scholarly journals IgG4-Mediated Neurologic Autoimmunities

2021 ◽  
Vol 9 (1) ◽  
pp. e1116
Author(s):  
Marinos C. Dalakas
Keyword(s):  
B Cells ◽  
Plasma Cells ◽  
Severe Disease ◽  
Structural Features ◽  
Immunoglobulin G4 ◽  
Cell Therapies ◽  
Neurologic Disorders ◽  
Clinical Benefits ◽  
Muscle Specific Kinase ◽  
Igg1 Subclass

Background and ObjectivesDescribe the unique functions of immunoglobulin G4 (IgG4) in IgG4-neurologic disorders (IgG4-ND) and explain why, in contrast to their IgG1-counterparts, they respond poorly to intravenous immune globulin (IVIg) but effectively to anti–B cell therapies.MethodsThe IgG4 structure and isotype switch, B cells and plasmablasts relevant to IgG4 production, and IgG4-induced disruption of the targeted antigens are reviewed and compared with IgG1-mediated autoimmune ND, where IVIg inhibits IgG1-triggered inflammatory effects.ResultsThe main IgG4-ND include muscle-specific kinase myasthenia; nodal/paranodal chronic inflammatory demyelinating polyradiculoneuropathy with antibodies to neurofascin-155, contactin-1/caspr-1, or pan-neurofascins; antileucine-rich, glioma-inactivated-1 and contactin-associated protein-like 2 associated-limbic encephalitis, Morvan syndrome, or neuromyotonia; and anti-IgLON5 disorder. The IgG4, because of its unique structural features in the hinge region, has noninflammatory properties being functionally monovalent and bispecific, unable to engage in cross-linking and internalization of the targeted antigen. In contrast to IgG1 subclass which is bivalent and monospecific, IgG4 does not activate complement and cannot bind to inhibitory Fcγ receptor (FcγRIIb) to activate cellular and complement-mediated immune responses, the key functions inhibited by IVIg. Because IVIg contains only 0.7%–2.6% IgG4, its idiotypes are of IgG1 subclass and cannot effectively neutralize IgG4 or sufficiently enhance IgG4 catabolism by saturating FcRn. In contrast, rituximab, by targeting memory B cells and IgG4-producing CD20-positive short-lived plasma cells, induces long-lasting clinical benefits.DiscussionRituximab is the preferred treatment in IgG4-ND patients with severe disease by effectively targeting the production of pathogenic IgG-4 antibodies. In contrast, IVIG is ineffective because it inhibits immunoinflammatory functions irrelevant to the mechanistic effects of IgG4 and contains IgG-1 idiotypes that cannot sufficiently neutralize or possibly catabolize IgG4. Controlled studies with anti-CD19/20 monoclonals that also activate FcγRIIb may be more promising in treating IgG4-ND.

scholarly journals O20 Histological and molecular features of the diseased synovium in early untreated PsA in comparison with RA

Rheumatology ◽  
2020 ◽  
Vol 59 (Supplement_2) ◽  
Author(s):  
Alessandra Nerviani ◽  
Gloria Lliso-Ribera ◽  
Marie-Astrid Boutet ◽  
Katriona Goldmann ◽  
Felice Rivellese ◽  
...  
Keyword(s):  
B Cells ◽  
Synovial Tissue ◽  
Plasma Cells ◽  
Severe Disease ◽  
Power Doppler ◽  
Inflammatory Cells ◽  
Molecular Characteristics ◽  
Molecular Features ◽  
Treatment Naïve ◽  
Gene Modules

Abstract Background Psoriatic arthritis (PsA) and rheumatoid arthritis (RA) are clinically distinct autoimmune joint disorders both marked by the chronic infiltration of the synovial tissue (ST) by inflammatory cells. It has been proposed that a more prominent thickening of the lining layer and a higher number of T/B-cells within the sublining characterised RA-ST. However, in most studies, patients had established disease and were already exposed to treatments. Furthermore, a prevalent number of samples from large joints may have affected these conclusions. Here, we intended to portrait the histological and molecular characteristics of the PsA-ST before any therapeutic modulation and early in the disease in comparison with RA and correlate them with the clinical features. Methods 183 consecutive patients naïve to DMARDs/steroids with ongoing symptoms for less than 12 months and at least one inflamed joint entered the Pathobiology of Early Arthritis Cohort (PEAC) at the Barts Health NHS Trust and underwent a US-guided synovial biopsy. ST was immuno-stained for CD3-CD20-CD138-CD68 to quantify the cellular infiltrate by T-cells, B-cells, plasma cells and macrophages, respectively. Based on the semi-quantitative score (0-4) of the immune markers, patients were categorised in lympho-myeloid (CD20≥2 or CD138>2), diffuse-myeloid (CD68 sublining≥2, CD20 and CD138<2) and pauci-immune (CD68sublining<2 and/or CD3-CD20-CD138<1). Molecular analysis was performed using RNA-sequencing of 93 RA and 15 PsA-ST. RNA cellular content was quantified using Fantom5-gene-modules. Results Of 183 patients, 39 were diagnosed with PsA (32 polyarticular, 7 oligoarticular) and 144 with RA (2010 ACR/EULAR criteria). Age was significantly lower in PsA patients. Small joints were biopsied in 74.4% of PsA and 82% of RA patients. US-synovial thickening score of the biopsied joint was, on average, higher in PsA while the power-doppler signal was similar. The histological comparison proved fewer infiltrating T/B-cells, plasma cells and sublining macrophages in PsA than RA, yet a comparable macrophage composition of the lining. The pathotypes' distribution was different, with prevalent pauci-immune in PsA (43.2%) and lympho-myeloid in RA (43.2%). At baseline, the number of tender/swollen joints was significantly higher in RA, while there were no differences in other clinical parameters such as DAS28. In PsA, synovial pathotypes did not define clinical phenotypes, whereas RA pauci-immune patients had less severe disease activity than lympho-myeloid; this relation was confirmed in an age/gender-matched to PsA subset of 26 RA subjects. The molecular profiling revealed that PsA-ST composition had a greater content of fibroblasts, eosinophils and neutrophils. Moreover, PsA-ST had higher expression of neutrophil recruitment/enrichment, cell migration and cytoskeleton remodelling gene-modules clusters. Conclusion Discovering distinct synovial tissue signatures characterising early treatment-naive PsA will provide a better understanding of the disease pathogenesis and suggest innovative therapeutic targets. Disclosures A. Nerviani None. G. Lliso-Ribera None. M. Boutet None. K. Goldmann None. F. Rivellese None. S. Kelly None. M. Bombardieri None. M. Lewis None. F. Humby None. C. Pitzalis None.

scholarly journals Absence of B Cells in Brainstem and White Matter Lesions Associates With Less Severe Disease and Absence of Oligoclonal Bands in MS

2021 ◽  
Vol 8 (2) ◽  
pp. e955
Author(s):  
Nina L. Fransen ◽  
Brigit A. de Jong ◽  
Katharina Heß ◽  
Tanja Kuhlmann ◽  
Maria C.J. Vincenten ◽  
...  
Keyword(s):  
B Cells ◽  
White Matter ◽  
B Cell ◽  
Clinical Characteristics ◽  
Plasma Cells ◽  
Severe Disease ◽  
Oligoclonal Bands ◽  
Clinical Cohort ◽  
G Ratio

ObjectiveTo determine whether B-cell presence in brainstem and white matter (WM) lesions is associated with poorer pathological and clinical characteristics in advanced MS autopsy cases.MethodsAutopsy tissue of 140 MS and 24 control cases and biopsy tissue of 24 patients with MS were examined for CD20+ B cells and CD138+ plasma cells. The presence of these cells was compared with pathological and clinical characteristics. In corresponding CSF and plasma, immunoglobulin (Ig) G ratio and oligoclonal band (OCB) patterns were determined. In a clinical cohort of 73 patients, the presence of OCBs was determined during follow-up and compared to status at diagnosis.ResultsIn 34% of active and 71% of mixed active/inactive lesions, B cells were absent, which correlated with less pronounced meningeal B-cell infiltration (p < 0.0001). The absence of B cells and plasma cells in brainstem and WM lesions was associated with a longer disease duration (p = 0.001), less frequent secondary progressive MS compared with relapsing and primary progressive MS (p < 0.0001 and p = 0.046, respectively), a lower proportion of mixed active/inactive lesions (p = 0.01), and less often perivascular T-cell clustering (p < 0.0001). Moreover, a lower CSF IgG ratio (p = 0.006) and more frequent absence of OCBs (p < 0.0001) were noted. In a clinical cohort, numbers of patients without OCBs in CSF were increased at follow-up (27.4%).ConclusionsThe absence of B cells is associated with a favorable clinical and pathological profile. This finding may reflect extremes of a continuum of genetic or environmental constitution, but also a regression of WM humoral immunopathology in the natural course of advanced MS.

scholarly journals Single cell transcriptomic re-analysis of immune cells in bronchoalveolar lavage fluids reveals the correlation of B cell characteristics and disease severity of patients with SARS-CoV-2 infection

2020 ◽  
Author(s):  
Chae Won Kim ◽  
Ji Eun Oh ◽  
Heung Kyu Lee
Keyword(s):  
B Cells ◽  
Bronchoalveolar Lavage ◽  
B Cell ◽  
Plasma Cells ◽  
Severe Disease ◽  
Clinical Signs ◽  
Mild Disease ◽  
Tnf Superfamily ◽  
Ccl2 Expression ◽  
Different Characteristics

AbstractThe COVID-19 pandemic (SARS-CoV-2) is a global infectious disease with rapid spread. Some patients have severe symptoms and clinical signs caused by an excessive inflammatory response, which increases the risk of mortality. In this study, we reanalyzed scRNA-seq data of cells from bronchoalveolar lavage fluids of patients with COVID-19 with mild and severe symptoms, focusing on antibody-producing cells. In patients with severe disease, B cells seemed to be more activated and expressed more immunoglobulin genes compared with cells from patients with mild disease, and macrophages expressed higher levels of the TNF superfamily member B-cell activating factor but not of APRIL (a proliferation-inducing ligand). In addition, macrophages from patients with severe disease had increased pro-inflammatory features and pathways associated with Fc receptor-mediated signaling, compared with patients with mild disease. CCR2-positive plasma cells accumulated in patients with severe disease, probably because of increased CCL2 expression on macrophages from patients with severe disease. Together, these results support that different characteristics of B cells might affect the severity of COVID-19 infection.

scholarly journals THU0036 FIRST-IN-HUMAN TRIAL OF BCMA-CD19 COMPOUND CAR IN THE TREATMENT OF AUTOANTIBODY MEDIATED DISORDERS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 231.1-231
Author(s):  
F. Liu ◽  
H. Zhang ◽  
X. Wang ◽  
J. Feng ◽  
Y. Cao ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
B Cells ◽  
Plasma Cells ◽  
Phase 1 ◽  
Human Clinical Trial ◽  
Hla Antibodies ◽  
Time Points ◽  
Car T ◽  
Reh Cells

Background:Donor-specific anti-HLA antibodies (DSAs) are antibodies in the recipient directed against donor class I/II HLA antigens. The existence of DSAs before allogenic hematopoietic stem cell transplantation (AHSCT) are known to cause primary graft failure. Currently there’s no established method of DSA desensitization due to the long half-life of plasma cells.Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease involving in multiple organ systems mediated by numerous autoantibodies. Recent results have shown that depletion of B cells by CD19 CAR-T cells effectively reversed some manifestations in two SLE mouse models. However, plasma cells could be spared with single CD19 CAR-T cells, and peripheral circulating anti-DNA IgG and IgM autoantibodies remain elevated or increased in treated mice.Objectives:We present the efficacy of BCMA-CD19 compound CAR (cCAR), which target on antibody- producing “root”, both B cells and plasma cells in preclinical study and in our first-in-human phase 1 clinical trial.Methods:We constructed a BCMA-CD19 cCAR composed of a complete BCMA-CAR fused to a complete CD19 CAR, separated by a self-cleaving P2A peptide. We assessed the functional activity of cCAR in co-culture assay with multiple cell lines. We also verified cCAR efficacy with two mouse models, injected with either BCMA-expressing MM.1S cells or CD19-expressing REH cells. In our phase 1 clinical trial, we enrolled patients with hematologic malignancies with antibody mediated disorders.Results:BCMA-CD19 cCAR exhibited robust cytotoxic activity against the K562 cells engineered to express either CD19 or BCMA in co-culture assays, indicating the ability of each complete CAR domain to specifically lyse target cells. In mouse model study, cCAR-T cells were able to eliminate tumor cells in mice injected with MM.1S cells and REH cells, indicating that both BCMA and CD19 are specifically and equally lysing B cells and plasma cells in vivo, making BCMA-CD19 cCAR a candidate for clinical use.In our first-in-human clinical trial, the first case is a 48-year-old female patient having resistant B-ALL with high DSA titers. She exhibited complete remission of B-ALL at day 14 post-CAR T treatment. MFI of DSA dropped from 7800 to 1400 at 8 weeks post cCAR treatment, the reduction percentage was approximately 80% (Figure 1). The patient had no CRS, and no neurotoxicity was observed.Figure 1.1. A) MFI of DSA and other HLA antibodies before and at different time points after cCAR T infusion. B) the percent reduction post-transfusion of cCAR T cells at different time points.The second case is a 41-year-old female patient having a refractory diffuse large B cell lymphoma with bone marrow (BM) involvement. Furthermore, she has a 20 years of SLE, with manifestation of fever dependent of corticosteroids. On day 28 after cCAR treatment, PET/CT scan showed CR, and BM turned negative. In addition, she is independent of steroids, has no fever and other manifestations, C3/C4 are within normal ranges, and all the ANA dropped significantly, especially the nuclear type ANA, which turned from> 1:1000 to be negative at day 64. She had Grade 1 CRS but with no neurotoxicity observed. The absence of B cells and plasma cells persisted more than 5 months post CAR therapy.Conclusion:Our first in human clinical trial on BCMA-CD19 cCAR demonstrated profound efficacy in reducing DSA levels in an AHSCT candidate and ANA titer in a SLE patient. There was strong clinical evidence of depletion of antibody-producing roots, B-cells and plasma cells in both patients. Our results further suggested that BCMA-CD19 cCAR has the potential to benefit patients receiving solid organ transplants or those with other antibody-mediated diseases.Figure 2.Reduction of different type of ANA titer at different time points.Acknowledgments:patients and their familiesDisclosure of Interests:Fang liu: None declared, Hongyu Zhang: None declared, Xiao Wang: None declared, Jia Feng: None declared, Yuanzhen cao Employee of: Employee of iCell Gene Therapeutics LLC, Yi Su: None declared, Masayuki Wada Employee of: employee of iCell Gene Therapeutics LLC, Yu Ma Employee of: employee of iCAR Bio Therapeutics Ltd, Yupo Ma Shareholder of: shareholder of iCell Gene Therapeutics LLC

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