Pathogenic Long-Lived Plasma Cells and Their Survival Niches in Autoimmunity, Malignancy, and Allergy

Published on Dec 1, 2012in Journal of Immunology4.72
· DOI :10.4049/jimmunol.1202317
Oliver Winter7
Estimated H-index: 7
Christof Dame23
Estimated H-index: 23
+ 1 AuthorsFalk Hiepe52
Estimated H-index: 52
Long-lived plasma cells survive in a protected microenvironment for years or even a lifetime and provide humoral memory by establishing persistent Ab titers. Long-lived autoreactive, malignant, and allergen-specific plasma cells are likewise protected in their survival niche and are refractory to immunosuppression, B cell depletion, and irradiation. Their elimination remains an essential therapeutic challenge. Recent data indicate that long-lived plasma cells reside in a multicomponent plasma cell niche with a stable mesenchymal and a dynamic hematopoietic component, both providing essential soluble and membrane-bound survival factors. Alternative niches with different hematopoietic cell components compensate fluctuations of single cell types but may also harbor distinct plasma cell subsets. In this Brief Review , we discuss conventional therapies in autoimmunity and multiple myeloma in comparison with novel drugs that target plasma cells and their niches. In the future, such strategies may enable the specific depletion of pathogenic plasma cells while leaving the protective humoral memory intact.
  • References (79)
  • Citations (53)
Published on Sep 15, 2012in Journal of Immunology4.72
Modesta N. Njau2
Estimated H-index: 2
(Emory University),
Jin Hyang Kim12
Estimated H-index: 12
(Emory University)
+ 4 AuthorsJoshy Jacob23
Estimated H-index: 23
(Emory University)
The interaction of CD28, which is constitutively expressed on T cells, with B7.1/B7.2 expressed on APCs is critical for T cell activation. CD28 is also expressed on murine and human plasma cells but its function on these cells remains unclear. There are two types of plasma cells: short-lived ones that appear in the secondary lymphoid tissue shortly after Ag exposure, and long-lived plasma cells that mainly reside in the bone marrow. We demonstrate that CD28-deficient murine short- and long-lived...
Published on Aug 16, 2012in Blood16.56
Daniel J. Dairaghi23
Estimated H-index: 23
Babatunde O. Oyajobi33
Estimated H-index: 33
(University of Texas Health Science Center at San Antonio)
+ 9 AuthorsPenglie Zhang8
Estimated H-index: 8
The chemokine CCL3/MIP-1α is a risk factor in the outcome of multiple myeloma (MM), particularly in the development of osteolytic bone disease. This chemokine, highly overexpressed by MM cells, can signal mainly through 2 receptors, CCR1 and CCR5, only 1 of which (CCR1) is responsive to CCL3 in human and mouse osteoclast precursors. CCR1 activation leads to the formation of osteolytic lesions and facilitates tumor growth. Here we show that formation of mature osteoclasts is blocked by the highly...
Published on Aug 1, 2012in British Journal of Haematology5.21
Jaehyup Kim14
Estimated H-index: 14
(UW: University of Wisconsin-Madison),
Ryan A. Denu7
Estimated H-index: 7
(UW: University of Wisconsin-Madison)
+ 5 AuthorsPeiman Hematti31
Estimated H-index: 31
(UW: University of Wisconsin-Madison)
Multiple myeloma (MM) is characterized by almost exclusive tropism of malignant cells for the bone marrow (BM) milieu. The survival and proliferation of malignant plasma cells have been shown to rely on interactions with nonmalignant stromal cells, in particular mesenchymal stromal cells (MSCs), in the BM microenvironment. However, the BM microenvironment is composed of a diverse array of cell types. This study examined the role of macrophages, an abundant component of BM stroma, as a potential ...
Published on Aug 1, 2012in The Journal of Rheumatology3.63
W. Winn Chatham27
Estimated H-index: 27
(UAB: University of Alabama at Birmingham),
Daniel J. Wallace71
Estimated H-index: 71
(Cedars-Sinai Medical Center)
+ 11 AuthorsTammy O. Utset22
Estimated H-index: 22
(U of C: University of Chicago)
Objective. In patients with systemic lupus erythematosus (SLE), evidence suggests that most vac - cines (except live-virus vaccines) are safe, although antibody response may be reduced. This sub - study from the phase III, randomized, double-blind, placebo-controlled BLISS-76 trial evaluated the effects of belimumab on preexisting antibody levels against pneumococcal, tetanus, and influenza antigens in patients with SLE. Methods. In BLISS-76, patients with autoantibody-positive, active SLE were ...
Published on Jul 1, 2012in Arthritis & Rheumatism9.00
William Stohl42
Estimated H-index: 42
(SC: University of Southern California),
Falk Hiepe52
Estimated H-index: 52
+ 12 AuthorsDouglas R. Hough5
Estimated H-index: 5
(Human Genome Sciences)
Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease associated with considerable morbidity, increased mortality, and poor health-related quality of life (1,2). Immunologic features of SLE include abnormal activation of B- and T-cell lymphocytes, and elevated titers of autoantibodies (3,4). B-lymphocyte stimulator (BLyS) is a 285-amino acid type-II protein member of the tumor necrosis factor ligand superfamily (5,6). In vitro and in vivo studies have demonstrated BLyS to be a...
Published on Apr 1, 2012in Lupus2.92
Martin Aringer44
Estimated H-index: 44
Harald Burkhardt37
Estimated H-index: 37
+ 22 AuthorsHj Lakomek1
Estimated H-index: 1
Systemic lupus erythematosus (SLE) can be a severe and potentially life-threatening disease that often represents a therapeutic challenge because of its heterogeneous organ manifestations. Only glucocorticoids, chloroquine and hydroxychloroquine, azathioprine, cyclophosphamide and very recently belimumab have been approved for SLE therapy in Germany, Austria and Switzerland. Dependence on glucocorticoids and resistance to the approved therapeutic agents, as well as substantial toxicity, are freq...
Published on Apr 1, 2012in Arthritis & Rheumatism9.00
Katrin Moser13
Estimated H-index: 13
(University of Lübeck),
Kathrin Kalies15
Estimated H-index: 15
(University of Lübeck)
+ 3 AuthorsRudolf A. Manz30
Estimated H-index: 30
(University of Lübeck)
Objective Autoantibody immune complexes and cellular infiltrates drive nephritis in patients with systemic lupus erythematosus (SLE) and in murine lupus. The chemokine receptor CXCR3 is assumed to promote cellular infiltration of inflamed tissues. Moreover, CXCR3 deficiency ameliorates lupus nephritis in the MRL/MpJ-Faslpr (MRL/lpr) mouse model of SLE. Hence, CXCR3 blockade has been suggested as a novel therapeutic strategy for the treatment of lupus nephritis. We undertook this study to test th...
Published on Feb 1, 2012in Journal of Immunology4.72
Elodie Belnoue11
Estimated H-index: 11
(WHO: World Health Organization),
Chantal Tougne19
Estimated H-index: 19
+ 3 AuthorsClaire-Anne Siegrist58
Estimated H-index: 58
According to commonly held concepts, plasma cell (PC) longevity in bone marrow (BM) depends upon their access to survival niches. These are thought to exist in nursery cell types, which support PCs by secreting PC survival factors. To better define PC survival niches and their functioning, we adoptively transferred traceable Blimp-1-GFP PCs into recipient mice lacking a proliferation-inducing ligand (APRIL), IL-6, or macrophage migration inhibitory factor. Transferred BMPCs were preferentially a...
Published on Feb 1, 2012in Stem Cells5.61
Song Xu8
Estimated H-index: 8
(Vrije Universiteit Brussel),
Eline Menu29
Estimated H-index: 29
(Vrije Universiteit Brussel)
+ 3 AuthorsIvan Van Riet32
Estimated H-index: 32
(Vrije Universiteit Brussel)
Multiple myeloma (MM) is a malignancy of terminally differentiated plasma cells that are predominantly localized in the bone marrow (BM). Mesenchymal stromal cells (MSCs) give rise to most BM stromal cells that interact with MM cells. However, the direct involvement of MSCs in the pathophysiology of MM has not been well addressed. In this study, in vitro and in vivo migration assays revealed that MSCs have tropism toward MM cells, and CCL25 was identified as a major MM cell-produced chemoattract...
Published on Jan 1, 2012in Nature43.07
Jörg H. Fritz26
Estimated H-index: 26
(U of T: University of Toronto),
Olga Rojas7
Estimated H-index: 7
(U of T: University of Toronto)
+ 15 AuthorsIvaylo I. Ivanov31
Estimated H-index: 31
(CUMC: Columbia University Medical Center)
IgA secreting plasma cells in the lamina propria are shown to be an important source of iNOS and TNF required to maintain the homeostatic balance between intestinal microbes and the immune system.
Cited By53
Published on Jul 2, 2019in Cells
Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction (NMJ). Autoantibodies target key molecules at the NMJ, such as the nicotinic acetylcholine receptor (AChR), muscle-specific kinase (MuSK), and low-density lipoprotein receptor-related protein 4 (Lrp4), that lead by a range of different pathogenic mechanisms to altered tissue architecture and reduced densities or functionality of AChRs, reduced neuromuscular transmission, and therefore a severe fatigable skeletal muscle...
Published on Apr 5, 2019in Frontiers in Immunology4.72
Laleh Khodadadi4
Estimated H-index: 4
Qingyu Cheng6
Estimated H-index: 6
+ 1 AuthorsFalk Hiepe52
Estimated H-index: 52
Published on 2019in Journal of Immunology4.72
Sophie Stephenson (St James's University Hospital), Matthew A. Care13
Estimated H-index: 13
(University of Leeds)
+ 4 AuthorsReuben Tooze (St James's University Hospital)
Recurrent mutational activation of the MAP kinase pathway in plasma cell myeloma implicates growth factor–like signaling responses in the biology of Ab-secreting cells (ASCs). Physiological ASCs survive in niche microenvironments, but how niche signals are propagated and integrated is poorly understood. In this study, we dissect such a response in human ASCs using an in vitro model. Applying time course expression data and parsimonious gene correlation network analysis (PGCNA), a new approach es...
Published on Oct 1, 2018in Thrombosis and Haemostasis4.73
Guosheng Li5
Estimated H-index: 5
(SDU: Shandong University),
Shuang Wang1
Estimated H-index: 1
(SDU: Shandong University)
+ 10 AuthorsChun-HongMa25
Estimated H-index: 25
(SDU: Shandong University)
Primary immune thrombocytopaenia (ITP) is the most common haemorrhagic disease. Although most patients respond initially to mainstream therapies, such as corticosteroids, immunosuppressants or rituximab, a large proportion of patients fail to respond or relapse. These treatments only affect B lymphocytes or short-lived plasma cells, but not already existing long-lived plasma cells (LLPCs) which persistently secrete antibodies. We hypothesized that LLPCs may play a role in the corticosteroid-resi...
Published on Aug 1, 2018in Cell Reports7.82
Wing Y. Lam8
Estimated H-index: 8
(WashU: Washington University in St. Louis),
Arijita Jash8
Estimated H-index: 8
(WashU: Washington University in St. Louis)
+ 6 AuthorsDeepta Bhattacharya24
Estimated H-index: 24
(UA: University of Arizona)
Summary Plasma cell survival and the consequent duration of immunity vary widely with infection or vaccination. Using fluorescent glucose analog uptake, we defined multiple developmentally independent mouse plasma cell populations with varying lifespans. Long-lived plasma cells imported more fluorescent glucose analog, expressed higher surface levels of the amino acid transporter CD98, and had more autophagosome mass than did short-lived cells. Low amino acid concentrations triggered reductions ...
Published on Jul 18, 2018in Frontiers in Immunology4.72
A. Razzaque Ahmed37
Estimated H-index: 37
(Tufts University),
Srini V. Kaveri60
Estimated H-index: 60
(French Institute of Health and Medical Research)
In this concept paper the authors presents a unique and novel protocol to treat autoimmune diseases that may have the potential to reverse autoimmunity. It uses a combination of B cell depletion therapy (BDT), specifically rituximab (RTX) and intravenous immunoglobulin (IVIg), based on a specifically designed protocol (Ahmed Protocol). Twelve infusions of RTX are given in six or fourteen months. Once the CD20+ B cells are depleted from the peripheral blood, IVIg is given monthly until B cells re...
Published on May 15, 2018in Journal of Immunology4.72
Kuan Yau Wong5
Estimated H-index: 5
(UQ: University of Queensland),
Rebecca Baron (UQ: University of Queensland)+ 3 AuthorsDavid J. Munster13
Estimated H-index: 13
(UQ: University of Queensland)
Anti-CD83 Ab capable of Ab-dependent cellular cytotoxicity can deplete activated CD83 + human dendritic cells, thereby inhibiting CD4 T cell–mediated acute graft-versus-host disease. As CD83 is also expressed on the surface of activated B lymphocytes, we hypothesized that anti-CD83 would also inhibit B cell responses to stimulation. We found that anti-CD83 inhibited total IgM and IgG production in vitro by allostimulated human PBMC. Also, Ag-specific Ab responses to immunization of SCID mice xen...
Published on May 1, 2018in European Journal of Immunology4.70
Konrad Haberland1
Estimated H-index: 1
(FAU: University of Erlangen-Nuremberg),
Jochen A. Ackermann7
Estimated H-index: 7
(FAU: University of Erlangen-Nuremberg)
+ 7 AuthorsGerhard Kroenke28
Estimated H-index: 28
(FAU: University of Erlangen-Nuremberg)
Published on Apr 5, 2018in Blood16.56
Julie Tellier11
Estimated H-index: 11