Vaccination against COVID-19 is highly effective in preventing severe disease and hospitalization, but primary COVID mRNA vaccination schedules often differed from those recommended by the ...manufacturers due to supply chain issues. We investigated the impact of delaying the second dose on antibody responses to COVID mRNA-vaccines in a prospective cohort of health-care workers in Quebec.
We recruited participants from the McGill University Health Centre who provided serum or participant-collected dried blood samples (DBS) at 28-days, 3 months, and 6 months post-second dose and at 28-days after a third dose. IgG antibodies to SARS-CoV2 spike (S), the receptor-binding domain (RBD), nucleocapsid (N) and neutralizing antibodies to the ancestral strain were assessed by enzyme-linked immunosorbent assay (ELISA). We examined associations between long (≤89 days) versus short (<89 days) between-dose intervals and antibody response through multivariable mixed-effects models adjusted for age, sex, prior covid infection status, time since vaccine dose, and assay batch.
The cohort included 328 participants who received up to three vaccine doses (>80% Pfizer-BioNTech). Weighted averages of the serum (n=744) and DBS (n=216) cohort results from the multivariable models showed that IgG anti-S was 31% higher (95% CI: 12% to 53%) and IgG anti-RBD was 37% higher (95% CI: 14% to 65%) in the long
. short interval participants, across all time points.
Our study indicates that extending the covid primary series between-dose interval beyond 89 days (approximately 3 months) provides stronger antibody responses than intervals less than 89 days. Our demonstration of a more robust antibody response with a longer between dose interval is reassuring as logistical and supply challenges are navigated in low-resource settings.
Conclusions We have determined that this group of CVID subjects have impaired Sema4C expression/induction, a molecule that may be important for CD27+memory B-cell development and formation of immune ...synapse upon IL-21 in vitro stimulation.
Abstract In the course of screening immunoglobulin G (IgG) sequences for T cell epitopes, we identified novel Treg epitope peptides, now called Tregitopes , contained in the highly conserved ...framework regions of Fab and Fc. Tregitopes may provide one explanation for the expansion and stimulation of Treg cells following intravenous immunoglobulin (IVIg) therapy. Their distinguishing characteristics include in silico signatures that suggest high-affinity binding to multiple human HLA class II DR and conservation across IgG isotypes and mammalian species with only minor amino acid modifications. Tregitopes induce expansion of CD4+ /CD25hi /FoxP3+ T cells and suppress immune responses to co-incubated antigens in vitro. By comparing the human IgG Tregitopes (hTregitopes 167 and 289, located in the IgG CH1 and CH2 domains) and Fab to murine sequences, we identified class II-restricted murine Tregitope homologs (mTregitopes). In vivo, mTregitopes suppress inflammation and reproducibly induce Tregs to expand. In vitro studies suggest that the Tregitope mechanism of action is to induce Tregs to respond, leading to production of regulatory signals, followed by modulation of dendritic cell phenotype. The identification of Treg epitopes in IgG suggests that additional Tregitopes may also be present in other autologous proteins; methods for identifying and validating such peptides are described here. The discovery of Tregitopes in IgG and other autologous proteins may lead to the development of new insights as to the role of Tregs in autoimmune diseases.
Immune dysfunction may contribute to or cause recurrent implantation failure. This article summarizes normal and pathologic immune responses at implantation and critically appraises currently used ...immunomodulatory therapies.
Recurrent implantation failure (RIF) may be defined as the absence of pregnancy despite the transfer of ≥3 good-quality blastocysts and is unexplained in up to 50% of cases. There are currently no effective treatments for patients with unexplained RIF. Since the maternal immune system is intricately involved in mediating endometrial receptivity and embryo implantation, both insufficient and excessive endometrial inflammatory responses during the window of implantation are proposed to lead to implantation failure. Recent strategies to improve conception rates in RIF patients have focused on modulating maternal immune responses at implantation, through either promoting or suppressing inflammation. Unfortunately, there are no validated, readily available diagnostic tests to confirm immune-mediated RIF. As such, immune therapies are often started empirically without robust evidence as to their efficacy. Like other chronic diseases, patient selection for immunomodulatory therapy is crucial, and personalized medicine for RIF patients is emerging. As the literature on the subject is heterogenous and rapidly evolving, we aim to summarize the potential efficacy, mechanisms of actions and side effects of select therapies for the practicing clinician.
CARD11 is a lymphocyte-specific scaffold molecule required for proper activation of B- and T-cells in response to antigen. Germline gain-of-function (GOF) mutations in the
gene cause a unique B cell ...lymphoproliferative disorder known as B cell Expansion with NF-κB and T cell Anergy (BENTA). In contrast, patients carrying loss-of-function (LOF), dominant negative (DN)
mutations present with severe atopic disease. Interestingly, both GOF and DN CARD11 variants cause primary immunodeficiency, with recurrent bacterial and viral infections, likely resulting from impaired adaptive immune responses. This report describes a unique four-generation family harboring a novel heterozygous germline indel mutation in
(c.701-713delinsT), leading to one altered amino acid and a deletion of 4 others (p.His234_Lys238delinsLeu). Strikingly, affected members exhibit both moderate B cell lymphocytosis
atopic dermatitis/allergies. Ectopic expression of this
variant stimulated constitutive NF-κB activity in T cell lines, similar to other BENTA patient mutations. However, unlike other GOF mutants, this variant significantly impeded the ability of wild-type CARD11 to induce NF-κB activation following antigen receptor ligation. Patient lymphocytes display marked intrinsic defects in B cell differentiation and reduced T cell responsiveness
. Collectively, these data imply that a single heterozygous
mutation can convey both GOF and DN signaling effects, manifesting in a blended BENTA phenotype with atopic features. Our findings further emphasize the importance of balanced CARD11 signaling for normal immune responses.
The regulatory properties of B cells have been studied in autoimmune diseases; however, their role in allergic diseases is poorly understood. We demonstrate that Semaphorin 4C (Sema4C), an axonal ...guidance molecule, plays a crucial role in B cell regulatory function. Mice deficient in Sema4C exhibited increased airway inflammation after allergen exposure, with massive eosinophilic lung infiltrates and increased Th2 cytokines. This phenotype was reproduced by mixed bone marrow chimeric mice with Sema4C deficient only in B cells, indicating that B lymphocytes were the key cells affected by the absence of Sema4C expression in allergic inflammation. We determined that Sema4C-deficient CD19
CD138
cells exhibited decreased IL-10 and increased IL-4 expression in vivo and in vitro. Adoptive transfer of Sema4c
CD19
CD138
cells induced marked pulmonary inflammation, eosinophilia, and increased bronchoalveolar lavage fluid IL-4 and IL-5, whereas adoptive transfer of wild-type CD19
CD138
IL-10
cells dramatically decreased allergic airway inflammation in wild-type and Sema4c
mice. This study identifies a novel pathway by which Th2-mediated immune responses are regulated. It highlights the importance of plasma cells as regulatory cells in allergic inflammation and suggests that CD138
B cells contribute to cytokine balance and are important for maintenance of immune homeostasis in allergic airways disease. Furthermore, we demonstrate that Sema4C is critical for optimal regulatory cytokine production in CD138
B cells.
Background Intravenous immunoglobulin (IVIG) is a frequently used disease-modifying therapy for a large spectrum of autoimmune and inflammatory conditions, yet its mechanisms of action are ...incompletely understood. Using a robust murine model of antigen-driven allergic airways disease, we have demonstrated that IVIG markedly improves ovalbumin (OVA)–induced airway hyperresponsiveness characterized by 4- to 6-fold enhancement in regulatory T (Treg) cells in pulmonary and associated lymphoid tissues. Objective We sought to determine whether IVIG induces antigen-specific Treg cells and to address cellular interactions that lead to induction of Treg cells by IVIG. Methods C57Bl/6 mice were sensitized and challenged by means of intranasal OVA exposure. IVIG or albumin control was administered 24 hours before challenge. Treg cells were tracked by using green fluorescent protein (GFP)-forkhead box protein 3 (Foxp3) knock-in reporter mice (Foxp3GFP ), and Treg cell and dendritic cell (DC) phenotypes and activities were elucidated by using coculture and flow cytometry. Results IVIG therapy of OVA-sensitized and OVA-challenged mice induced antigen-specific forkhead box protein 3 (Foxp3)–positive Treg cells from non-Treg cell precursors. The induced Treg cells home specifically to the lungs and draining lymph nodes and have greatly potentiated suppressive activity compared with that seen in Treg cells purified from control mice. Induction of Treg cells is mediated by tolerogenic DCs generated after IVIG exposure. Compared with albumin-treated, OVA-exposed mice, IVIG-primed DCs express altered Notch ligands, including increased Delta-4 and reduced Jagged-1 levels, reflecting decreased TH 2 polarization. Furthermore, IVIG-primed DCs can stimulate Treg cell differentiation from uncommitted Foxp3− CD4+ T cells ex vivo , and adoptive transfer of IVIG-primed DCs abrogates airway hyperresponsiveness and induces Treg cells. Conclusion The anti-inflammatory effects of IVIG therapy can be mediated by the immunomodulation of DCs, creating a bridge that induces antigen-specific, highly suppressive Treg cells.
The purpose of this study is to describe recent advances in our understanding of the role of interleukin-21 (IL-21) in B-cell maturation, and how defects in IL-21 receptor (IL-21R) signalling ...pathways (IL-21R/γc/JAK3/STAT3) are related to primary immune deficiencies.
Abnormal signalling through IL-21R/γc/JAK3/STAT3 pathway has been related to decreased specific antibody responses following vaccination, and to increased susceptibility to encapsulated bacterial infections. This is manifested in the hyper-IgE syndrome, X-linked and JAK3-related severe combined immunodeficiency (SCID) and loss-of-function mutations in the IL-21R gene. Common variable immunodeficiency is associated with impaired in-vitro development of peripheral blood mononuclear cells or purified B-cells into memory or CD38 B-cells following addition of IL-21.
IL-21 is a key cytokine in development of B-cells into immunoglobulin-secreting cells. Abnormal signalling through the IL-21R/γc/JAK3/STAT3 pathway leads to defective humoral immune responses to both T-dependent and T-independent antigens and impairs the establishment of long-lasting B-cell memory. Studies involving patients with hyper-IgE syndrome demonstrated the nonredundant role of STAT3 in B-cell production of high-affinity specific antibodies, while total serum immunoglobulins could be maintained through STAT3-independent activation of AID (activation-induced cytidine-deaminase). IL-21 related defects may also be associated with reduced natural killer (NK)-cell cytotoxicity and TH17 cytokine production, indicating that abnormalities in the IL-21-IL-21R pathway have profound effects on crucial immune responses.
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