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1.
Int J Mol Sci ; 21(14)2020 Jul 15.
Article in English | MEDLINE | ID: covidwho-1934090

ABSTRACT

Questions concerning the influences of nuclear receptors and their ligands on mammalian B cells are vast in number. Here, we briefly review the effects of nuclear receptor ligands, including estrogen and vitamins, on immunoglobulin production and protection from infectious diseases. We describe nuclear receptor interactions with the B cell genome and the potential mechanisms of gene regulation. Attention to the nuclear receptor/ligand regulation of B cell function may help optimize B cell responses, improve pathogen clearance, and prevent damaging responses toward inert- and self-antigens.


Subject(s)
B-Lymphocytes/immunology , Receptors, Steroid/immunology , Animals , B-Lymphocytes/metabolism , Gene Expression Regulation , Humans , Immunity , Immunoglobulins/genetics , Immunoglobulins/immunology , Receptors, Steroid/genetics , Thyroid Hormones/genetics , Thyroid Hormones/immunology , Vitamin A/genetics , Vitamin A/immunology , Vitamin D/genetics , Vitamin D/immunology
2.
Clin Infect Dis ; 73(11): e4020-e4024, 2021 12 06.
Article in English | MEDLINE | ID: covidwho-1560662

ABSTRACT

We provide detailed clinical, virological, and immunological data of a B-cell-depleted patient treated with obinutuzumab for follicular lymphoma with protracted coronavirus disease 2019 (COVID-19) and viremia. A sustained response was achieved after 2 courses of remdesivir and subsequent convalescent plasma therapy. Immunocompromised patients might require combined and prolonged antiviral treatment regimens.


Subject(s)
COVID-19 , Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , COVID-19/drug therapy , COVID-19/therapy , Humans , Immunization, Passive , SARS-CoV-2
3.
J Immunother Cancer ; 9(4)2021 04.
Article in English | MEDLINE | ID: covidwho-1261212

ABSTRACT

Chimeric antigen receptor (CAR) T-cell therapies that specifically target the CD19 antigen have emerged as a highly effective treatment option in patients with refractory B-cell hematological malignancies. Safety and efficacy outcomes from the pivotal prospective clinical trials of axicabtagene ciloleucel, tisagenlecleucel and lisocabtagene maraleucel and the retrospective, postmarketing, real-world analyses have confirmed high response rates and durable remissions in patients who had failed multiple lines of therapy and had no meaningful treatment options. Although initially administered in the inpatient setting, there has been a growing interest in delivering CAR-T cell therapy in the outpatient setting; however, this has not been adopted as standard clinical practice for multiple reasons, including logistic and reimbursement issues. CAR-T cell therapy requires a multidisciplinary approach and coordination, particularly if given in an outpatient setting. The ability to monitor patients closely is necessary and proper protocols must be established to respond to clinical changes to ensure efficient, effective and rapid evaluation either in the clinic or emergency department for management decisions regarding fever, sepsis, cytokine release syndrome and neurological events, specifically immune effector cell-associated neurotoxicity syndrome. This review presents the authors' institutional experience with the preparation and delivery of outpatient CD19-directed CAR-T cell therapy.


Subject(s)
Ambulatory Care , Antigens, CD19/immunology , Immunotherapy, Adoptive , Lymphoma, B-Cell/therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Receptors, Chimeric Antigen/genetics , T-Lymphocytes/transplantation , Ambulatory Care/economics , Cost-Benefit Analysis , Hospital Costs , Humans , Immunotherapy, Adoptive/adverse effects , Immunotherapy, Adoptive/economics , Immunotherapy, Adoptive/mortality , Lymphoma, B-Cell/economics , Lymphoma, B-Cell/immunology , Lymphoma, B-Cell/mortality , Patient Safety , Precursor Cell Lymphoblastic Leukemia-Lymphoma/economics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/immunology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Risk Assessment , Risk Factors , T-Lymphocytes/immunology , Treatment Outcome
4.
JCI Insight ; 6(9)2021 05 10.
Article in English | MEDLINE | ID: covidwho-1243741

ABSTRACT

Abs that neutralize SARS-CoV-2 are thought to provide the most immediate and effective treatment for those severely afflicted by this virus. Because coronavirus potentially diversifies by mutation, broadly neutralizing Abs are especially sought. Here, we report a possibly novel approach to rapid generation of potent broadly neutralizing human anti-SARS-CoV-2 Abs. We isolated SARS-CoV-2 spike protein-specific memory B cells by panning from the blood of convalescent subjects after infection with SARS-CoV-2 and sequenced and expressed Ig genes from individual B cells as human mAbs. All of 43 human mAbs generated in this way neutralized SARS-CoV-2. Eighteen of the forty-three human mAbs exhibited half-maximal inhibitory concentrations (IC50) of 6.7 × 10-12 M to 6.7 × 10-15 M for spike-pseudotyped virus. Seven of the human mAbs also neutralized (with IC50 < 6.7 × 10-12 M) viruses pseudotyped with mutant spike proteins (including receptor-binding domain mutants and the S1 C-terminal D614G mutant). Neutralization of the Wuhan Hu-1 founder strain and of some variants decreased when coding sequences were reverted to germline, suggesting that potency of neutralization was acquired by somatic hypermutation and selection of B cells. These results indicate that infection with SARS-CoV-2 evokes high-affinity B cell responses, some products of which are broadly neutralizing and others highly strain specific. We also identify variants that would potentially resist immunity evoked by infection with the Wuhan Hu-1 founder strain or by vaccines developed with products of that strain, suggesting evolutionary courses that SARS-CoV-2 could take.


Subject(s)
Antibodies, Neutralizing/genetics , Antibodies, Viral/genetics , COVID-19/immunology , SARS-CoV-2/immunology , Adult , Aged , Antibodies, Monoclonal/genetics , Antibodies, Monoclonal/immunology , Antibody Specificity , B-Lymphocytes/immunology , Broadly Neutralizing Antibodies/genetics , COVID-19/therapy , COVID-19/virology , Humans , Immunoglobulin Heavy Chains/genetics , Immunoglobulin Variable Region/genetics , Immunologic Memory , Middle Aged , Neutralization Tests , Pandemics , SARS-CoV-2/genetics , Somatic Hypermutation, Immunoglobulin , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology
5.
Pathogens ; 10(4)2021 Apr 01.
Article in English | MEDLINE | ID: covidwho-1238927

ABSTRACT

Mesenchymal stem cells (MSCs) are adult, immunomodulatory stem cells which reside in almost all postnatal tissues. Viral antigens and damage-associated molecular patterns released from injured and infected cells activate MSCs, which elicit strong antiviral immune response. MSC-sourced interferons and inflammatory cytokines modulate the cytotoxicity of NK cells and CTLs, enhance the antigen-presentation properties of DCs and macrophages, regulate cytokine synthesis in CD4+ T helper cells and promote antibody production in B cells. After the elimination of viral pathogens, MSCs produce immunoregulatory cytokines and trophic factors, prevent the over-activation of immune cells and promote tissue repair and regeneration. In this review article, we summarize the current knowledge on the molecular mechanisms that are responsible for the MSC-dependent elimination of virus-infected cells, and we emphasize the therapeutic potential of MSCs and their secretomes in the treatment of viral diseases.

6.
Cell ; 184(11): 2955-2972.e25, 2021 05 27.
Article in English | MEDLINE | ID: covidwho-1237636

ABSTRACT

Natural antibodies (Abs) can target host glycans on the surface of pathogens. We studied the evolution of glycan-reactive B cells of rhesus macaques and humans using glycosylated HIV-1 envelope (Env) as a model antigen. 2G12 is a broadly neutralizing Ab (bnAb) that targets a conserved glycan patch on Env of geographically diverse HIV-1 strains using a unique heavy-chain (VH) domain-swapped architecture that results in fragment antigen-binding (Fab) dimerization. Here, we describe HIV-1 Env Fab-dimerized glycan (FDG)-reactive bnAbs without VH-swapped domains from simian-human immunodeficiency virus (SHIV)-infected macaques. FDG Abs also recognized cell-surface glycans on diverse pathogens, including yeast and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike. FDG precursors were expanded by glycan-bearing immunogens in macaques and were abundant in HIV-1-naive humans. Moreover, FDG precursors were predominately mutated IgM+IgD+CD27+, thus suggesting that they originated from a pool of antigen-experienced IgM+ or marginal zone B cells.


Subject(s)
Antibodies, Neutralizing/immunology , HIV-1/immunology , Immunoglobulin Fab Fragments/immunology , Polysaccharides/immunology , SARS-CoV-2/immunology , Simian Immunodeficiency Virus/immunology , Spike Glycoprotein, Coronavirus/immunology , env Gene Products, Human Immunodeficiency Virus/immunology , Animals , B-Lymphocytes/immunology , Broadly Neutralizing Antibodies/immunology , COVID-19/immunology , Dimerization , Epitopes/immunology , Glycosylation , HIV Antibodies/immunology , HIV Infections/immunology , Humans , Immunoglobulin Fab Fragments/chemistry , Macaca mulatta , Polysaccharides/chemistry , Receptors, Antigen, B-Cell/chemistry , Simian Immunodeficiency Virus/genetics , Vaccines/immunology , env Gene Products, Human Immunodeficiency Virus/chemistry , env Gene Products, Human Immunodeficiency Virus/genetics
7.
Mult Scler Relat Disord ; 52: 103014, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1230681

ABSTRACT

OBJECTIVE: Ocrelizumab (OCR) is a monoclonal antibody directed at B-cells that is FDA approved for treatment of RRMS and PPMS. Prior studies have raised concerns about patients' ability to form antibodies in response to various antigens, especially SARS-CoV-2. The objective of this study is to determine whether OCR attenuates the antibody response to SARS-CoV-2 in patients with MS as compared with other disease modifying therapies. METHODS: This is a case-control study looking at the odds of developing antibodies to SARS-CoV-2 in patients treated with OCR versus other disease modifying therapies. From May 13, 2020 through March 1, 2021, patients with a RT-PCR-confirmed infection to SARS-CoV-2 were tested for presence of antibodies and the data was recorded. Outpatients with MS at the Methodist Hospitals Comprehensive MS Center were selected who had a prior infection with COVID-19 as demonstrated by RT-PCR in the electronic health records. Odds ratios were calculated to compare rates of antibody formation with OCR exposure vs other DMT. RESULTS: 24 patients had evidence of COVID-19 and had antibody testing available at the time of analysis. Patients who received OCR had decreased odds of forming antibodies (OR 0.045, p = 0.011, 95% CI (0.004,0.488)). CONCLUSIONS: Patients who received OCR within the prior 6 months of COVID-19 infection had decreased odds of developing antibodies as compared with other DMTs. This suggests that OCR may attenuate the antibody response to SARS-CoV-2. Additional studies should analyze the odds of spike protein antibody formation in response to SARS-CoV-2 vaccines for patients on OCR.


Subject(s)
COVID-19 , Multiple Sclerosis , Antibodies, Monoclonal, Humanized , Antibodies, Viral , Antibody Formation , COVID-19 Vaccines , Case-Control Studies , Humans , SARS-CoV-2
8.
Front Oncol ; 11: 662211, 2021.
Article in English | MEDLINE | ID: covidwho-1207705

ABSTRACT

COVID-19 has become the biggest public health problem and one of the most important causes of death in many countries in the world. SARS-CoV-2 infection is most likely to be fatal in elderly patients with concomitant diseases. In this article we present two cases of asymptomatic SARS-CoV-2-positive patients suffering from cancer who were treated with chemotherapy. The first case, a patient with primary mediastinal B-cell lymphoma, shows that confirmed SARS-CoV-2 infection does not have to be a contraindication to chemotherapy. We describe the course of disease and discuss doubts related to the choice of chemotherapy regimen. The second patient was a male with metastatic sigmoid cancer treated with FOLFOX4 as first-line palliative chemotherapy. This case draws attention to asymptomatic SARS-CoV-2 carriers who underwent chemotherapy. Our patient was safely treated with chemotherapy without long break caused by viral infection. It should be remembered that there are asymptomatic carriers among cancer patients and that they may spread infection to others. On the other hand, delaying chemotherapy can cause rapid disease progression and reduce overall survival of our patients.

9.
J Leukoc Biol ; 109(1): 77-90, 2021 01.
Article in English | MEDLINE | ID: covidwho-1188012

ABSTRACT

B cells play a central role in antiviral and antiparasitic immunity, not only as producers of antibodies, but also as APCs and mediators of inflammation. In this study, we used 16-color flow cytometry analysis to investigate the frequency, differentiation, and activation status of peripheral B cells of patients with SARS-CoV-2 infection or acute Plasmodium falciparum malaria compared with the healthy individuals. As a main result, we observed an increase of the frequency of (CD27-, CD21-) atypical memory B cells and (CD19+, CD27+, CD38+) plasmablasts in malaria and COVID-19 patients. Additionally, CD86, PD-1, CXCR3, and CD39 expression was up-regulated, whereas CD73 was down-regulated on plasmablasts of COVID-19 and malaria patients compared with the bulk B cell population. In particular, there was a more pronounced loss of CD73+ B cells in malaria. The frequency of plasmablasts positively correlated with serum levels of CRP, IL-6, and LDH of COVID-19 patients. In the longitudinal course of COVID-19, a rapid normalization of the frequency of atypical memory B cells was observed. The role and function of plasmablasts and atypical memory B cells in COVID-19 and other acute infections remain to be further investigated. The role of B cells as either "driver or passenger" of hyperinflammation during COVID-19 needs to be clarified.


Subject(s)
COVID-19/immunology , Immunologic Memory , Malaria, Falciparum/immunology , Plasma Cells/immunology , Plasmodium falciparum/immunology , SARS-CoV-2/immunology , Adult , Aged , Antigens, CD/immunology , COVID-19/pathology , Female , Humans , Malaria, Falciparum/pathology , Male , Middle Aged , Plasma Cells/pathology
10.
Thromb Haemost ; 121(11): 1395-1399, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1182893

ABSTRACT

A series of cases with rare thromboembolic incidents including cerebral sinus vein thrombosis (some of them fatal) and concomitant thrombocytopenia occurring shortly after vaccination with the coronavirus disease 2019 (COVID-19) vaccine AZD1222 (Vaxzevria) have caused significant concern and led to its temporary suspension in many countries. Immediate laboratory efforts in four of these patients have identified a tentative pathomechanism underlying this syndrome termed initially vaccine-induced prothrombotic immune thrombocytopenia (VIPIT) and renamed recently vaccine-induced immune thrombotic thrombocytopenia (VITT). It encompasses the presence of platelet-activating antibodies to platelet factor-4/heparin complexes, possibly emulated by polyanionic constituents of AZD1222, and thus resembles heparin-induced thrombocytopenia (HIT). Because these immune complexes bind and activate platelets via Fcγ receptor IIA (FcγRIIA), high-dose intravenous immunoglobulin G has been suggested for treatment of VITT in addition to non-heparin anticoagulants. Here we propose inhibitors of Bruton tyrosine kinase (Btk) approved for B cell malignancies (e.g., ibrutinib) as another therapeutic option in VITT, as they are expected to pleiotropically target multiple pathways downstream of FcγRIIA-mediated Btk activation, for example, as demonstrated for the effective inhibition of platelet aggregation, dense granule secretion, P-selectin expression and platelet-neutrophil aggregate formation stimulated by FcγRIIA cross-linking. Moreover, C-type lectin-like receptor CLEC-2- and GPIb-mediated platelet activation, the interactions and activation of monocytes and the release of neutrophil extracellular traps, as encountered in HIT, could be attenuated by Btk inhibitors. As a paradigm for emergency repurposing of approved drugs in COVID-19, off-label use of Btk inhibitors in a low-dose range not affecting haemostatic functions could thus be considered a sufficiently safe option to treat VITT.


Subject(s)
Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Blood Platelets/drug effects , COVID-19 Vaccines/adverse effects , Platelet Activation/drug effects , Protein Kinase Inhibitors/therapeutic use , Purpura, Thrombocytopenic, Idiopathic/drug therapy , Vaccination/adverse effects , Agammaglobulinaemia Tyrosine Kinase/metabolism , Animals , Autoantibodies/blood , Blood Platelets/enzymology , Blood Platelets/immunology , COVID-19 Vaccines/administration & dosage , Humans , Molecular Targeted Therapy , Platelet Factor 4/immunology , Purpura, Thrombocytopenic, Idiopathic/blood , Purpura, Thrombocytopenic, Idiopathic/enzymology , Purpura, Thrombocytopenic, Idiopathic/immunology , Receptors, IgG/metabolism , Signal Transduction
11.
Science ; 372(6543): 738-741, 2021 05 14.
Article in English | MEDLINE | ID: covidwho-1180894

ABSTRACT

Vaccination and infection promote the formation, tissue distribution, and clonal evolution of B cells, which encode humoral immune memory. We evaluated pediatric and adult blood and deceased adult organ donor tissues to determine convergent antigen-specific antibody genes of similar sequences shared between individuals. B cell memory varied for different pathogens. Polysaccharide antigen-specific clones were not exclusive to the spleen. Adults had higher clone frequencies and greater class switching in lymphoid tissues than blood, while pediatric blood had abundant class-switched convergent clones. Consistent with reported serology, prepandemic children had class-switched convergent clones to severe acute respiratory syndrome coronavirus 2 with weak cross-reactivity to other coronaviruses, while adult blood or tissues showed few such clones. These results highlight the prominence of early childhood B cell clonal expansions and cross-reactivity for future responses to novel pathogens.


Subject(s)
Antibodies, Viral/immunology , B-Lymphocytes/immunology , Coronavirus/immunology , Immunologic Memory , SARS-CoV-2/immunology , Adolescent , Adult , Aged , Aged, 80 and over , Aging , Child, Preschool , Cross Reactions , Ebolavirus/immunology , Female , Fetal Blood/immunology , Genes, Immunoglobulin , Humans , Immunoglobulin Class Switching , Immunoglobulin D/genetics , Immunoglobulin D/immunology , Immunoglobulin Heavy Chains/immunology , Immunoglobulin M/genetics , Immunoglobulin M/immunology , Infant , Lymph Nodes/immunology , Male , Middle Aged , Receptors, Antigen, B-Cell/immunology , Somatic Hypermutation, Immunoglobulin , Spleen/immunology , Young Adult
12.
J Clin Invest ; 131(1)2021 01 04.
Article in English | MEDLINE | ID: covidwho-1169921

ABSTRACT

A considerable fraction of B cells recognize severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with germline-encoded elements of their B cell receptor, resulting in the production of neutralizing and nonneutralizing antibodies. We found that antibody sequences from different discovery cohorts shared biochemical properties and could be retrieved across validation cohorts, confirming the stereotyped character of this naive response in coronavirus disease 2019 (COVID-19). While neutralizing antibody sequences were found independently of disease severity, in line with serological data, individual nonneutralizing antibody sequences were associated with fatal clinical courses, suggesting detrimental effects of these antibodies. We mined 200 immune repertoires from healthy individuals and 500 repertoires from patients with blood or solid cancers - all acquired prior to the pandemic - for SARS-CoV-2 antibody sequences. While the largely unmutated B cell rearrangements occurred in a substantial fraction of immune repertoires from young and healthy individuals, these sequences were less likely to be found in individuals over 60 years of age and in those with cancer. This reflects B cell repertoire restriction in aging and cancer, and may to a certain extent explain the different clinical courses of COVID-19 observed in these risk groups. Future studies will have to address if this stereotyped B cell response to SARS-CoV-2 emerging from unmutated antibody rearrangements will create long-lived memory.


Subject(s)
Antibodies, Viral/immunology , COVID-19/immunology , Gene Rearrangement, B-Lymphocyte , Immunologic Memory , SARS-CoV-2/immunology , Adult , Aged , COVID-19/epidemiology , Cohort Studies , Female , Humans , Male , Middle Aged
13.
Curr Opin Neurol ; 34(3): 295-302, 2021 06 01.
Article in English | MEDLINE | ID: covidwho-1158063

ABSTRACT

PURPOSE OF REVIEW: Treatments targeting B cells are increasingly used for patients with multiple sclerosis (MS). We review the mechanisms of action, clinical effectiveness and safety of treatment, with emphasis on recently published studies. RECENT FINDINGS: Several monoclonal antibodies targeting the surface molecule CD20 on B cells are approved or being developed for treatment of MS. Overall, they seem comparable in terms of strongly suppressing radiological disease activity and relapse biology. Novel approaches include anti-CD19 antibody therapy and treatment with oral drugs targeting Bruton's tyrosine kinase (BTK). The main safety issue with persistent B cell depletion is an increased risk of infections - possibly including an increased risk of severe COVID-19. Vaccine responses are also blunted in patients treated with anti-CD20 antibodies. Lower doses or longer infusion intervals may be sufficient for control of disease activity. Whether this might also improve the safety of treatment and increase vaccination responses remains to be determined. SUMMARY: Available data support the widespread use of therapies targeting B cells in MS. Whether novel approaches targeting CD19 or BTK will have advantages compared to anti-CD20 antibody therapy remains to be established. Furthermore, trials investigating alternative dosing regimens for anti-CD20 antibody treatment are warranted.


Subject(s)
B-Lymphocytes/immunology , Immunotherapy/adverse effects , Immunotherapy/methods , Multiple Sclerosis/therapy , Antibodies, Monoclonal/therapeutic use , COVID-19/complications , Humans , Infection Control , Multiple Sclerosis/complications , Risk
14.
Cell ; 184(7): 1790-1803.e17, 2021 04 01.
Article in English | MEDLINE | ID: covidwho-1139467

ABSTRACT

The long non-coding RNA (lncRNA) XIST establishes X chromosome inactivation (XCI) in female cells in early development and thereafter is thought to be largely dispensable. Here, we show XIST is continually required in adult human B cells to silence a subset of X-linked immune genes such as TLR7. XIST-dependent genes lack promoter DNA methylation and require continual XIST-dependent histone deacetylation. XIST RNA-directed proteomics and CRISPRi screen reveal distinctive somatic cell-type-specific XIST complexes and identify TRIM28 that mediates Pol II pausing at promoters of X-linked genes in B cells. Single-cell transcriptome data of female patients with either systemic lupus erythematosus or COVID-19 infection revealed XIST dysregulation, reflected by escape of XIST-dependent genes, in CD11c+ atypical memory B cells (ABCs). XIST inactivation with TLR7 agonism suffices to promote isotype-switched ABCs. These results indicate cell-type-specific diversification and function for lncRNA-protein complexes and suggest expanded roles for XIST in sex-differences in biology and medicine.


Subject(s)
B-Lymphocytes/immunology , COVID-19 , Lupus Erythematosus, Systemic , RNA, Long Noncoding/physiology , Toll-Like Receptor 7/immunology , X Chromosome Inactivation , COVID-19/genetics , COVID-19/immunology , Cell Line , DNA Methylation , Female , Gene Silencing , Humans , Lupus Erythematosus, Systemic/genetics , Lupus Erythematosus, Systemic/immunology
15.
Cancers (Basel) ; 13(5)2021 Mar 04.
Article in English | MEDLINE | ID: covidwho-1129684

ABSTRACT

Bruton tyrosine kinase (Btk) is expressed in B-lymphocytes, myeloid cells and platelets, and Btk-inhibitors (BTKi) are used to treat patients with B-cell malignancies, developed against autoimmune diseases, have been proposed as novel antithrombotic drugs, and been tested in patients with severe COVID-19. However, mild bleeding is frequent in patients with B-cell malignancies treated with the irreversible BTKi ibrutinib and the recently approved 2nd generation BTKi acalabrutinib, zanubrutinib and tirabrutinib, and also in volunteers receiving in a phase-1 study the novel irreversible BTKi BI-705564. In contrast, no bleeding has been reported in clinical trials of other BTKi. These include the brain-penetrant irreversible tolebrutinib and evobrutinib (against multiple sclerosis), the irreversible branebrutinib, the reversible BMS-986142 and fenebrutinib (targeting rheumatoid arthritis and lupus erythematodes), and the reversible covalent rilzabrutinib (against pemphigus and immune thrombocytopenia). Remibrutinib, a novel highly selective covalent BTKi, is currently in clinical studies of autoimmune dermatological disorders. This review describes twelve BTKi approved or in clinical trials. By focusing on their pharmacological properties, targeted disease, bleeding side effects and actions on platelets it attempts to clarify the mechanisms underlying bleeding. Specific platelet function tests in blood might help to estimate the probability of bleeding of newly developed BTKi.

16.
Front Oncol ; 10: 582901, 2020.
Article in English | MEDLINE | ID: covidwho-1084178

ABSTRACT

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infects humans through the angiotensin converting enzyme-2 (ACE-2) receptor expressed on many cells, including lymphocytes. In Covid-19 patients IL-6 is overexpressed, and hyperactivated plasmacytoid lymphocytes are detected in peripheral blood film. We hypothesize that, due to the unpredictable interaction between the new virus and the B cell lineage of infected patients, a cascade of out of control events can ensue, capable of determining unexpected pathologic disorders involving such lineage. Here we report two cases of autoimmune hemolytic anemia (AIHA) and two cases of B-cell hematological malignancies developed or reactivated during acute SARS-CoV-2 infection. The temporal relationship of the events may suggest a potential causal relationship between SARS-CoV-2 infection and the hematopoietic disorders. We suggest that special attention should be paid to COVID-19 patients with underlining B cell lineage disorders.

17.
Ren Fail ; 43(1): 335-339, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1078673

ABSTRACT

The introduction of Bruton's tyrosine kinase inhibitor ibrutinib has made a significant progress in the treatment of chronic lymphocytic leukemia and other B-cell malignancies. Due to the reduction of cytokine release, it is effective in chronic graft-versus-host disease, and its use has also been suggested in autoimmune diseases and in prevention of COVID-19-associated lung damage. Despite this effect on the immune response, we report a severe hypersensitivity reaction in a 76-year-old male patient diagnosed with prolymphocytic leukemia. Four weeks after the ibrutinib start, non-oliguric acute kidney injury with proteinuria and microscopic hematuria developed and that was accompanied by lower limb purpuras and paresthesia. Renal biopsy revealed acute interstitial nephritis. Employing 1 mg/kg methylprednisolone administration, serum creatinine decreased from 365 µmol/L to 125 µmol/L at 11 days and the proteinuria-hematuria as well as the purpura, paresthesia resolved. Three months later at stabile eGFR of 56 ml/min/1.73 m2 methylprednisolone was withdrawn and a rituximab-venetoclax treatment was initiated without side effects. We conclude that despite the beneficial effect on cytokines response in Th1 direction, ibrutinib can cause acute interstitial nephritis. Early detection, discontinuation of ibrutinib, glucocorticoid administration may help to better preserve renal function, thereby lowering the risk of potential subsequent kidney injury.


Subject(s)
Acute Kidney Injury/chemically induced , Adenine/analogs & derivatives , Nephritis, Interstitial/chemically induced , Piperidines/adverse effects , Proteinuria/chemically induced , Acute Kidney Injury/drug therapy , Adenine/adverse effects , Aged , Cytokines/drug effects , Glucocorticoids/therapeutic use , Humans , Kidney/pathology , Leukemia, Prolymphocytic/drug therapy , Male , Nephritis, Interstitial/drug therapy , Protein Kinase Inhibitors , Proteinuria/drug therapy
18.
J Clin Invest ; 131(1)2021 01 04.
Article in English | MEDLINE | ID: covidwho-1072855

ABSTRACT

A considerable fraction of B cells recognize severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with germline-encoded elements of their B cell receptor, resulting in the production of neutralizing and nonneutralizing antibodies. We found that antibody sequences from different discovery cohorts shared biochemical properties and could be retrieved across validation cohorts, confirming the stereotyped character of this naive response in coronavirus disease 2019 (COVID-19). While neutralizing antibody sequences were found independently of disease severity, in line with serological data, individual nonneutralizing antibody sequences were associated with fatal clinical courses, suggesting detrimental effects of these antibodies. We mined 200 immune repertoires from healthy individuals and 500 repertoires from patients with blood or solid cancers - all acquired prior to the pandemic - for SARS-CoV-2 antibody sequences. While the largely unmutated B cell rearrangements occurred in a substantial fraction of immune repertoires from young and healthy individuals, these sequences were less likely to be found in individuals over 60 years of age and in those with cancer. This reflects B cell repertoire restriction in aging and cancer, and may to a certain extent explain the different clinical courses of COVID-19 observed in these risk groups. Future studies will have to address if this stereotyped B cell response to SARS-CoV-2 emerging from unmutated antibody rearrangements will create long-lived memory.


Subject(s)
Antibodies, Viral/immunology , COVID-19/immunology , Gene Rearrangement, B-Lymphocyte , Immunologic Memory , SARS-CoV-2/immunology , Adult , Aged , COVID-19/epidemiology , Cohort Studies , Female , Humans , Male , Middle Aged
19.
J Taibah Univ Med Sci ; 16(3): 465-469, 2021 Jun.
Article in English | MEDLINE | ID: covidwho-1053612

ABSTRACT

Burkitt's lymphoma (BL) is an aggressive non-Hodgkin B-cell lymphoma. Superior vena cava obstruction (SVCO) is considered a rare presentation of BL and it is usually associated with other types of non-Hodgkin lymphoma such as diffuse large-cell. We report a rare case of sporadic BL with SVCO in a 16-year-old boy with nasopharyngeal, mediastinal, and adrenal masses. The patient presented with a two-month history of left upper neck swelling that increased with time and was not associated with other symptoms. The patient tested positive for COVID-19 on the second day after admission. On examination, he had enlarged solitary lateral cervical and bilateral posterior auricular lymph nodes. There were no signs or symptoms of SVCO regardless of the findings suggested by the computed tomography of the chest. The patient was treated with hyper-CVAD chemotherapy and showed a remarkable resolution of the nasopharyngeal and mediastinal masses with a mild response of his adrenal mass. There were no complications detected during this patient's management.

20.
Int Arch Allergy Immunol ; 182(3): 195-209, 2021.
Article in English | MEDLINE | ID: covidwho-1042227

ABSTRACT

We report perhaps the most comprehensive study of subsets of CD4+ and CD8+ and subsets of B cells in a mild symptomatic SARS-CoV-2+ immunocompetent patient and a common variable immunodeficiency disease (CVID) patient who had normal absolute lymphocyte counts and remained negative for SARS-CoV-2 IgG antibodies. Naïve (TN), central memory (TCM), effector memory (TEM), and terminally differentiated effector memory (TEMRA) subsets of CD4+ and CD8+ T cells, subsets of T follicular helper cells (cTFH, TFH1, TFH2, TFH17, TFH1/TFH17, and TFR), CD4 Treg, CD8 Treg, mature B cells, transitional B cells, marginal zone B cells, germinal center (GC) B cells, CD21low B cells, antibody-secreting cells (plasmablasts), and Breg cells were examined in patients and age-matched controls with appropriate monoclonal antibodies and isotype controls using multicolor flow cytometry. Different patterns of abnormalities (often contrasting) were observed in the subsets of CD4+ T, CD8+ T, B-cell subsets, and regulatory lymphocytes among the immunocompetent patient and CVID patient as compared to corresponding healthy controls. Furthermore, when data were analyzed between the 2 patients, the immunocompetent patient demonstrated greater changes in various subsets as compared to the CVID patient. These data demonstrate different immunological responses to SARS-CoV-2 infection in an immunocompetent patient and the CVID patient. A marked decrease in GC B cells and plasmablasts may be responsible for failure to make SARS-CoV-2 antibodies. The lack of SARS-CoV-2 antibodies with mild clinical disease suggests an important role of T-cell response in defense against SARS-CoV-2 infection.


Subject(s)
COVID-19/immunology , Common Variable Immunodeficiency/immunology , SARS-CoV-2/immunology , T-Lymphocyte Subsets/immunology , Adult , B-Lymphocyte Subsets/immunology , Female , Humans , Immunocompetence , Male , Middle Aged
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