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Background: Omalizumab (OMA) was the first FDA-approved biological drug for severe chronic spontaneous urticaria (CSU), and until today is the only beneficial and truly safe one. The objectives were: To assess the prevalence of CSU patients in whom OMA cannot be stopped over time. We also asked if biomarkers (e.g., anti-TPO antibodies and total IgE) could assist in anticipating this issue., Methods: We used our prospective registry of 93 patients, which included CSU disease duration, the onset of OMA treatment, Urticaria Activity Score (UAS7) during follow-up, co-morbidities, serum IgE levels and the presence of anti-TPO antibodies. Finally, we assessed the response to OMA during a period of six years., Results: Out of the 93 treated CSU patients, OMA was stopped in ten patients after six months being defined as failures. In another ten patients, OMA was discontinued after 2-4 years of therapy, achieving a remission. Seventy-three patients are still treated between 2 and 6 years, having different degrees of response. Of these, in thirty-eight (52%) patients, we could not stop OMA even after six years due to CSU relapses. The prevalence of lower serum IgE levels and anti-TPO antibody positivity was significantly higher in CSU patients in whom OMA could not be stopped., Conclusion: This is the first study where OMA-treated CSU patients were followed up to six years. In half of them, long-term therapy of six years is still required., 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., (© 2024 Schichter-Konfino, Mubariki, Toubi and Vadasz.)

Background: The proximity of activated T cells and mast cells in the lesional skin of patients with chronic spontaneous urticaria (CSU) is held to contribute to the development of wheals and angioedema. In a previous study, we demonstrated that increased IL-17 expression in T cells and mast cells in skin lesions of patients with CSU is associated with T/mast cell proximity, but the mechanisms that drive T cell/mast cell co-localization remain unknown., Objectives: To assess if chemokines expressed in lesional CSU skin contribute to T cell/mast cell proximity., Patients and Methods: Biopsies from lesional CSU skin were compared to biopsies from healthy skin for expression of CCR5 and its ligand CCL3 by CD4 + T cells and mast cells, respectively., Results: Numbers of CCR5-positive CD4 + T cells in lesional CSU skin were significantly increased as compared to healthy normal skin (p < 0.0001). The number of mast cells expressing CCL3 (ligand for CCR5) in CSU skin was also increased (p < 0.0002) and significant association with T-cell close proximity (p < 0.0001) is noticed., Conclusions: The close proximity of T cells and mast cells in the skin of severe CSU may be driven, at least in part by increased CCR5 and CCL3 expression. Therapies that target CCL3 interaction with CCR5 should be assessed for their effects in CSU., 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., (Copyright © 2024 Mubariki, Samara, Gimenez-Arnua, Maurer, Bejar, Toubi and Vadasz.)

The Lymphocyte-Activation Protein 3 (LAG-3) inhibitory receptor is expressed on regulatory plasma cells (PCs). Micro-environmental cells that express LAG-3 were found to be increased during the progression of smoldering multiple myeloma (SMM). To assess the possible role of LAG-3 expression on regulatory PCs in patients with plasma cell dyscrasia. Purified Cluster of Differentiation 138 (CD138 +) PCs from patients with premalignant conditions, active multiple myeloma (MM), and controls were analyzed for the expression of LAG-3 by flow cytometry. Autologous CD8 + T cells were incubated with sorted LAG-3 pos or LAG-3 neg PCs for 24 h. The expression of granzyme (Grz) in CD8 + T cells was assessed by flow cytometry. LAG-3 expression on PCs in active MM (newly diagnosed and relapse refractory MM) was significantly increased compared to monoclonal gammopathy of undetermined significance (MGUS)/ SMM. Grz expression was significantly decreased in CD8 + T cells incubated with CD138 + LAG-3 pos PCs, compared to CD138 + LAG-3 neg PCs in patients with plasma cell dyscrasia, n = 31, p = 0.0041. LAG-3 expression on malignant PCs can be involved in the development of MM from MGUS by decreasing the expression of Grz in CD8 + T cells.

B cells are major players in immune responses being the source of protective antibodies and antigen presenting cells. When self-tolerance fails, auto reactive B cells produce autoantibodies and pro-inflammatory cytokines leading to the development of autoimmune diseases. Many recent studies have assessed importance of metabolic pathways in B cells, demonstrating their role in controlling autoimmunity and maintaining immune homeostasis. Alterations in B cell functions in autoimmune diseases are closely associated with abnormal metabolic shifts, allowing auto reactive B cells to escape tolerogenic checkpoints. Understanding the metabolic changes in B cells, opens up new possibilities for targeting metabolic pathways and manipulating metabolic avenues as a therapeutic strategy for the treatment of autoimmune diseases., (Copyright © 2022. Published by Elsevier B.V.)

We retrospectively examined the yield of a cerebrospinal fluid (CSF) multiplex real-time PCR assay of febrile young infants undergoing a full sepsis work-up. Eighty infants were included in the study: Forty-nine (61%) neonates and 31 (39%) 29-90 day-old patients were included in the study. A viral pathogen was detected in 59% (47/80) of the samples, human enterovirus in 53% (42/80) and Human parechovirus in 6% (5/80). The CSF of nearly half of the subjects with CNS infection was without pleocytosis; all CSF cultures were negative. Multiplex PCR CSF testing enhances the diagnosis of pathogen-specific viral CNS infection among febrile young infants.

Background: Most infants with congenital cytomegalovirus (cCMV) have no overt manifestations at birth, yet may later develop CMV-related sensorineural hearing loss (SNHL). With targeted screening, many asymptomatic neonates are missed and lose the opportunity for timely anti-viral treatment to ameliorate SNHL. Saliva is the preferred screening specimen given its ease of collection., Objectives: Assess a pooled saliva CMV DNA detection technique for cCMV screening of healthy full-term neonates., Study Design: We conducted a prospective laboratory CMV PCR screening study in a secondary hospital from March-June 2019. Saliva specimens were obtained from 1000 newborns two-four hours after birth. Specimens were analyzed for CMV DNA with a real-time PCR platform (Altona) in pools of 10 and individually (40 μL and 400 μL, respectively). Neonates with positive saliva CMV DNA detection required urine CMV PCR testing to confirm cCMV diagnosis., Results: From the 1000 saliva samples, there were 6 urine-confirmed cCMV cases, yielding a prevalence rate of 0.6 %. The specificity was high for both pooled and individual saliva sampling (99.9 % and 98.1 %, respectively). The positive predictive value of the pooled sample was 85.7 %, compared to 24.0 % for a single saliva sample., Conclusions: Pooling saliva of healthy newborns appears to be a reliable method to identify asymptomatic cCMV infection when positive results are confirmed by urine CMV DNA. Pooling in sizes appropriate to the cCMV prevalence rate may improve the laboratory workflow and decrease costs. Further studies should evaluate the clinical implications of this widespread cCMV pooled screening technique., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Kirrel/Neph proteins are evolutionarily conserved members of the immunoglobulin superfamily of adhesion proteins. Kirrel3 is the mouse orthologue of Dumbfounded (Duf), a family member that regulates myoblast pre-fusion events in Drosophila. Yet, the role of Kirrel3 in mammalian myogenesis has not been demonstrated. Experiments performed here indicate that the mouse Kirrel3 protein regulates morphological changes of myoblasts that are required for their subsequent fusion into multinucleated myotubes. We show that Kirrel3 is transiently expressed at the tips of myocytes during early myoblast differentiation and that its expression is dependent on the myogenic transcription factor, MyoD. Kirrel3 is transported in vesicles into the plasma membrane and its extracellular domain is cleaved in a proteasome-dependent manner. C-terminal deletion mutant lacking most of the intracellular domain accumulates at cellular extensions, does not undergo extracellular cleavage and induces the formation of large cell aggregates. This result suggests that the processing of the extracellular domain is regulated by the receptor's intracellular region. Knock-down of Kirrel3 in primary muscle progenitor cells (MPCs) prevented spindle shape myocyte formation, and significantly reduced their fusion with other myocytes to form multinucleated myotubes. In addition, migration of Kirrel3-deficient MPCs was randomized relative to the directed migration of control MPCs. We conclude that mouse Kirrel3 is a myobast adhesion molecule which promotes the morphological change of rounded MPC to a spindle shaped myocyte that migrates in a directed fashion and participates in the tight interactions between myocytes prior to their fusion.