this process leads to immune homeostasis in the intestine., (Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.)

Objective: To evaluate maternal hemoglobin levels and red cell indices as predictive factors for gestational diabetes (GDM)., Method: Data from 1,538 women were analyzed. At the first visit for prenatal care, the 50-gram glucose challenge test was followed by the 75-gram glucose tolerance test in those who screened positive. GDM was diagnosed based on the WHO (1999) criteria. Maternal complete blood count was obtained at the first visit, hospitalization for birth, and after birth. Receiver operator characteristic curves were generated to establish thresholds. Multivariable logistic regression analyses were performed to establish independent predictors of GDM., Results: GDM was diagnosed in 182/1,538 (11.8%). GDM was associated with hemoglobin level, hematocrit and erythrocyte count at the first visit for prenatal care only. Hemoglobin threshold at the first visit was established at 11.5 g/dl. After adjustment, high hemoglobin [AOR 1.5 (95% CI 1.0-2.1); p = 0.027] remained predictive of GDM., Conclusions: High maternal hemoglobin level at the first prenatal visit is independently predictive of GDM.