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Article ; Online: Monoclonal Immunoglobulin Crystalline Membranous Nephropathy.

Mignano, Salvatore E / Pascal, Virginie / Odioemene, Nnaemezie E / Forehand, William / Javaugue, Vincent / Said, Samar M / Sethi, Sanjeev / Sirac, Christophe / Nasr, Samih H

American journal of kidney diseases : the official journal of the National Kidney Foundation

2024

Abstract: Monoclonal immunoglobulin (MIg) crystalline nephropathies are rare lesions resulting from precipitation of MIgs in the kidney as intracellular or extracellular crystals. We describe a patient with multiple myeloma (IgGλ) and diabetes who presented with ... ...

Abstract	Monoclonal immunoglobulin (MIg) crystalline nephropathies are rare lesions resulting from precipitation of MIgs in the kidney as intracellular or extracellular crystals. We describe a patient with multiple myeloma (IgGλ) and diabetes who presented with nephrotic range proteinuria. Kidney biopsy revealed membranous nephropathy superimposed on diabetic glomerulosclerosis. Glomeruli were negative for PLA2R, THSD7A, and NELL-1. Ultrastructurally, the subepithelial deposits were composed of crystals (ranging from rhomboid to rod to needle shaped), which failed to stain for immunoglobulins by routine immunofluorescence but stained for IgG+λ by paraffin immunofluorescence after pronase digestion. RNA-based immunoglobulin repertoire sequencing performed on bone marrow aspirate identified an IgGλ (γ1) clone, which was highly atypical, combining an extensively mutated (23.6%) Ig heavy chain derived from the IGHV1-24 with low pI and unusual mutations and a light chain derived from an extremely rare germline gene (IGLV10-54). This report expands the pathologic spectrum of MIg crystalline nephropathies by describing a unique case of crystalline nephropathy with IgGλ deposits manifesting as membranous nephropathy.
Language	English
Publishing date	2024-01-23
Publishing country	United States
Document type	Case Reports
ZDB-ID	604539-x
ISSN	1523-6838 ; 0272-6386
ISSN (online)	1523-6838
ISSN	0272-6386
DOI	10.1053/j.ajkd.2023.11.011
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Article: History of IgA Nephropathy Mouse Models.

Wehbi, Batoul / Pascal, Virginie / Zawil, Lina / Cogné, Michel / Aldigier, Jean-Claude

Journal of clinical medicine

2021 Volume 10, Issue 14

Abstract: IgA nephropathy (IgAN) is the most common primary glomerulonephritis in the world. It was first described in 1968 by Jean Berger and Nicole Hinglais as the presence of intercapillary deposits of IgA. Despite this simple description, patients with IgAN ... ...

Abstract	IgA nephropathy (IgAN) is the most common primary glomerulonephritis in the world. It was first described in 1968 by Jean Berger and Nicole Hinglais as the presence of intercapillary deposits of IgA. Despite this simple description, patients with IgAN may present very broad clinical features ranging from the isolated presence of IgA in the mesangium without clinical or biological manifestations to rapidly progressive kidney failure. These features are associated with a variety of histological lesions, from the discrete thickening of the mesangial matrix to diffuse cell proliferation. Immunofluorescence on IgAN kidney specimens shows the isolated presence of IgA or its inconsistent association with IgG and complement components. This clinical heterogeneity of IgAN clearly echoes its complex and multifactorial pathophysiology in humans, inviting further analyses of its various aspects through the use of experimental models. Small-animal models of IgAN provide the most pertinent strategies for studying the multifactorial aspects of IgAN pathogenesis and progression. Although only primates have the IgA1 subclass, several murine models have been developed in which various aspects of immune responses are deregulated and which are useful in the understanding of IgAN physiopathology as well as in the assessment of IgAN therapeutic approaches. In this manuscript, we review all murine IgAN models developed since 1968 and discuss their remarkable contribution to understanding the disease.
Language	English
Publishing date	2021-07-16
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2662592-1
ISSN	2077-0383
ISSN	2077-0383
DOI	10.3390/jcm10143142
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Article ; Online: Homéostasie de la réponse IgA et microbiote.

Pascal, Virginie / Hiblot, Margaux / Wehbi, Batoul / Aldigier, Jean-Claude / Cogné, Michel

Medecine sciences : M/S

2021 Volume 37, Issue 1, Page(s) 35–40

Abstract: Mucosal immunity has to deal with a patchy mix of commensal but also eventually pathogenic bugs. Immunoglobulins of the A class (IgA) are opposing to this duality a functional balance going from tolerance to protective response or even to hyper- ... ...

Title translation	Microbiota and IgA response homeostasis.
Abstract	Mucosal immunity has to deal with a patchy mix of commensal but also eventually pathogenic bugs. Immunoglobulins of the A class (IgA) are opposing to this duality a functional balance going from tolerance to protective response or even to hyper-inflammation. Recent reports have shown the binding of polyreactive natural IgA, but also of affinity maturated protective IgA to the commensal microbiota, to superantigens and also to vaccinal antigens. Diverse types of humoral responses thus altogether contribute to the homeostasis of mucosal immunity. Their knowledge has to be taken into consideration for defining strategies of immuno-intervention, for mucosal vaccination as much as for immunotherapy of chronic inflammatory bowel disease.
MeSH term(s)	Animals ; Gastrointestinal Microbiome/immunology ; Gastrointestinal Microbiome/physiology ; Homeostasis/physiology ; Humans ; Immune Tolerance/physiology ; Immunity/physiology ; Immunity, Mucosal/physiology ; Immunoglobulin A/metabolism ; Inflammatory Bowel Diseases/immunology ; Inflammatory Bowel Diseases/microbiology ; Intestinal Mucosa/immunology ; Intestinal Mucosa/microbiology ; Microbiota/immunology ; Microbiota/physiology
Chemical Substances	Immunoglobulin A
Language	French
Publishing date	2021-01-25
Publishing country	France
Document type	Journal Article ; Review
ZDB-ID	632733-3
ISSN	1958-5381 ; 0767-0974
ISSN (online)	1958-5381
ISSN	0767-0974
DOI	10.1051/medsci/2020258
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Article ; Online: De novo natural anti-M alloantibody emergence in severe Coronavirus Disease 2019.

Jeannet, Robin / Descazeaud, Alexandra / Daix, Thomas / Pauthier, Hélène / Pascal, Virginie / Hantz, Sébastien / Cam, Sophie Le / Francois, Bruno / Feuillard, Jean / Lafarge, Xavier

Journal of infection and public health

2022 Volume 15, Issue 12, Page(s) 1455–1458

Abstract: The immune response is a key player in the course of SARS-CoV-2 infection, and is often seriously dysfunctional in severe Coronavirus Disease 2019. The hyperinflammatory status has been described to be accompanied by the appearance of autoantibodies. In ... ...

Abstract	The immune response is a key player in the course of SARS-CoV-2 infection, and is often seriously dysfunctional in severe Coronavirus Disease 2019. The hyperinflammatory status has been described to be accompanied by the appearance of autoantibodies. In a lethal COVID-19 infection, we observed the emergence of a de novo natural alloantibody which targeted the M antigen from the MNS blood group on red blood cells (RBC) without evidence of any cross-reaction with SARS-CoV-2 antigens. This IgM lambda alloantibody was unmutated and unswitched. Here, we describe for the first time the emergence of a bystander de novo natural alloantibody against RBCs in a severe COVID-19 patient, highlighting the extra-follicular humoral response reported in these cases.
MeSH term(s)	Humans ; COVID-19 ; SARS-CoV-2 ; Blood Group Antigens ; Erythrocytes
Chemical Substances	Blood Group Antigens
Language	English
Publishing date	2022-11-02
Publishing country	England
Document type	Journal Article
ZDB-ID	2467587-8
ISSN	1876-035X ; 1876-0341
ISSN (online)	1876-035X
ISSN	1876-0341
DOI	10.1016/j.jiph.2022.10.025
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Article ; Online: Demultiplexing Ig repertoires by parallel mRNA/DNA sequencing shows major differential alterations in severe COVID-19.

iScience

2023 Volume 26, Issue 3, Page(s) 106260

Abstract: To understand the fine differential elements that can lead to or prevent acute respiratory distress syndrome (ARDS) in COVID-19 patients, it is crucial to investigate the immune response architecture. We herein dissected the multiple layers of B cell ... ...

Abstract	To understand the fine differential elements that can lead to or prevent acute respiratory distress syndrome (ARDS) in COVID-19 patients, it is crucial to investigate the immune response architecture. We herein dissected the multiple layers of B cell responses by flow cytometry and Ig repertoire analysis from acute phase to recovery. Flow cytometry with FlowSOM analysis showed major changes associated with COVID-19 inflammation such as an increase of double-negative B-cells and ongoing plasma cell differentiation. This paralleled COVID-19-driven expansion of two disconnected B-cell repertoires. Demultiplexing successive DNA and RNA Ig repertoire patterns characterized an early expansion of IgG1 clonotypes with atypically long and uncharged CDR3, the abundance of this inflammatory repertoire being correlated with ARDS and likely pejorative. A superimposed convergent response included convergent anti-SARS-CoV-2 clonotypes. It featured progressively increasing somatic hypermutation together with normal-length or short CDR3 and it persisted until a quiescent memory B-cell stage after recovery.
Language	English
Publishing date	2023-02-21
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2023.106260
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Article ; Online: RNA-based immunoglobulin repertoire sequencing is a new tool for the management of monoclonal gammopathy of renal (kidney) significance.

Javaugue, Vincent / Pascal, Virginie / Bender, Sébastien / Nasraddine, Sarah / Dargelos, Mathilde / Alizadeh, Mehdi / Saintamand, Alexis / Filloux, Matthieu / Derouault, Paco / Bouyer, Sabrina / Desport, Estelle / Jaccard, Arnaud / Bridoux, Frank / Cogné, Michel / Sirac, Christophe

Kidney international

2021 Volume 101, Issue 2, Page(s) 331–337

Abstract: The diagnostic approach of monoclonal gammopathy of renal significance is based on the detection of a monoclonal immunoglobulin in the blood and urine, and the identification of the underlying clone through bone marrow and/or peripheral blood cytologic ... ...

Abstract	The diagnostic approach of monoclonal gammopathy of renal significance is based on the detection of a monoclonal immunoglobulin in the blood and urine, and the identification of the underlying clone through bone marrow and/or peripheral blood cytologic and flow cytometry analysis. However, the monoclonal component and its corresponding clone may be undetectable using these routine techniques. Since clone identification is the cornerstone for guiding therapy and assessing disease response, more sensitive methods are required. We recently developed a high-throughput sequencing assay from bone marrow mRNA encoding immunoglobulins (RACE-RepSeq). This technique provides both full-length V(D)J region (variable, diversity and joining genes that generate unique receptors as antigen receptors) of the monoclonal immunoglobulin and the dominant immunoglobulin repertoire. This allows analysis of mutational patterns, immunoglobulin variable gene frequencies and diversity due to somatic hypermutation. Here, we evaluated the diagnostic performance of RACE-RepSeq in 16 patients with monoclonal-associated kidney lesions, and low serum monoclonal immunoglobulin and free light chain levels at diagnosis. Bone marrow immunohistochemical analysis was negative in all 11 patients so tested and 7 of 12 patients had no detectable clone matching the kidney deposits using flow cytometry analysis. By contrast, RACE-RepSeq detected a dominant clonal light chain sequence of matched isotype with respect to kidney deposits in all patients. Thus, high throughput mRNA sequencing appears highly sensitive to detect subtle clonal disorders in monoclonal gammopathy of renal significance and suggest this novel approach could help improve the management of this kidney disease.
MeSH term(s)	Humans ; Immunoglobulin Light Chains ; Kidney/pathology ; Kidney Diseases/diagnosis ; Kidney Diseases/genetics ; Kidney Diseases/therapy ; Paraproteinemias/diagnosis ; Paraproteinemias/genetics ; Paraproteinemias/therapy ; RNA
Chemical Substances	Immunoglobulin Light Chains ; RNA (63231-63-0)
Language	English
Publishing date	2021-11-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	120573-0
ISSN	1523-1755 ; 0085-2538
ISSN (online)	1523-1755
ISSN	0085-2538
DOI	10.1016/j.kint.2021.10.017
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Zs.A 797: Show issues

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Article ; Online: Flow cytometry detection of CD138 expression continuum between monotypic B and plasma cells is associated with both high IgM peak levels and MYD88 mutation and contributes to diagnosis of Waldenström macroglobulinemia.

Gayet, Mylene / Leymarie, Vincent / Derouault, Paco / Guérin, Estelle / Vaidié, Julien / Pascal, Virginie / Boulin, Mélanie / Dmytruk, Nataliya / Chauzeix, Jasmine / Trimoreau, Franck / Gachard, Nathalie / Feuillard, Jean / Rizzo, David

Cytometry. Part B, Clinical cytometry

2021 Volume 102, Issue 1, Page(s) 62–69

Abstract: Background: Differential diagnosis of Waldenström macroglobulinemia (WM) with other indolent B-cell malignancies is still a challenge. Here, we propose an original and simple analysis of routine flow cytometry (FCM) unraveling the characteristic ongoing ...

Abstract	Background: Differential diagnosis of Waldenström macroglobulinemia (WM) with other indolent B-cell malignancies is still a challenge. Here, we propose an original and simple analysis of routine flow cytometry (FCM) unraveling the characteristic ongoing plasma cell (PC) differentiation of WM tumor B-cells. Methods: FCM analysis of both B-cells and PC was performed on a series of 77 patients with IgM peak. MYD88 and CXCR4 mutations were studied using an allele-specific PCR and by high throughput sequencing. Results: Twenty seven (35%), 46 (58%) and 4 (5%) patients were classified as WM, IgM monoclonal gammopathy of undetermined significance (MGUS) or other B-NHL respectively. MYD88 mutation was found in 25/27 WM (93%) and in 29/46 MGUS (63%). Using FCM, monotypic B-cells were found in 27/27 WM (100%) and 34/46 MGUS (74%). Monotypic CD138pos/CD38pos PCs were detected in 23/27 WM (85%) and 25/46 MGUS (54%). Highlighting the ongoing PC differentiation of WM tumor B-cells by FCM, we evidenced a CD138 expression continuum between monotypic B-cells and PCs. This pattern remained absent in control samples and was significantly associated with higher IgM peaks (p = 6.10 Conclusions: FCM exploration of both B-cells and PC led to identify a CD138 expression continuum as an objective marker of ongoing PC differentiation of WM tumor cells and was strongly associated with increased IgM peak levels and MYD88 mutations. This approach could contribute to place FCM at the forefront of WM diagnosis.
MeSH term(s)	Flow Cytometry ; Humans ; Immunoglobulin M/genetics ; Mutation/genetics ; Myeloid Differentiation Factor 88/genetics ; Plasma Cells/pathology ; Syndecan-1/genetics ; Waldenstrom Macroglobulinemia/diagnosis ; Waldenstrom Macroglobulinemia/genetics
Chemical Substances	Immunoglobulin M ; MYD88 protein, human ; Myeloid Differentiation Factor 88 ; SDC1 protein, human ; Syndecan-1
Language	English
Publishing date	2021-02-25
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2099657-3
ISSN	1552-4957 ; 1552-4949 ; 0196-4763
ISSN (online)	1552-4957
ISSN	1552-4949 ; 0196-4763
DOI	10.1002/cyto.b.21995
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Article ; Online: Production of human or humanized antibodies in mice.

Laffleur, Brice / Pascal, Virginie / Sirac, Christophe / Cogné, Michel

Methods in molecular biology (Clifton, N.J.)

2012 Volume 901, Page(s) 149–159

Abstract: Mice are widely available laboratory animals that can easily be used for the production of antibodies against a broad range of antigens, using well-defined immunization protocols. Such an approach allows optimal in vivo affinity maturation of the humoral ...

Abstract	Mice are widely available laboratory animals that can easily be used for the production of antibodies against a broad range of antigens, using well-defined immunization protocols. Such an approach allows optimal in vivo affinity maturation of the humoral response. In addition, high-affinity antibodies arising in this context can readily be further characterized and produced as monoclonals after immortalizing and selecting specific antibody-producing cells through hybridoma derivation. Using such conventional strategies combined with mice that are either genetically engineered to carry humanized immunoglobulin (Ig) genes or engrafted with a human immune system, it is thus easy to obtain and immortalize clones that produce either fully human Ig or antibodies associating variable (V) domains with selected antigen specificities to customized human-like constant regions, with defined effector functions. In some instances, where there is a need for in vivo functional assays of a single antibody with a known specificity, it might be of interest to transiently express that gene in mice by in vivo gene transfer. This approach allows a rapid functional assay. More commonly, mice are used to obtain a diversified repertoire of antibody specificities after immunization by producing antibody molecules in the mouse B cell lineage from mouse strains with transgene Ig genes which are of human, humanized, or chimeric origin. After in vivo maturation of the immune response, this will lead to the secretion of antibodies with optimized antigen binding sites, associated to the desired human constant domains. This chapter focuses on two simple methods: (1) to obtain such humanized Ig mice and (2) to transiently express a human Ig gene in mice using hydrodynamics-based transfection.
MeSH term(s)	Animals ; Antibodies, Monoclonal, Humanized/genetics ; Antibodies, Monoclonal, Humanized/metabolism ; Genes, Immunoglobulin/genetics ; Humans ; Mice ; Mice, Transgenic
Chemical Substances	Antibodies, Monoclonal, Humanized
Language	English
Publishing date	2012
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-61779-931-0_9
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Article ; Online: Class-specific effector functions of therapeutic antibodies.

Pascal, Virginie / Laffleur, Brice / Cogné, Michel

Methods in molecular biology (Clifton, N.J.)

2012 Volume 901, Page(s) 295–317

Abstract: Physiology usually combines polyclonal antibodies of multiple classes in a single humoral response. Beyond their common ability to bind antigens, these various classes of human immunoglobulins carry specific functions which can each serve specific goals. ...

Abstract	Physiology usually combines polyclonal antibodies of multiple classes in a single humoral response. Beyond their common ability to bind antigens, these various classes of human immunoglobulins carry specific functions which can each serve specific goals. In many cases, the function of a monoclonal therapeutic antibody may thus be modulated according to the class of its constant domains. Depending on the immunoglobulin class, different functional assays will be used in order to evaluate the functional activity of a monoclonal antibody.
MeSH term(s)	Animals ; Antibodies/adverse effects ; Antibodies/immunology ; Antibodies/metabolism ; Antibodies/therapeutic use ; Antibodies, Monoclonal/adverse effects ; Antibodies, Monoclonal/immunology ; Antibodies, Monoclonal/metabolism ; Antibodies, Monoclonal/therapeutic use ; Apoptosis/drug effects ; Cell Line ; Cell Survival/drug effects ; Humans ; Immunoglobulins/adverse effects ; Immunoglobulins/immunology ; Immunoglobulins/metabolism ; Immunoglobulins/therapeutic use ; Mice
Chemical Substances	Antibodies ; Antibodies, Monoclonal ; Immunoglobulins
Language	English
Publishing date	2012
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-61779-931-0_19
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Article ; Online: Immunoglobulin variable domain high-throughput sequencing reveals specific novel mutational patterns in POEMS syndrome.

Bender, Sébastien / Javaugue, Vincent / Saintamand, Alexis / Ayala, Maria Victoria / Alizadeh, Mehdi / Filloux, Matthieu / Pascal, Virginie / Gachard, Nathalie / Lavergne, David / Auroy, Fabienne / Cogné, Michel / Bridoux, Frank / Sirac, Christophe / Jaccard, Arnaud

Blood

2020 Volume 135, Issue 20, Page(s) 1750–1758

Abstract: Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome is a rare multisystem disease resulting from an underlying plasma cell (PC) dyscrasia. The pathophysiology of the disease remains unclear, but the role ...

Abstract	Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome is a rare multisystem disease resulting from an underlying plasma cell (PC) dyscrasia. The pathophysiology of the disease remains unclear, but the role of the monoclonal immunoglobulin (Ig) light chain (LC) is strongly suspected because of the highly restrictive usage of 2 λ variable (V) domains (IGLV1-40 and IGLV1-44) and the general improvement of clinical manifestations after PC clone-targeted treatment. However, the diagnostic value of Ig LC sequencing, especially in the case of incomplete forms of the disease, remains to be determined. Using a sensitive high-throughput Ig repertoire sequencing on RNA (rapid amplification of cDNA ends-based repertoire sequencing [RACE-RepSeq]), we detected a λ LC monoclonal expansion in the bone marrow (BM) of 83% of patients with POEMS syndrome, including some in whom BM tests routinely performed to diagnose plasma cell dyscrasia failed to detect λ+ monoclonal PCs. Twenty-four (83%) of the 29 LC clonal sequences found were derived from the IGLV1-40 and IGLV1-44 germline genes, as well as 2 from the closely related IGLV1-36 gene, and all were associated with an IGLJ3*02 junction (J) gene, confirming the high restriction of VJ region usage in POEMS syndrome. RACE-RepSeq VJ full-length sequencing additionally revealed original mutational patterns, the strong specificity of which might crucially help establish or eliminate the diagnosis of POEMS syndrome in uncertain cases. Thus, RACE-RepSeq appears as a sensitive, rapid, and specific tool to detect low-abundance PC clones in BM and assign them to POEMS syndrome, with all the consequences for therapeutic options.
MeSH term(s)	Biopsy ; Bone Marrow/metabolism ; Bone Marrow/pathology ; DNA Mutational Analysis/methods ; Germ-Line Mutation ; High-Throughput Nucleotide Sequencing ; Humans ; Immunoglobulin Light Chains/analysis ; Immunoglobulin Light Chains/genetics ; Immunoglobulin lambda-Chains/analysis ; Immunoglobulin lambda-Chains/genetics ; Lymph Nodes/metabolism ; Lymph Nodes/pathology ; Molecular Diagnostic Techniques/methods ; POEMS Syndrome/genetics ; POEMS Syndrome/pathology ; Sequence Analysis, Protein
Chemical Substances	Immunoglobulin Light Chains ; Immunoglobulin lambda-Chains
Language	English
Publishing date	2020-03-31
Publishing country	United States
Document type	Evaluation Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood.2019004197
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