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Life (Basel, Switzerland) Dec 2023Light-chain amyloidosis (AL) is a disease of protean manifestations due to a wide spectrum of organs that can be affected. The disorder is caused by the deposition of an... (Review)
Review
Light-chain amyloidosis (AL) is a disease of protean manifestations due to a wide spectrum of organs that can be affected. The disorder is caused by the deposition of an extracellular amorphous material, the amyloid, which is produced by malignant plasma cells. The latter usually reside in the bone marrow; plasma cell infiltration is often low, in sharp contrast to what we observe in multiple myeloma. The disease may run below the physician's radar for a while before clinical suspicion is raised and targeted tests are performed. In this short review, we try to answer most of the questions that a practicing physician may ask in a relative clinical setting. The text is formed as a series of reader-friendly questions that cover the subject of AL amyloidosis from history to current therapy.
PubMed: 38255657
DOI: 10.3390/life14010042 -
Annual Review of Immunology Jun 2024Autoimmune diseases with B cell-directed therapeutics approved by the US Food and Drug Administration are surprisingly diverse in clinical manifestations and... (Review)
Review
Autoimmune diseases with B cell-directed therapeutics approved by the US Food and Drug Administration are surprisingly diverse in clinical manifestations and pathophysiology. In this review, we focus on recent clinical and mechanistic insights into the efficacy of B cell depletion in these diverse autoimmune disorders, the rapidly expanding armamentarium of approved agents, and future approaches. The pathogenic roles for B cells include direct functions such as production of autoantibodies and proinflammatory cytokines and indirect functions via antigen presentation to T cells. The efficacy of B cell-depleting strategies varies across diseases and likely reflects the complexity of disease pathogenesis and relative contribution of B cell roles. Additionally, B cell-depleting therapies do not equally target all B cell subsets in all patients, and this likely explains some of the variability in responses. Recent reports of B cell depletion with novel chimeric antigen receptor (CAR) T cell approaches in an expanding number of autoimmune diseases highlight the potential role of B cell depletion in resetting immune tolerance. The relative importance of eliminating autoreactive B cells and plasma cells and approaches to doing so will also be discussed.
Topics: Humans; Autoimmune Diseases; B-Lymphocytes; Autoimmunity; Animals; Lymphocyte Depletion; Immunotherapy, Adoptive; Immune Tolerance; Autoantibodies; Receptors, Chimeric Antigen
PubMed: 38011889
DOI: 10.1146/annurev-immunol-083122-044829 -
Science Translational Medicine Dec 2023Immunoglobulin E (IgE) is a key driver of type 1 hypersensitivity reactions and allergic disorders, which are globally increasing in number and severity. Although...
Immunoglobulin E (IgE) is a key driver of type 1 hypersensitivity reactions and allergic disorders, which are globally increasing in number and severity. Although eliminating pathogenic IgE may be a powerful way to treat allergy, no therapeutic strategy reported to date can fully ablate IgE production. Interleukin-4 receptor α (IL-4Rα) signaling is required for IgE class switching, and IL-4Rα blockade gradually reduces, but does not eliminate, IgE. The persistence of IgE after IL-4Rα blockade may be due to long-lived IgE plasma cells that maintain serological memory to allergens and thus may be susceptible to plasma cell-targeted therapeutics. We demonstrate that transient administration of a B cell maturation antigen x CD3 (BCMAxCD3) bispecific antibody markedly depletes IgE, as well as other immunoglobulins, by ablating long-lived plasma cells, although IgE and other immunoglobulins rapidly rebound after treatment. Concomitant IL-4Rα blockade specifically and durably prevents the reemergence of IgE by blocking IgE class switching while allowing the restoration of other immunoglobulins. Moreover, this combination treatment prevented anaphylaxis in mice. Together with additional cynomolgus monkey and human data, our studies demonstrate that allergic memory is primarily maintained by both non-IgE memory B cells that require class switching and long-lived IgE plasma cells. Our combination approach to durably eliminate pathogenic IgE has potential to benefit allergy in humans while preserving antibody-mediated immunity.
Topics: Mice; Humans; Animals; Immunoglobulin E; Macaca fascicularis; Anaphylaxis; Plasma Cells; Allergens
PubMed: 38091405
DOI: 10.1126/scitranslmed.adf9561 -
Nature Apr 2024There is increasing interest in how immune cells in the meninges-the membranes that surround the brain and spinal cord-contribute to homeostasis and disease in the...
There is increasing interest in how immune cells in the meninges-the membranes that surround the brain and spinal cord-contribute to homeostasis and disease in the central nervous system. The outer layer of the meninges, the dura mater, has recently been described to contain both innate and adaptive immune cells, and functions as a site for B cell development. Here we identify organized lymphoid structures that protect fenestrated vasculature in the dura mater. The most elaborate of these dural-associated lymphoid tissues (DALT) surrounded the rostral-rhinal confluence of the sinuses and included lymphatic vessels. We termed this structure, which interfaces with the skull bone marrow and a comparable venous plexus at the skull base, the rostral-rhinal venolymphatic hub. Immune aggregates were present in DALT during homeostasis and expanded with age or after challenge with systemic or nasal antigens. DALT contain germinal centre B cells and support the generation of somatically mutated, antibody-producing cells in response to a nasal pathogen challenge. Inhibition of lymphocyte entry into the rostral-rhinal hub at the time of nasal viral challenge abrogated the generation of germinal centre B cells and class-switched plasma cells, as did perturbation of B-T cell interactions. These data demonstrate a lymphoid structure around vasculature in the dura mater that can sample antigens and rapidly support humoral immune responses after local pathogen challenge.
Topics: Administration, Intranasal; Antigens; Bone Marrow; Central Nervous System; Dura Mater; Germinal Center; Immunity, Humoral; Lymphatic Vessels; Lymphoid Tissue; Plasma Cells; Skull; T-Lymphocytes; Veins; Humans; Male; Female; Adult; Middle Aged; Animals; Mice; Aged, 80 and over
PubMed: 38509366
DOI: 10.1038/s41586-024-07202-9 -
Medicina (Kaunas, Lithuania) Dec 2023In 1968, Jean Berger first introduced the medical world to IgA nephropathy (IgAN). Fifty-five years later, its pathogenesis is still unclear, but treatments such as... (Review)
Review
In 1968, Jean Berger first introduced the medical world to IgA nephropathy (IgAN). Fifty-five years later, its pathogenesis is still unclear, but treatments such as renin-angiotensin-aldosterone system inhibitors (RAAS-Is), tonsillectomies, and glucocorticoids are currently used worldwide. There have been great strides in the past 20 years since the discoveries of the specific dysregulation of mucosal immunity, galactose-deficient IgA1 (Gd-IgA1), and Gd-IgA1 immune complexes in patients with IgAN. According to these findings, a multi-hit hypothesis was developed, and this multi-hit hypothesis has provided several putative therapeutic targets. A number of novel agents, including molecularly targeted drugs for targets such as APRIL, plasma cells, complement systems, and endothelin, are undergoing clinical trials. Some candidate drugs have been found to be effective, with minimal side effects. Over half a century after the discovery of IgAN, these therapies will soon be available for clinical use.
Topics: Humans; Glomerulonephritis, IGA; Drug Delivery Systems; Glucocorticoids; Plasma Cells
PubMed: 38256315
DOI: 10.3390/medicina60010054 -
Acta Dermatovenerologica Croatica : ADC Dec 2023Plasma cell mucositis (PCM) is an unusual disorder most evident in the accessible mucosa and usually reported in the upper aerodigestive tract, although it is named... (Review)
Review
Plasma cell mucositis (PCM) is an unusual disorder most evident in the accessible mucosa and usually reported in the upper aerodigestive tract, although it is named according to its specific anatomical site of involvement, such as plasma cell cheilitis, plasma cell gingivitis, plasma cell vulvitis, and Zoon's balanitis. PCM reflects a dense polyclonal, rather than a monoclonal, plasma cell proliferation of unclear and unknown etiology. This perplexing disorder tends to be treated by avoiding possible triggers and intralesional and/or systemic steroids. Herein we review and provide an update on PCM, which often represents a clinical conundrum.
Topics: Humans; Mucositis; Plasma Cells
PubMed: 38651846
DOI: No ID Found -
Clinical Immunology (Orlando, Fla.) Nov 2023Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the dysregulation of B cell subpopulation and function. Recent studies have suggested...
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the dysregulation of B cell subpopulation and function. Recent studies have suggested a potential role of ferroptosis, an iron-dependent form of regulated cell death, in the pathogenesis of SLE. Here, we demonstrate that B-cell ferroptosis occurs both in lupus patients and MRL/lpr mice. Treatment with liproxstatin-1, a potent ferroptosis inhibitor, could reduce autoantibody production, improve renal damage, and alleviate lupus symptoms in vivo. Furthermore, our results suggest that ferroptosis may regulate B cell differentiation and plasma cell formation, indicating a potential mechanism for its involvement in SLE. Taken together, targeting ferroptosis in B cells may be a promising therapeutic strategy for SLE.
Topics: Humans; Mice; Animals; Ferroptosis; Mice, Inbred MRL lpr; Lupus Erythematosus, Systemic; B-Lymphocytes; Kidney
PubMed: 37730009
DOI: 10.1016/j.clim.2023.109778 -
European Journal of Ophthalmology Sep 2023Plasma cell dyscrasias are a wide range of severe monoclonal gammopathies caused by pre-malignant or malignant plasma cells that over-secrete an abnormal monoclonal... (Review)
Review
Plasma cell dyscrasias are a wide range of severe monoclonal gammopathies caused by pre-malignant or malignant plasma cells that over-secrete an abnormal monoclonal antibody. These disorders are associated with various systemic findings, including ophthalmological disorders. A search of PubMed, EMBASE, Scopus and Cochrane databases was performed in March 2021 to examine evidence pertaining to ocular complications in patients diagnosed with plasma cell dyscrasias. This review outlines the ocular complications associated with smoldering multiple myeloma and monoclonal gammopathy of undetermined significance, plasmacytomas, multiple myeloma, Waldenström's macroglobulinemia, systemic amyloidosis, Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy and Skin changes (POEMS) syndrome, and cryoglobulinemia. Although, the pathological mechanisms are not completely elucidated yet, wide-ranging ocular presentations have been identified over the years, evolving both the anterior and posterior segments of the eye. Moreover, the presenting symptoms also help in early diagnosis in asymptomatic patients. Therefore, it is imperative for the treating ophthalmologist and oncologist to maintain a high clinical suspicion for identifying the ophthalmological signs and diagnosing the underlying disease, preventing its progression through efficacious treatment strategies.
Topics: Humans; Paraproteinemias; Eye; Eye Diseases; Treatment Outcome
PubMed: 36760117
DOI: 10.1177/11206721231155974 -
International Journal of Molecular... Jul 2023Extramedullary multiple myeloma (or extramedullary disease, EMD) is an aggressive form of multiple myeloma (MM) that occurs when malignant plasma cells become... (Review)
Review
Extramedullary multiple myeloma (or extramedullary disease, EMD) is an aggressive form of multiple myeloma (MM) that occurs when malignant plasma cells become independent of the bone marrow microenvironment. This may occur alongside MM diagnosis or in later stages of relapse and confers an extremely poor prognosis. In the era of novel agents and anti-myeloma therapies, the incidence of EMD is increasing, making this a more prevalent and challenging cohort of patients. Therefore, understanding the underlying mechanisms of bone marrow escape and EMD driver events is increasingly urgent. The role of genomics in MM has been studied extensively; however, much less is known about the genetic background of EMD. Recently there has been an increased focus on driver events for the establishment of distant EMD sites. Generally, high-risk cytogenetic abnormalities and gene signatures are associated with EMD, alongside mutations in RAS signalling pathways. More recently, changes in epigenetic regulation have also been documented, specifically the hypermethylation of DNA promoter regions. Therefore, the focus of this review is to summarize and discuss what is currently known about the genetic background of EMD in MM.
Topics: Humans; Multiple Myeloma; Epigenesis, Genetic; Neoplasm Recurrence, Local; Plasma Cells; Bone Marrow; Tumor Microenvironment
PubMed: 37511018
DOI: 10.3390/ijms241411259