Clonal expansion of B-cells in human systemic lupus erythematosus: Evidence from studies before and after therapeutic B-cell depletion

Sfikakis, Petros P.; Karali, Vassiliki; Λιλάκος, Κωνσταντίνος; Georgiou, George; Panayiotidis, Panayiotis

doi:10.1016/j.clim.2009.02.010

Cited by 24 publications

(10 citation statements)

References 52 publications

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“…Plasma cells from subjects with active SLE manifest extensively mutated V H and V L genes, and the pattern of mutation is comparable to that noted following T cell-dependent antigen stimulation [14-17,44-46,68] (Figure 2). The Ig gene rearrangements of such plasma cells show an increased replacement-to-silent (R/S) mutation ratio within complementarity-determining regions (CDRs) 1 and 2 compared with the framework regions (FRs) as well as exhibiting mutational targeting into RGYW/WRCY mutation hot spots.…”

Section: Models To Explain B-cell Abnormalities Observed In the Contesupporting

confidence: 53%

Mechanisms of B cell autoimmunity in SLE

2011

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Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that is known to be associated with polyclonal B-cell hyperreactivity. The underlying causes of the diffuse B-cell over-reactivity are unclear, but potential candidates include (a) intrinsic hyper-reactivity leading to polyclonal B-cell activation with disturbed activation thresholds and ineffective negative selection; (b) lack of immunoregulatory functions; (c) secondary effects of an overactive inflammatory environment, such as overactive germinal center and ectopic follicular activity; and/or (d) disturbed cytokine production by non-B immune cells. These mechanisms are not mutually exclusive and may operate to varying extents and at varying times in SLE. Phenotypic and molecular studies as well as the results of recent clinical trials have begun to provide new insights to address these possibilities. Of importance, new information has made it possible to distinguish between the contribution played by abnormalities in central checkpoints that could lead to a pre-immune repertoire enriched in autoreactive B cells, on the one hand, and the possibility that autoimmunity arises in the periphery from somatic hypermutation and abnormal selection during T cell-dependent B-cell responses on the other. There is an intriguing possibility that apoptotic material bound to the surface of follicular dendritic cells positively selects autoreactive B cells that arise from non-autoreactive B-cell precursors as a result of somatic hypermutation and thereby promotes the peripheral emergence of autoimmunity.

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Section: Models To Explain B-cell Abnormalities Observed In the Contesupporting

confidence: 53%

Mechanisms of B cell autoimmunity in SLE

2011

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“…While the titre of some anti‐nuclear antibodies reduced after treatment, they did not find evidence of a reduction in clone sizes over this time. In a study of patients with active SLE given rituximab, clonally related B‐cells were found to be persistent in all seven patients, but not found in any of the four age‐matched healthy controls 53. This is consistent with preferential depletion of naïve and CD20 high B‐cells, with the surviving B‐cell population consisting of CD20 low B‐cells, including plasmablasts60 and mucosal IgA + plasmablasts that are not removed by B‐cell depletion therapy.…”

Section: Slementioning

confidence: 59%

Antibody repertoire analysis in polygenic autoimmune diseases

2018

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SummaryHigh‐throughput sequencing of the DNA/RNA encoding antibody heavy‐ and light‐chains is rapidly transforming the field of adaptive immunity. It can address key questions, including: (i) how the B‐cell repertoire differs in health and disease; and (ii) if it does differ, the point(s) in B‐cell development at which this occurs. The advent of technologies, such as whole‐genome sequencing, offers the chance to link abnormalities in the B‐cell antibody repertoire to specific genomic variants and polymorphisms. Here, we discuss the current research using B‐cell antibody repertoire sequencing in three polygenic autoimmune diseases where there is good evidence for a pathological role for B‐cells, namely systemic lupus erythematosus, multiple sclerosis and rheumatoid arthritis. These autoimmune diseases exhibit significantly skewed B‐cell receptor repertoires compared with healthy controls. Interestingly, some common repertoire defects are shared between diseases, such as elevated IGHV4‐34 gene usage. B‐cell clones have effectively been characterized and tracked between different tissues and blood in autoimmune disease. It has been hypothesized that these differences may signify differences in B‐cell tolerance; however, the mechanisms and implications of these defects are not clear.

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“…Monoclonal or oligoclonal B-cell expansion occurs in the thyroid gland in Hashimoto's thyroiditis [146], salivary glands in Sjögren's syndrome [147, 148], synovium in RA [149, 150], cerebrospinal fluid in MS [151], liver in primary biliary cirrhosis [152], muscle in dermatomyositis and polymyositis [153], and blood in SLE [154]. These clonally expanded B cells exhibit the molecular hallmarks of an antigen-driven germinal centre reaction, namely, somatic hypermutation and high replacement-to-silent mutation ratios in the complementarity-determining regions of the Ig variable (V) region genes [148, 150, 151].…”

Section: Steps To Autoimmunitymentioning

confidence: 99%

CD8+ T-Cell Deficiency, Epstein-Barr Virus Infection, Vitamin D Deficiency, and Steps to Autoimmunity: A Unifying Hypothesis

Pender

2012

Autoimmune Diseases

139

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CD8+ T-cell deficiency is a feature of many chronic autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, dermatomyositis, primary biliary cirrhosis, primary sclerosing cholangitis, ulcerative colitis, Crohn's disease, psoriasis, vitiligo, bullous pemphigoid, alopecia areata, idiopathic dilated cardiomyopathy, type 1 diabetes mellitus, Graves' disease, Hashimoto's thyroiditis, myasthenia gravis, IgA nephropathy, membranous nephropathy, and pernicious anaemia. It also occurs in healthy blood relatives of patients with autoimmune diseases, suggesting it is genetically determined. Here it is proposed that this CD8+ T-cell deficiency underlies the development of chronic autoimmune diseases by impairing CD8+ T-cell control of Epstein-Barr virus (EBV) infection, with the result that EBV-infected autoreactive B cells accumulate in the target organ where they produce pathogenic autoantibodies and provide costimulatory survival signals to autoreactive T cells which would otherwise die in the target organ by activation-induced apoptosis. Autoimmunity is postulated to evolve in the following steps: (1) CD8+ T-cell deficiency, (2) primary EBV infection, (3) decreased CD8+ T-cell control of EBV, (4) increased EBV load and increased anti-EBV antibodies, (5) EBV infection in the target organ, (6) clonal expansion of EBV-infected autoreactive B cells in the target organ, (7) infiltration of autoreactive T cells into the target organ, and (8) development of ectopic lymphoid follicles in the target organ. It is also proposed that deprivation of sunlight and vitamin D at higher latitudes facilitates the development of autoimmune diseases by aggravating the CD8+ T-cell deficiency and thereby further impairing control of EBV. The hypothesis makes predictions which can be tested, including the prevention and successful treatment of chronic autoimmune diseases by controlling EBV infection.

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Clonal expansion of B-cells in human systemic lupus erythematosus: Evidence from studies before and after therapeutic B-cell depletion

Cited by 24 publications

References 52 publications

Mechanisms of B cell autoimmunity in SLE

Mechanisms of B cell autoimmunity in SLE

Antibody repertoire analysis in polygenic autoimmune diseases

CD8+ T-Cell Deficiency, Epstein-Barr Virus Infection, Vitamin D Deficiency, and Steps to Autoimmunity: A Unifying Hypothesis

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