Hormonal regulation of B-cell function and systemic lupus erythematosus

Jf, Cohen-Solal; Jeganathan,; Hill, Latia; Kawabata, Daisuke; Rodríguez-Pinto, Daniel; Grimaldi, Christine; Diamond, Betty

doi:10.1177/0961203308089402

Cited by 73 publications

(47 citation statements)

References 69 publications

(92 reference statements)

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“…Gender bias has been previously described for multiple animal models of lupus in which females are more sus- ceptible to disease (22). Sex hormones have been implicated in driving the maturation of high-affinity autoreactive B cells (25). Therefore, additional effects conferred by the female genetic background might be required to develop higher levels of systemic autoantibodies than those found in male TIM-4 −/− mice.…”

Section: Discussionmentioning

confidence: 99%

T and B cell hyperactivity and autoimmunity associated with niche-specific defects in apoptotic body clearance in TIM-4-deficient mice

Rodriguez-Manzanet

Sanjuán

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

167

177

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TIM-4, a member of the TIM family expressed on antigen-presenting cells, binds to phosphatidylserine exposed on the surface of apoptotic bodies. However, the significance of this interaction in vivo remains unknown because other receptors have been implicated in the clearance of apoptotic bodies and could compensate for the TIM-4 deficiency in vivo. In this study, we describe the generation of TIM-4-deficient mice and address whether TIM-4 serves a unique function in vivo. We show that TIM-4 −/− peritoneal macrophages and B-1 cells do not efficiently engulf apoptotic bodies in vitro, or clear apoptotic bodies in vivo. TIM-4-deficient mice have hyperactive T and B cells, elevated levels of serum Ig, and develop antibodies to double-stranded DNA. Taken together, we show that TIM-4 is critical for the clearance of apoptotic bodies in vivo, and that lack of TIM-4 results in aberrant persistence of apoptotic bodies leading to dysregulated lymphocyte activation and signs of systemic autoimmunity.phosphatidylserine receptor | phagocytosis | autoantibody | apoptosis T he T cell, Ig, mucin domain (TIM) family includes four expressed Tim genes (Tim-1 through Tim-4) and four predicted genes (Tim-5 through Tim-8) on mouse chromosome 11B1.1, whereas a syntenic region on human chromosome 5q33.2 contains three TIM genes (TIM-1, TIM-3, and TIM-4) (1-3). The syntenic genetic intervals containing the TIM loci in both mice and man have been linked to susceptibility to autoimmune and allergic disorders (2-4).TIM-4, the only TIM protein not expressed on T cells, is found on antigen-presenting cells (APC), including dendritic cells and macrophages (5, 6). First described as a ligand for TIM-1 (7), which is expressed on activated T cells, we showed that TIM-4 costimulates T cell activation by promoting cell survival (5). We now know that TIM-4 exerts a bimodal effect on T cell immunity by inhibiting naïve T cells during the initiation phase of an immune response, and later enhancing T cell responses during the elicitation phase of T cell immunity (6). It is unclear, though, whether activating or inhibitory functions of TIM-4 predominate in vivo. With the generation of TIM-4-deficient mice, we are able to directly address the in vivo role of TIM-4.Two independent groups found that TIM-4 binds to phosphatidylserine (PtdSer) and that blocking TIM-4 with anti-TIM-4 mAb inhibits the engulfment of apoptotic bodies (AB) by TIM-4-expressing macrophages (8,9). Although these studies clearly showed that TIM-4 binds to AB through PtdSer, the physiologic role of TIM-4 in vivo has not been addressed owing to lack of TIM-4-deficient mice. It remains unknown whether TIM-4 is necessary for clearing AB in vivo or whether other receptors that bind AB, such as BAI1 (10) and stabilin-2 (11), compensate for TIM-4 deficiency.Clearance of AB is a critical mechanism for maintaining normal tissue homeostasis in multicellular organisms. AB that are not rapidly cleared progress to secondary necrosis, during which autoand neoantigens are exposed in an inflammato...

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Section: Discussionmentioning

confidence: 99%

T and B cell hyperactivity and autoimmunity associated with niche-specific defects in apoptotic body clearance in TIM-4-deficient mice

Rodriguez-Manzanet

Sanjuán

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

167

177

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“…PRL gene is located close to the risk SLE region. Prolactin may act as a cytokine and recent data show that PRL can break an autoreactive B-cells apoptosis and cause SLE in susceptible animals [25,26]. In humans, elevated serum PRL levels have been associated with active SLE [27] and immune cells from SLE patients produce more PRL than those from healthy individuals.…”

Section: Introductionmentioning

confidence: 99%

HLA class II, MICA and PRL gene polymorphisms: the common contribution to the systemic lupus erythematosus development in Czech population

et al. 2010

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ObjectiveThe genetic components contribute to the Systemic lupus erythematosus development. This study for the first time determined the distribution of the polymorphisms and linkage disequilibrium in HLA class II, MICA and PRL gene among patients suffering from SLE and healthy Czech individuals. Patients and Methods DNA ConclusionHLA class II-MICA combinations may increase/decrease a risk for SLE development.Multiple studies focusing on the ethnical differences as well as genetic-epigenetic relationships are necessary for better understanding SLE pathogenesis.

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“…Физиологические состояния с повышенной продукцией эстрогенов (например, беременность) ассоции-О Б З О Р Ы НАУЧНО-ПРАКТИЧЕСКАЯ РЕВМАТОЛОГИЯ, 2010, № 1 руются с редукцией В-клеточного лимфопоэза, в то время как овариэктомия, сопровождающаяся снижением уровня эстро-генов, приводит к его увеличению. Ингибирующий эффект эстрогенов на В-клеточный лимфопоэз является следствием как их прямого воздействия на В-клетки, так и опосредован-ного эффекта на стромальные клетки, участвующие в В-кле-точном лимфопоэзе, через продукцию ИЛ-17 [68,69].…”

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“…Cohen-Solal и соавт. на мышах линии R4A BALB/c [69]. Непрерывная стимуляция эстрогенами этих мышей показала, что высокоаффинные ДНК-реактивные В-клетки созревали до иммунокомпетентных клеток, а низкоаффинные ДНК-реактивные В-клетки определялись в уменьшенных количествах по сравнению с контролем.…”

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“…Поскольку низкоаффинные ДНК-реактивные В-клетки могут играть протективную роль и предотвращать развитие патогенных ДНК-реактивных В-клеток, снижение их кон-центрации, возможно, предрасполагает к развитию СКВ. Более того, введение эстрогенов приводит к повышению уровня В-клеточного активирующего фактора (BAFF) в крови, который изменяет популяцию В-клеток в сторону аутоиммунной реактивности [69].…”

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