scholarly journals Efficacy of tocilizumab therapy in a patient with severe pancytopenia associated with a STAT3 gain-of-function mutation

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Wenjie Wang ◽  
Luyao Liu ◽  
Xiaoying Hui ◽  
Ying Wang ◽  
Wenjing Ying ◽  
...  
Keyword(s):  
T Cells ◽  
Next Generation Sequencing ◽  
B Cells ◽  
Early Onset ◽  
De Novo ◽  
Gene Sequencing ◽  
Immune Dysregulation ◽  
Effector Memory ◽  
Gain Of Function ◽  
Generation Sequencing

Abstract Background We aimed to report the clinical characteristics, immunological features, and treatment of one patient with a de novo STAT3 gain-of-function mutation identified by next generation sequencing. We investigated the efficacy of tocilizumab therapy in immune dysregulation diseases caused by STAT3 mutation. Results The patient was a 16-year-old girl. She presented with recurrent respiratory infections and chronic diarrhea after birth. She had life-threatening autoimmune pancytopenia at 14 years old. After receiving glucocorticoid therapy, she developed diabetes. However, her pancytopenia relapsed when the glucocorticoid was tapered. Next-generation sequencing showed a de novo heterozygous mutation in the STAT3 gene, c.1261G > A (p. G421R), which was previously described as a gain-of-function mutation. After tocilizumab therapy, her pancytopenia fully resolved, and insulin and glucocorticoid therapies were gradually discontinued within 12 months. She had lymphopenia and an inverted CD4/CD8 ratio before therapy. Lymphocyte subpopulation analysis indicated an expansion of effector memory CD4+, effector memory CD8+ and central memory CD4+ T cells. The proportions of memory B cells and naive CD4+ T cells were decreased, and the proportion of naïve B cells was increased. None of the abnormal lymphocytic changes improved significantly. STAT3 GOF mutations were identified by next gene sequencing in those with early-onset multi-organ autoimmunity. Including our patient, 13 patients with STAT3 GOF mutations received targeted treatment. Twelve of them were treated with tocilizumab alone or combination tocilizumab with JAK inhibitor, and ten patients improved. Conclusions Gene sequencing should be performed for patients with early-onset refractory or multiorgan immune dysregulation diseases. Targeted drugs can effectively improve the clinical problems associated with STAT3 gain-of-function mutations, while nontargeted immunosuppressive therapy is usually insufficient.

scholarly journals Duplication of the IL2RA locus causes excessive IL-2 signaling and may predispose to very early onset colitis

2021 ◽  
Author(s):  
Maria E. Joosse ◽  
Fabienne Charbit-Henrion ◽  
Remy Boisgard ◽  
Rolien C. Raatgeep ◽  
Dicky J. Lindenbergh-Kortleve ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Early Onset ◽  
Intestinal Inflammation ◽  
De Novo ◽  
Cell Receptor ◽  
Effector Memory ◽  
Colonic Disease ◽  
Cd25 Expression

AbstractSingle genetic mutations predispose to very early onset inflammatory bowel disease (VEO-IBD). Here, we identify a de novo duplication of the 10p15.1 chromosomal region, including the IL2RA locus, in a 2-year-old girl with treatment-resistant pancolitis that was brought into remission by colectomy. Strikingly, after colectomy while the patient was in clinical remission and without medication, the peripheral blood CD4:CD8 ratio was constitutively high and CD25 expression was increased on circulating effector memory, Foxp3+, and Foxp3neg CD4+ T cells compared to healthy controls. This high CD25 expression increased IL-2 signaling, potentiating CD4+ T-cell-derived IFNγ secretion after T-cell receptor (TCR) stimulation. Restoring CD25 expression using the JAK1/3-inhibitor tofacitinib controlled TCR-induced IFNγ secretion in vitro. As diseased colonic tissue, but not the unaffected duodenum, contained mainly CD4+ T cells with a prominent IFNγ-signature, we hypothesize that local microbial stimulation may have initiated colonic disease. Overall, we identify that duplication of the IL2RA locus can associate with VEO-IBD and suggest that increased IL-2 signaling predisposes to colonic intestinal inflammation.

scholarly journals Next‐generation sequencing in two cases of de novo acute basophilic leukaemia

2021 ◽  
Author(s):  
Takuya Shimizu ◽  
Tadakazu Kondo ◽  
Yasuhito Nannya ◽  
Mizuki Watanabe ◽  
Toshio Kitawaki ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
De Novo ◽  
Next Generation ◽  
Generation Sequencing

scholarly journals B cell depletion impairs vaccination-induced CD8+ T cell responses in a type I interferon-dependent manner

2021 ◽  
pp. annrheumdis-2021-220435
Author(s):  
Theresa Graalmann ◽  
Katharina Borst ◽  
Himanshu Manchanda ◽  
Lea Vaas ◽  
Matthias Bruhn ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Expansion ◽  
De Novo ◽  
T Cell Responses ◽  
Type I ◽  
Cell Responses ◽  
T Cell Expansion

ObjectivesThe monoclonal anti-CD20 antibody rituximab is frequently applied in the treatment of lymphoma as well as autoimmune diseases and confers efficient depletion of recirculating B cells. Correspondingly, B cell-depleted patients barely mount de novo antibody responses during infections or vaccinations. Therefore, efficient immune responses of B cell-depleted patients largely depend on protective T cell responses.MethodsCD8+ T cell expansion was studied in rituximab-treated rheumatoid arthritis (RA) patients and B cell-deficient mice on vaccination/infection with different vaccines/pathogens.ResultsRituximab-treated RA patients vaccinated with Influvac showed reduced expansion of influenza-specific CD8+ T cells when compared with healthy controls. Moreover, B cell-deficient JHT mice infected with mouse-adapted Influenza or modified vaccinia virus Ankara showed less vigorous expansion of virus-specific CD8+ T cells than wild type mice. Of note, JHT mice do not have an intrinsic impairment of CD8+ T cell expansion, since infection with vaccinia virus induced similar T cell expansion in JHT and wild type mice. Direct type I interferon receptor signalling of B cells was necessary to induce several chemokines in B cells and to support T cell help by enhancing the expression of MHC-I.ConclusionsDepending on the stimulus, B cells can modulate CD8+ T cell responses. Thus, B cell depletion causes a deficiency of de novo antibody responses and affects the efficacy of cellular response including cytotoxic T cells. The choice of the appropriate vaccine to vaccinate B cell-depleted patients has to be re-evaluated in order to efficiently induce protective CD8+ T cell responses.

Molecular marker information from de novo assembled transcriptomes of chilli pepper (Capsicum annuum L.) varieties based on next-generation sequencing technology

2014 ◽  
Vol 12 (S1) ◽  
pp. S83-S86 ◽  
Author(s):  
Yul-Kyun Ahn ◽  
Swati Tripathi ◽  
Young-Il Cho ◽  
Jeong-Ho Kim ◽  
Hye-Eun Lee ◽  
...  
Keyword(s):  
Molecular Markers ◽  
Next Generation Sequencing ◽  
De Novo ◽  
Transcriptome Assembly ◽  
Sequence Variant ◽  
Nucleotide Polymorphisms ◽  
Next Generation ◽  
Chilli Pepper ◽  
Next Generation Sequencing Technology ◽  
Generation Sequencing

Next-generation sequencing technique has been known as a useful tool for de novo transcriptome assembly, functional annotation of genes and identification of molecular markers. This study was carried out to mine molecular markers from de novo assembled transcriptomes of four chilli pepper varieties, the highly pungent ‘Saengryeg 211’ and non-pungent ‘Saengryeg 213’ and variably pigmented ‘Mandarin’ and ‘Blackcluster’. Pyrosequencing of the complementary DNA library resulted in 361,671, 274,269, 279,221, and 316,357 raw reads, which were assembled in 23,607, 19,894, 18,340 and 20,357 contigs, for the four varieties, respectively. Detailed sequence variant analysis identified numerous potential single-nucleotide polymorphisms (SNPs) and simple sequence repeats (SSRs) for all the varieties for which the primers were designed. The transcriptome information and SNP/SSR markers generated in this study provide valuable resources for high-density molecular genetic mapping in chilli pepper and Quantitative trait loci analysis related to fruit qualities. These markers for pepper will be highly valuable for marker-assisted breeding and other genetic studies.

scholarly journals Targeted Next Generation Sequencing (NGS) to Diagnose Hereditary Hemolytic Anemias

2020 ◽  
Author(s):  
Rishab Bharadwaj ◽  
Thulasi Raman ◽  
Ravikumar Thangadorai ◽  
Deenadayalan Munirathnam
Keyword(s):  
Next Generation Sequencing ◽  
Gene Sequencing ◽  
Accurate Diagnosis ◽  
Next Generation ◽  
Diagnostic Challenge ◽  
Targeted Next Generation Sequencing ◽  
Appropriate Treatment ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Hereditary hemolytic anemias present a unique diagnostic challenge due to their wide phenotypic and genotypic spectrum. Accurate diagnosis is essential to ensure appropriate treatment. We report two cases, which presented as hemolytic anemias, but initial workup was inconclusive and they were finally diagnosed with the help of Next Generation Sequencing (Dehydrated Hereditary Stomatocytosis and Kӧln Hemoglobinopathy). The introduction of gene sequencing to aid diagnosis of these disorders is a revolutionary step forward and should be incorporated earlier in the workup of such patients.

scholarly journals Heterozygous OAS1 gain-of-function variants cause an autoinflammatory immunodeficiency

2021 ◽  
Vol 6 (60) ◽  
pp. eabf9564
Author(s):  
Thomas Magg ◽  
Tsubasa Okano ◽  
Lars M. Koenig ◽  
Daniel F.R. Boehmer ◽  
Samantha L. Schwartz ◽  
...  
Keyword(s):  
B Cells ◽  
Hematopoietic Cell Transplantation ◽  
De Novo ◽  
Dynamics Simulation ◽  
Recurrent Fever ◽  
Type I ◽  
Rnase L ◽  
Oligoadenylate Synthetase ◽  
Gain Of Function ◽  
Translational Arrest

Analysis of autoinflammatory and immunodeficiency disorders elucidates human immunity and fosters the development of targeted therapies. Oligoadenylate synthetase 1 is a type I interferon–induced, intracellular double-stranded RNA (dsRNA) sensor that generates 2′-5′-oligoadenylate to activate ribonuclease L (RNase L) as a means of antiviral defense. We identified four de novo heterozygous OAS1 gain-of-function variants in six patients with a polymorphic autoinflammatory immunodeficiency characterized by recurrent fever, dermatitis, inflammatory bowel disease, pulmonary alveolar proteinosis, and hypogammaglobulinemia. To establish causality, we applied genetic, molecular dynamics simulation, biochemical, and cellular functional analyses in heterologous, autologous, and inducible pluripotent stem cell–derived macrophages and/or monocytes and B cells. We found that upon interferon-induced expression, OAS1 variant proteins displayed dsRNA-independent activity, which resulted in RNase L–mediated RNA cleavage, transcriptomic alteration, translational arrest, and dysfunction and apoptosis of monocytes, macrophages, and B cells. RNase L inhibition with curcumin modulated and allogeneic hematopoietic cell transplantation cured the disorder. Together, these data suggest that human OAS1 is a regulator of interferon-induced hyperinflammatory monocyte, macrophage, and B cell pathophysiology.

scholarly journals Specific niches for lung-resident memory CD8+ T cells at the site of tissue regeneration enable CD69-independent maintenance

2016 ◽  
Vol 213 (13) ◽  
pp. 3057-3073 ◽  
Author(s):  
Shiki Takamura ◽  
Hideki Yagi ◽  
Yoshiyuki Hakata ◽  
Chihiro Motozono ◽  
Sean R. McMaster ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
De Novo ◽  
Memory T Cells ◽  
Tissue Injury ◽  
Effector Memory ◽  
Respiratory Pathogens ◽  
Damage Site ◽  
Memory Cd8 T Cells ◽  
Specific Localization

CD8+ tissue-resident memory T cells (TRM cells) reside permanently in nonlymphoid tissues and provide a first line of protection against invading pathogens. However, the precise localization of CD8+ TRM cells in the lung, which physiologically consists of a markedly scant interstitium compared with other mucosa, remains unclear. In this study, we show that lung CD8+ TRM cells localize predominantly in specific niches created at the site of regeneration after tissue injury, whereas peripheral tissue-circulating CD8+ effector memory T cells (TEM cells) are widely but sparsely distributed in unaffected areas. Although CD69 inhibited sphingosine 1–phosphate receptor 1–mediated egress of CD8+ T cells immediately after their recruitment into lung tissues, such inhibition was not required for the retention of cells in the TRM niches. Furthermore, despite rigid segregation of TEM cells from the TRM niche, prime-pull strategy with cognate antigen enabled the conversion from TEM cells to TRM cells by creating de novo TRM niches. Such damage site–specific localization of CD8+ TRM cells may be important for efficient protection against secondary infections by respiratory pathogens.

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