Genetic Factors in Systemic Lupus Erythematosus: Contribution to Disease Phenotype

Ceccarelli, Fulvia; Perricone, Carlo; Borgiani, Paola; Ciccacci, Cinzia; Rufini, Sara; Cipriano, Enrica; Alessandri, Cristiano; Spinelli, Francesca Romana; Scavalli, A. Sili; Novelli, Giuseppe; Valesini, Guido; Conti, Fabrizio

doi:10.1155/2015/745647

Cited by 94 publications

(68 citation statements)

References 90 publications

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“…IFN-a, a product of activated plasmacytoid cells, is thought to exert its SLE effects in part by its ability to potentiate B cell differentiation and Ab secretion in vitro and in vivo to worsen B cell-mediated pathology in SLE mouse models (127). Further support of the role of B cells in SLE come from genetic studies where susceptibility loci in SLE have been described that are involved with B cell-related functions including MHC haplotype Ag presentation and transcription factors involved in B cell Ab production (128)(129)(130). Of particular importance is the genetic association of Aiolos (64) and Ikaros (65), which are essential factors in B cell differentiation and Ab secretion, and in the case of Aiolos, found to be overexpressed in the B cells of SLE patients (Fig.…”

Section: Discussionmentioning

confidence: 99%

Aiolos Overexpression in Systemic Lupus Erythematosus B Cell Subtypes and BAFF-Induced Memory B Cell Differentiation Are Reduced by CC-220 Modulation of Cereblon Activity

Nakayama¹,

Kosek²,

Capone³

et al. 2017

The Journal of Immunology

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BAFF is a B cell survival and maturation factor implicated in the pathogenesis of systemic lupus erythematosus (SLE). In this in vitro study, we describe that soluble BAFF in combination with IL-2 and IL-21 is a T cell contact-independent inducer of human B cell proliferation, plasmablast differentiation, and IgG secretion from circulating CD27+ memory and memory-like CD27−IgD− double-negative (DN) B cells, but not CD27−IgD+ naive B cells. In contrast, soluble CD40L in combination with IL-2 and IL-21 induces these activities in both memory and naive B cells. Blood from healthy donors and SLE patients have similar circulating levels of IL-2, whereas SLE patients exhibit elevated BAFF and DN B cells and reduced IL-21. B cell differentiation transcription factors in memory, DN, and naive B cells in SLE show elevated levels of Aiolos, whereas Ikaros levels are unchanged. Treatment with CC-220, a modulator of the cullin ring ligase 4-cereblon E3 ubiquitin ligase complex, reduces Aiolos and Ikaros protein levels and BAFF- and CD40L-induced proliferation, plasmablast differentiation, and IgG secretion. The observation that the soluble factors BAFF, IL-2, and IL-21 induce memory and DN B cell activation and differentiation has implications for extrafollicular plasmablast development within inflamed tissue. Inhibition of B cell plasmablast differentiation by reduction of Aiolos and Ikaros may have utility in the treatment of SLE, where elevated levels of BAFF and Aiolos may prime CD27+ memory and DN memory-like B cells to become Ab-producing plasmablasts in the presence of BAFF and proinflammatory cytokines.

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Section: Discussionmentioning

confidence: 99%

Aiolos Overexpression in Systemic Lupus Erythematosus B Cell Subtypes and BAFF-Induced Memory B Cell Differentiation Are Reduced by CC-220 Modulation of Cereblon Activity

Nakayama¹,

Kosek²,

Capone³

et al. 2017

The Journal of Immunology

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“…Ze względu na zwiększoną częstość występowania u rasy czarnej podejrzewa się również udział czynników genetycznych [1,2,3].…”

Section: Wstępunclassified

Wpływ wybranych cytokin na uszkodzenie narządów w toczniu rumieniowatym układowym

Kapłon

Brzosko

2018

Pomeranian J Life Sci

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Systemic lupus erythematosus (SLE) is a rheumatic disease with unclear pathogenesis. In the course of this disease a dysfunction of the immune system occurs, which involves the production of autoantibodies and the deposition of immune complexes, which contributes to the damage of various organs. The most commonly involved organs include: kidneys, skin, joints, the eye, respiratory system, and the cardiovascular and nervous systems, both central and peripheral. In recent years there have been reports regarding the role of cytokines in the pathogenesis of various organs' involvement. However, until now it has not been entirely clear which cytokines are responsible for either the stimulation or inhibition of the inflammatory response, which could be helpful in establishing a relationship with the clinical picture. In this article reports are summarized regarding Interleukins 4, 7, 10, 18 (IL-4, IL-7, IL-10, IL-18) and their relationship with organ involvement in SLE. Interleukin 4 is indicated as a protective cytokine by its role in preventing the development of an autoimmune response. In the case of IL-7, it has a role in increasing the proliferation of autoreactive T-cell clones and the development of the disease. The IL-10, despite its protective effect, is found in patients with SLE at significantly higher concentrations than in the general population and correlates with the SLEDAI disease activity level scale. Interleukin 18 has a pro-inflammatory effect, contributing to damage to tissues and organs. In the serum of patients with SLE significantly higher levels of IL-18 were found than in the control group; there was also a statistically significant positive correlation between serum IL-18 levels and SLEDAI disease activity level scale and anti-dsDNA antibody titers. Increasing levels of serum IL-18 in SLE patients is associated with an increased risk of cardiovascular disease. In addition, IL-18 has an important role in the involvement of the kidneys and skin in SLE patients. Keywords: systemic lupus erythematosus; organ involvement; cytokines. ABSTRAKTToczeń rumieniowaty układowy (TRU) jest chorobą reumatyczną o nie w pełni poznanej patogenezie. W przebiegu tej choroby występuje dysfunkcja układu immunologicznego polegająca na wytwarzaniu autoprzeciwciał i odkładaniu się kompleksów immunologicznych, które przyczyniają się do uszkodzeń różnych narządów. Najczęściej zajęte narządy to: nerki, skóra, układ ruchu, narząd wzroku, układ oddechowy, układ sercowo--naczyniowy oraz nerwowy, zarówno ośrodkowy, jak i obwodowy. W ostatnich latach pojawiły się doniesienia dotyczące roli cytokin w patogenezie zajęcia różnych narządów. Jednakże do tej pory nie jest w pełni jasne, które cytokiny są odpowiedzialne za nasilenie, a które za zmniejszenie odpowiedzi zapalnej, co mogłoby pomóc w ustaleniu związku z obrazem klinicznym. W artykule zestawione zostały doniesienia dotyczące Interleukin (IL) 4, 7, 10, 18 oraz ich związku z zajęciem narządowym w przebiegu TRU. W przypadku IL-4 wskazuje się na ochronną rolę tej cyt...

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“…Multiple genes, that are causing SLE, are linked to the function of the immune system and difference in this most likely effect proper controls and targeting of the immune system. Genetic factors along with environmental factors play an important role in the determination of SLE susceptibility [22]. It is suggested that genetic factors play an important role not only in disease susceptibility but also in the development of SLE phenotype [22].…”

Section: Genetic Factorsmentioning

confidence: 99%

“…Genetic factors along with environmental factors play an important role in the determination of SLE susceptibility [22]. It is suggested that genetic factors play an important role not only in disease susceptibility but also in the development of SLE phenotype [22]. The genes that can increase SLE susceptibility are the genes included in the interferon pathway, also containing IRF5, IF1H1, and STAT4 [23].…”

Section: Genetic Factorsmentioning

confidence: 99%

Introductory Chapter: Systemic Lupus Erythematosus - Different Predisposing Factors

Khan¹

2017

Lupus

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Genetic Factors in Systemic Lupus Erythematosus: Contribution to Disease Phenotype

Cited by 94 publications

References 90 publications

Aiolos Overexpression in Systemic Lupus Erythematosus B Cell Subtypes and BAFF-Induced Memory B Cell Differentiation Are Reduced by CC-220 Modulation of Cereblon Activity

Aiolos Overexpression in Systemic Lupus Erythematosus B Cell Subtypes and BAFF-Induced Memory B Cell Differentiation Are Reduced by CC-220 Modulation of Cereblon Activity

Wpływ wybranych cytokin na uszkodzenie narządów w toczniu rumieniowatym układowym

Introductory Chapter: Systemic Lupus Erythematosus - Different Predisposing Factors

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