Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a novel pathogen that emerged in December of 2019 and has since infected people of all ages around the world. Children with acute SARS-CoV-2 infection are largely spared of the severe disease seen in adults. However, a life-threatening, post-viral inflammatory condition known as Multisystem Inflammatory Syndrome – Children (MIS-C) develops in a small fraction of children four to six weeks after either past SARS-CoV-2 infection or exposure and is characterized by high fevers, significant gastrointestinal symptoms and severe cardiac complications. Little is known about the lasting immune profiles of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection in children, let alone the long-term effects of the disease in this population. This study presents clinical features and serologic immune profiles of forty-nine pediatric patients (ages 12.4 ± 6.7 years) enrolled in the Massachusetts General Hospital Pediatric COVID-19 Biorepository with previous diagnoses of SARS-CoV-2 infection or the COVID-19-related MIS-C. Thirty-two children ages 0-22 years completed a questionnaire which captured lingering clinical symptoms of COVID-19 and MIS-C at the follow-up timepoint. This questionnaire study revealed significant on-going symptoms in both cohorts, including respiratory, gastrointestinal, neurologic and cardiovascular symptoms. To characterize lasting immune responses following the acute presentation, serum antibodies to S, RBD and N proteins of SARS-CoV-2 were quantified at the follow-up timepoint in forty-nine pediatric patients with past COVID-19 or MIS-C at a mean follow-up timepoint of 6.56 ± 1.75 months. Serologic signatures against SARS-CoV-2 in COVID-19 and severe MIS-C patients were compared at acute illness and at follow-up timepoints. Anti-SARS-CoV-2 antibodies remained elevated over time showing adequate seroconversion. Interestingly, anti-SARS-CoV-2 IgA remained elevated in the vast majority of individuals at follow-up, suggesting continued antigen exposure and mucosal inflammation. This research elucidates whether children maintain antibody levels to SARS-CoV-2 over time and speaks to the differences in antibody recovery to baseline in COVID-19 and MIS-C patients. It also highlights the lingering symptoms in both the COVID-19 and MIS-C cohorts, and suggests the need for significant long-term follow-up in children months, or even years after resolution of acute illness or disease. In total, this study addresses the substantial gap in understanding of the recovery of the adaptive immune system after SARS-CoV-2 infection in children. / 2023-11-09T00:00:00Z

Background: Idiopathic inflammatory bowel disease (IBD) and food-responsive diarrhea (FRD) are common categories of chronic inflammatory enteropathy (CIE) in dogs. The intestinal microbiota is considered a major contributing factor to the pathogenesis of IBD. Intestinal dysbiosis has been identified in dogs with IBD, but only little information is available on differences in the mucosal microbiota of dogs diagnosed with IBD and FRD. In humans, dyslipidemia has also been described in patients with IBD. However, studies on the lipid profile in dogs with IBD or FRD are currently lacking. Objectives: This is the first study to (1) compare the intestinal mucosal microbiota of dogs with IBD and FRD in the duodenum and the colon, (2) evaluate differences in the mucosal microbiota of each dog before and after the induction phase of treatment, and (3) evaluate the systemic phospholipid profile of dogs with IBD or FRD also both prior to and after the induction phase of treatment. Materials and Methods: Duodenal and colonic mucosal biopsies from 24 dogs with CIE (15 FRD, 9 IBD) and EDTA-plasma and whole blood from 32 dogs (16 FRD, 16 IBD) were retrieved from a former study on canine CIE. All client-owned dogs were prospectively enrolled in the study. All dogs received a standardized diagnostic work-up and treatment including a dietary trial. Dogs that responded to the elimination diet within 14 days were classified as FRD; the remaining dogs requiring additional immunosuppressant treatment were classified as IBD. Biopsy specimens of duodenum and colon were obtained endoscopically both before and after standard therapy. DNA was extracted from these biopsies and the intestinal mucosal microbiota of the duodenum and colon were evaluated by Illumina sequencing of the bacterial 16S rRNA gene. The phospholipids in whole blood and EDTA plasma, collected both before and after treatment, were analyzed by hydrophilic interaction liquid chromatography (HILIC). Differences in the composition were statistically assessed by alpha diversity indices, principal coordinate analysis, analysis of similarities (ANOSIM) and linear discriminant (LDA) analysis effect size (LEfSe) for the microbiota and by principal component analysis (PCA), analysis of variance (ANOVA) and random forest analysis for the phospholipid profile. Results: All differences in the microbial composition and phospholipid profile described below are statistically confirmed with significance set at p-value < 0.05 or LDA score > 2.0. No difference in the global bacterial composition was identified neither between the two disease groups of dogs nor with the treatment status. However, abundances of several bacterial taxa varied between disease groups and also with the treatment status. When comparing disease groups, an unclassified genus of Neisseriaceae was more abundant in the duodenum in the IBD group, whereas Bilophila spp. occurred more frequently in the duodenum of the FRD group. Comparison before and after treatment revealed Enterococcus spp., Corynebacterium spp. and Proteobacteria to be enriched in the duodenum of FRD dogs before treatment. Bacteroides spp. was more abundant in the colon in the FRD group post-treatment. In the IBD dogs, Unclassified_Neisseriaceae was more abundant in the duodenum and mainly Proteobacteria (Burkholderia spp., Citrobacter spp.) in the colon prior to treatment. Bacteroides spp. was significantly more abundant in the colon after treatment. The phospholipidome differed dependent on the type of specimen (whole blood vs. plasma). In addition, treatment and disease severity presented the most significant factors determining the variance of the phospholipid profile. An increase in lysolipids and a significant shift of the phosphatidylcholine (PC) species from PC 38:4 (18:0 / 20:4) to mainly lysophosphatidylcholine 18:0 was observed after treatment. Conclusions: Some differences in individual bacterial taxa were identified both between disease groups of dogs and with regard to treatment status. The role of these bacterial groups in the pathogenesis of IBD and FRD is still unknown. However, Bacteroides spp. might be of importance, and this species could potentially serve as marker of treatment response. Furthermore, significant variances were identified in the phospholipid profiles of dogs with IBD and FRD, which were particularly associated with the type of specimen used, disease severity, and treatment status. These alterations in the phospholipid profile could potentially aid in monitoring the response to treatment. Subsequently, specific modulation of the intestinal microbiota and the phospholipid profile might also present novel therapeutic strategies in dogs with CIE.

Marginal zone (MZ) lymphomas (MZLs) represent a group of lymphomas originating from B lymphocytes of the “marginal zone” which is the external part of the secondary lymphoid follicles. The WHO classifies MZL into 3 entities; extranodal MZL, splenic MZL and nodal MZL. Extranodal marginal zone lymphoma (EMZL) can arise in different tissues, including the stomach, salivary gland, lung, small bowel, thyroid, ocular adnexa and skin. We present a 25 years old female with a history of angioedema and chronic cutaneous eczema who developed an unusual EMZL. Patient presented with a history of rapidly enlarging skin nodule on her left elbow that had been present for almost one year. Over a period of 2-3 weeks she felt the nodule rapidly changed in size and shape. Excisional biopsy of the mass revealed a lymphoid infiltrate based in the reticular dermis and focally extending into the subcutaneous adipose tissue with formation of disrupted lymphoid follicles positive for CD20, CD23 and BCL2 but negative for CD10, Cyclin D1 and SOX11. Diagnosis was consistent with extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). Patient on presentation did not have any B symptoms other cutaneous lesions, lymphadenopathy or hepatosplenomegaly. PET scan revealed no evidence of abnormal uptake leading to a final Stage IE definition. Patient initiated definitive radiation therapy. EMZL accounts for 5 -10 % of non-Hodgkin lymphoma. It has been described often in organs that are normally devoid of germinal centers. It may arise in reactive lymphoid tissue induced by chronic inflammation in extranodal sites. Primary cutaneous marginal zone lymphoma (PCMZL) is associated with infectious etiologies such as Borrelia burgdorferi and less commonly with viral infections or in relation to autoimmune disorders. Autoimmune disorders, specifically Sjögren's syndrome is associated with a 30-fold increased risk of marginal zone lymphoma. Localized disease can be treated by local radiotherapy, intralesional injections or excision. Widespread skin disease is usually treated with a CD20 directed monoclonal antibody-Rituximab. Patients with PCMZL usually have an indolent clinical course. Extracutaneous dissemination of MALT Lymphoma is uncommon and happens in 6-8 % of patients. The 5 years overall survival is between 98-100%. Family physicians and dermatologists should have a high index of suspicion for this rare lymphoma subtype especially in patients with inflammatory chronic skin conditions and atopy.

Advances in technology have lowered the limits of viability in premature births to 24 weeks of gestation. This brought forth a new population of children, who are born 3-4 months early and spent considerable amounts of time in neonatal intensive care unit (NICU), instead of sterile environment of mother’s womb. Besides, other problems associated with prematurity, these children often undergo invasive procedures resulting in mucosal inflammation and/ or injury by feeding tubes, endotracheal tubes, and prolonged IV catheter. To test whether “ex-preemie-infants” were different than “term-infants” with regard to their immunity, preterm infants (< 32 weeks) and term infants (control) at the corrected age of 9-12 months were analyzed for their resting and stimulated immune responses. Preterm infants had a significant Th1 skewed response, higher number of activated and functionally competent T cells compared to term infants. The critical role of neonatal environmental exposure on immune system development is imminent; nevertheless detailed mechanistic studies on pathways are warranted.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18131号 / 医博第3851号 / 新制||医||1001(附属図書館) / 30989 / 京都大学大学院医学研究科医学専攻 / (主査)教授 千葉 勉, 教授 坂井 義治, 教授 羽賀 博典 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第12978号 / 論医博第2104号 / 新制||医||1012(附属図書館) / 32448 / 京都大学大学院医学研究科医学専攻 / (主査)教授 三森 経世, 教授 椛島 健治, 教授 生田 宏一 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

Bovine viral diarrhea virus (BVDV) is an important viral pathogen affecting all ages of cattle, resulting in significant economic losses worldwide. BVDV infection is associated with a diverse array of symptoms including gastrointestinal disorder, respiratory distress, fetal malformation, stillbirth, abortions, and mucosal disease (MD). Transplacental infections of fetuses between 42 and 125 days of gestation can result in immune-tolerance and the surviving fetuses become persistently infected (PI). PI animals are major reservoir of BVDV and it becomes problematic to control the disease. The objectives of this dissertation were to: 1) develop a cost-effective testing scheme to detect BVDV PI animals from exposed herds, 2) characterize two virulent BVDV-2 Mississippi isolates associated with severe hemorrhagic diseases, and 3) perform phylogenetic analysis based on sequences of 5'UTR, E2, and NS5B regions. First, we developed a BVDV testing scheme by combining pooled real-time RT-PCR with antigen capture enzyme-linked immunosorbent assay (ACE) to screen cattle herds. From positive pools individual positives were identified using ACE. Data from a three year period indicated that 92.94% PI animals were infected with BVDV-1, 3.53% with BVDV-2, and 3.53% with both BVDV-1 and BVDV-2. Analysis of the 5'UTR of 22 isolates revealed the predominance of BVDV-1b followed by BVDV-2a. Second, two virulent BVDV isolates, M10-3432 and M10-5347, were successfully recovered from an adult beef breeding cow and feedlot calf respectively. When compared to the reference strain BVDV-2 125c, five and three unique amino acids in E2 regions were different from M10-5347 and M10-3432 respectively. Phylogenetic analysis of E2 region grouped both Mississippi isolates in BVDV-2a, a subtype containing high virulent strains. M10-3432 was clustered with high virulent strain 890 while M10-5347 was clustered with high virulent strain CD87. Third, we compared the phylogenetic analyses of BVDV based on the sequences of 5'UTR, E2, and NS5B at either nucleotides or amino acids level. Although slight differences were observed, the virulent BVDV isolates were consistently classified into BVDV-2a cluster regardless of region of sequences used. Furthermore, phylogenetic tree constructed using combined two or more regions had higher posterior probability and bootstrap value than phylogenetic trees constructed using a single region

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