The recent emergence of the Omicron variant has raised concerns on vaccine efficacy and the urgent need to study more efficient vaccination strategies. Here we observed that an mRNA vaccine booster ...in individuals vaccinated with two doses of inactivated vaccine significantly increased the plasma level of specific antibodies that bind to the receptor-binding domain (RBD) or the spike (S) ectodomain (S1 + S2) of both the G614 and the Omicron variants, compared to two doses of homologous inactivated vaccine. The level of RBD- and S-specific IgG antibodies and virus neutralization titers against variants of concern in the heterologous vaccination group were similar to that in individuals receiving three doses of homologous mRNA-vaccine or a boost of mRNA vaccine after infection, but markedly higher than that in individuals receiving three doses of a homologous inactivated vaccine. This heterologous vaccination regime furthermore significantly enhanced the RBD-specific memory B cell response and S1-specific T cell response, compared to two or three doses of homologous inactivated vaccine. Our study demonstrates that mRNA vaccine booster in individuals vaccinated with inactivated vaccines can be highly beneficial, as it markedly increases the humoral and cellular immune responses against the virus, including the Omicron variant.
The etiology of 80% of patients with primary antibody deficiency (PAD), the second most common type of human immune system disorder after human immunodeficiency virus infection, is yet unknown.
...Clinical/immunological phenotyping and exome sequencing of a cohort of 126 PAD patients (55.5% male, 95.2% childhood onset) born to predominantly consanguineous parents (82.5%) with unknown genetic defects were performed. The American College of Medical Genetics and Genomics criteria were used for validation of pathogenicity of the variants.
This genetic approach and subsequent immunological investigations identified potential disease-causing variants in 86 patients (68.2%); however, 27 of these patients (31.4%) carried autosomal dominant (24.4%) and X-linked (7%) gene defects. This genetic approach led to the identification of new phenotypes in 19 known genes (38 patients) and the discovery of a new genetic defect (CD70 pathogenic variants in 2 patients). Medical implications of a definite genetic diagnosis were reported in ~50% of the patients.
Due to misclassification of the conventional approach for targeted sequencing, employing next-generation sequencing as a preliminary step of molecular diagnostic approach to patients with PAD is crucial for management and treatment of the patients and their family members.
There is growing evidence to suggest that severe disease in children infected with common viruses that are typically benign in other children can result from inborn errors of immunity or their ...phenocopies. Infection with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), a cytolytic respiratory RNA virus, can lead to acute hypoxemic COVID‐19 pneumonia in children with inborn errors of type I interferon (IFN) immunity or autoantibodies against IFNs. These patients do not appear to be prone to severe disease during infection with Epstein–Barr virus (EBV), a leukocyte‐tropic DNA virus that can establish latency. By contrast, various forms of severe EBV disease, ranging from acute hemophagocytosis to chronic or long‐term illnesses, such as agammaglobulinemia and lymphoma, can manifest in children with inborn errors disrupting specific molecular bridges involved in the control of EBV‐infected B cells by cytotoxic T cells. The patients with these disorders do not seem to be prone to severe COVID‐19 pneumonia. These experiments of nature reveal surprising levels of redundancy of two different arms of immunity, with type I IFN being essential for host defense against SARS‐CoV‐2 in respiratory epithelial cells, and certain surface molecules on cytotoxic T cells essential for host defense against EBV in B lymphocytes.
Summary
The clinical course of follicular lymphoma (FL) is highly variable. Recently the m7‐FL international prognostic index (FLIPI) integrating performance status, FLIPI score and the mutational ...status of seven genes, was shown to stratify patients into “low‐risk” and “high‐risk” with respect to 5‐year failure‐free survival after first‐line immunochemotherapy. Our aim was to evaluate the model after rituximab without chemotherapy. The Nordic Lymphoma Group performed two randomized clinical trials on indolent lymphoma patients receiving single rituximab and rituximab with interferon‐α2a. In total, 95 FL patients had sufficient fresh‐frozen diagnostic material for sequencing. A targeted panel for the genes EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP and CARD11 was utilized for m7‐FLIPI score calculation. With a median follow‐up of 10·6 years, 76% of patients were alive. No difference in time to treatment failure (TTF), defined as the interval between start of trial therapy and initiation of new therapy or death, nor overall survival (OS) was found between the m7‐FLIPI risk groups (log‐rank P = 0·94 and 0·99, respectively). EZH2 mutations were associated with longer TTF (log‐rank P = 0·04) and in EP300 mutations were associated with shorter TTF (log‐rank P = 0·01). We conclude that the prognostic value of the m7‐FLIPI clinicogenetic model seems dependent on therapeutic regimen.
Background Recombination-activating gene 1 (RAG1) deficiency presents with a varied spectrum of combined immunodeficiency, ranging from a T− B− NK+ type of disease to a T+ B+ NK+ phenotype. Objective ...We sought to assess the genetic background of patients with common variable immunodeficiency (CVID). Methods A patient given a diagnosis of CVID, who was born to a consanguineous family and thus would be expected to show an autosomal recessive inheritance, was subjected to clinical evaluation, immunologic assays, homozygosity gene mapping, exome sequencing, Sanger sequencing, and functional analysis. Results The 14-year-old patient, who had liver granuloma, extranodal marginal zone B-cell lymphoma, and autoimmune neutropenia, presented with a clinical picture resembling CVID. Genetic analysis of this patient showed a homozygous hypomorphic RAG1 mutation (c.1073 G>A, p.C358Y) with a residual functional capacity of 48% of wild-type protein. Conclusion Our finding broadens the range of disorders associated with RAG1 mutations and might have important therapeutic implications.
Towards precision medicine in lymphoid malignancies Bühler, Marco M.; Martin‐Subero, José I.; Pan‐Hammarström, Qiang ...
Journal of internal medicine,
August 2022, Letnik:
292, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Careful histopathologic examination remains the cornerstone in the diagnosis of the clinically and biologically heterogeneous group of lymphoid malignancies. However, recent advances in genomic and ...epigenomic characterization using high‐throughput technologies have significantly improved our understanding of these tumors. Although no single genomic alteration is completely specific for a lymphoma entity, some alterations are highly recurrent in certain entities and thus can provide complementary diagnostic information when integrated in the hematopathological diagnostic workup. Moreover, other alterations may provide important information regarding the clinical course, that is, prognostic or risk‐stratifying markers, or response to treatment, that is, predictive markers, which may allow tailoring of the patient's treatment based on (epi)genetic characteristics. In this review, we will focus on clinically relevant diagnostic, prognostic, and predictive biomarkers identified in more common types of B‐cell malignancies, and discuss how diagnostic assays designed for comprehensive molecular profiling may pave the way for the implementation of precision diagnostics/medicine approaches. We will also discuss future directions in this rapidly evolving field, including the application of single‐cell sequencing and other omics technologies, to decipher clonal dynamics and evolution in lymphoid malignancies.
Antibody therapy for COVID-19 Hammarström, Lennart; Marcotte, Harold; Piralla, Antonio ...
Current opinion in allergy and clinical immunology,
12/2021, Letnik:
21, Številka:
6
Journal Article
Odprti dostop
Purpose of review
To provide an update of the current state of antibody therapy for Severe Acute Respiratory Syndrome Coronavirus 2 infection that has progressed immensely in a very short time ...period.
Recent findings
Limited clinical effect of classical passive immunotherapy (plasma therapy, hyperimmune immunoglobulin IgG preparations) whereas monoclonal antibody therapy, if initiated early in the disease process, shows promising results.
Summary
Although antibody therapy still remains to be fully explored in patients with COVID-19, a combination of IgG monoclonal antibodies against the receptor-binding domain of the spike protein currently appears to provide the best form of antibody therapy, Immunoglobulin A dimers and Immunoglobulin M pentamers also show promising preliminary therapeutic results.
Severe combined immunodeficiency (SCID) and X-linked agammaglobulinemia (XLA) are inborn errors of immune function that require prompt diagnosis and treatment to prevent life-threatening infections. ...The lack of functional T or B lymphocytes in these diseases serves as a diagnostic criterion and can be applied to neonatal screening. A robust triplex PCR method for quantitation of T-cell receptor excision circles (TRECs) and κ-deleting recombination excision circles (KRECs), using a single Guthrie card punch, was developed and validated in a cohort of 2560 anonymized newborn screening cards and in 49 original stored Guthrie cards from patients diagnosed with SCID, XLA, ataxia-telangiectasia, Nijmegen-breakage-syndrome, common variable immunodeficiency, immunoglobulin A deficiency, or X-linked hyper-IgMsyndrome. Simultaneous measurement of TREC and KREC copy numbers in Guthrie card samples readily identified patients with SCID, XLA, ataxia-telangiectasia and Nijmegen-breakage-syndrome and thus facilitates effective newborn screening for severe immunodeficiency syndromes characterized by the absence of T or B cells.
Mucosal IgA against SARS-CoV-2 Omicron Infection Zuo, Fanglei; Marcotte, Harold; Hammarström, Lennart ...
The New England journal of medicine,
11/2022, Letnik:
387, Številka:
21
Journal Article
Recenzirano
Odprti dostop
To the Editor:
Havervall et al. (Oct. 6 issue)
1
suggest that wild-type SARS-CoV-2 spike-specific mucosal IgA may provide protection against omicron (B.1.1.529) breakthrough infection. We detected ...salivary anti–receptor-binding domain (RBD) IgA antibodies against G614 RBD in 48 of 67 vaccinated healthy persons (72%) at 5 to 59 days after receiving a dose of messenger RNA (mRNA) vaccine — in 12 of 18 (67%) after dose 1, in 22 of 34 (65%) after dose 2, and in 14 of 15 (93%) after dose 3. We also observed these antibodies in 12 of 12 persons (100%) 8 to 43 days after they . . .
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