The role of IgM antibodies in the recognition and clearance of apoptotic cells

Peng, You; Kowalewski, Robert; Kim, SunJung; Elkon, Keith B.

doi:10.1016/j.molimm.2004.07.045

Cited by 94 publications

(76 citation statements)

References 48 publications

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“…Phagocytosis of apoptotic cells induces production of TGF-b1, but not proinflammatory cytokines [15]. However, phagocytosis of apoptotic cells is enhanced by serum opsonins, including Ab [16], and Ab to apoptotic cells can lead to secretion of proinflammatory cytokines [15,17].…”

Section: Introductionmentioning

confidence: 99%

Apoptotic lymphocytes treated with IgG from Trypanosoma cruzi infection increase TNF‐α secretion and reduce parasite replication in macrophages

et al. 2010

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Phagocytic removal of apoptotic lymphocytes exacerbates replication of Trypanosoma cruzi in macrophages. We investigated the presence of Ab against apoptotic lymphocytes in T. cruzi infection and the role of these Ab in parasite replication. Both control and chagasic serum contained IgG Ab that opsonized apoptotic lymphocytes. Treatment of apoptotic lymphocytes with purified IgG from chagasic, but not control serum, reduced T. cruzi replication in macrophages. The protective effect of chagasic IgG depended on Fcc receptors, as demonstrated by the requirement for the intact Fc portion of IgG, and the effect could be abrogated by treating macrophages with an anti-CD16/CD32 Fab fragment. Chagasic IgG displayed increased reactivity against a subset of apoptotic cell Ag, as measured by flow cytometry and immunoblot analyses. Apoptotic lymphocytes treated with chagasic IgG, but not control IgG, increased production of TNF-a, while decreasing production of TGF-b1 by infected macrophages. Increased control of parasite replication required TNF-a production. Previous immunization with apoptotic cells or injection of apoptotic cells opsonized with chagasic IgG reduced parasitemia in infected mice. These results indicate that Ab raised against apoptotic cells could play a protective role in control of T. cruzi replication by macrophages.Key words: Ab . Apoptosis . Fc receptors . Phagocytosis . Trypanosoma cruzi IntroductionInfection with Trypanosoma cruzi, the causative agent of Chagas' disease, induces Ab against both parasite Ag [1-4] and self molecules [5][6][7]. Ab play a protective role in T. cruzi infection [1][2][3][4][5]7], but the mechanisms involved are not completely understood.Infection with T. cruzi induces lymphocyte apoptosis [8][9][10][11][12], and the phagocytic clearance of apoptotic lymphocytes drives replication of T. cruzi in macrophages [13]. Parasite replication results from a biochemical cascade that originates from binding of apoptotic cells Ã These authors contributed equally to this work. Eur. J. Immunol. 2010. 40: 417-425 DOI 10.1002 Immunity to infection 417 to a V b 3 integrin, followed by production of PGE 2 and TGF-b1, induction of ornithine decarboxylase and increased production of the polyamine putrescine [13]. T. cruzi is unable to synthesize putrescine and depends on uptake of exogenous putrescine for intracellular growth [14]. Phagocytosis of apoptotic cells induces production of TGF-b1, but not proinflammatory cytokines [15]. However, phagocytosis of apoptotic cells is enhanced by serum opsonins, including Ab [16], and Ab to apoptotic cells can lead to secretion of proinflammatory cytokines [15,17].Immunization with apoptotic cells induces production of autoantibodies [18]. However, it is unclear whether such autoantibodies play an immunoregulatory role. In the present study, we sought to determine whether infection with T. cruzi elicited production of Ab against apoptotic lymphocytes. We found that apoptotic lymphocytes treated with chagasic IgG induced a proinflammatory cytokine resp...

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Section: Introductionmentioning

confidence: 99%

Apoptotic lymphocytes treated with IgG from Trypanosoma cruzi infection increase TNF‐α secretion and reduce parasite replication in macrophages

et al. 2010

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“…9,10 IgM biological roles also include opsonization of apoptotic cells, resulting in accelerated clearance by phagocytic cells. 11 Many of the circulating IgM correspond to natural antibodies that exist prior to infection or immunization. [12][13][14] Natural IgM are polyreactive to evolutionary conserved structures 15 and bind efficiently to previously un-encountered antigen.…”

Section: Introductionmentioning

confidence: 99%

“…16 These antibodies compensate their low-antigen affinity with relatively high avidity and furthermore the effectiveness of the antigen-antibody interaction is enhanced by the high efficiency of IgM in engaging the complement pathway. 11,17 The preimmune Ig repertoire is thought to be composed by mature B cells either recirculating through follicles of secondary lymphoid organs (B2 cells), or joining compartments in specific locations as the marginal zone in the spleen (MZ B-cells) and the pleural or peritoneal cavities (B1 cells). 12 B2 and marginal zone B-cell development is initiated in the bone marrow and completed in the periphery 18,19 throughout life.…”

Section: Introductionmentioning

confidence: 99%

Irf4 is a positional and functional candidate gene for the control of serum IgM levels in the mouse

et al. 2008

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Natural IgM are involved in numerous immunological functions but the genetic factors that control the homeostasis of its secretion and upholding remain unknown. Prompted by the finding that C57BL/6 mice had significantly lower serum levels of IgM when compared with BALB/c mice, we performed a genome-wide screen and found that the level of serum IgM was controlled by a QTL on chromosome 13 reaching the highest level of association at marker D13Mit266 (LOD score¼3.54). This locus was named IgMSC1 and covered a region encompassing the interferon-regulatory factor 4 gene (Irf4). The number of splenic mature B cells in C57BL/6 did not differ from BALB/c mice but we found that low serum levels of IgM in C57BL/6 mice correlated with lower frequency of IgM-secreting cells in the spleen and in the peritoneal cavity. These results suggested that C57BL/6 mice have lower efficiency in late B-cell maturation, a process that is highly impaired in Irf4 knockout mice. In fact, we also found reduced Irf4 gene expression in B cells of C57BL/6 mice. Thus, we propose Irf4 as a candidate for the IgMSC1 locus, which controls IgM homeostatic levels at the level of B-cell terminal differentiation

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“…Furthermore, plasma levels of anti‐CD3 and anti‐CD4 ‐specific IgM antibodies were also elevated by 78% and 100%, respectively, in RMT1‐10 treated mice ( P <0.05; Figure 3A). As lesion IgM facilitates removal of apoptotic cells32 and prevents accumulation of oxLDL in lesions,1 we examined whether RMT1‐10 treatment affected lesion IgM and oxLDL. RMT1‐10 treatment increased lesion IgM levels by ≈170% ( P <0.05; Figure 3B).…”

Section: Resultsmentioning

confidence: 99%

Anti‐TIM‐1 Monoclonal Antibody (RMT1‐10) Attenuates Atherosclerosis By Expanding IgM‐producing B1a Cells

Hosseini

Kanellakis

et al. 2018

JAHA

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BackgroundPeritoneal B1a cells attenuate atherosclerosis by secreting natural polyclonal immunoglobulin M (IgM). Regulatory B cells expressing T‐cell immunoglobulin mucin domain‐1 (TIM‐1) expanded through TIM‐1 ligation by anti‐TIM‐1 monoclonal antibody (RMT1‐10) induces immune tolerance.Methods and ResultsWe examined the capacity of RMT1‐10 to expand peritoneal B1a cells to prevent atherosclerosis development and retard progression of established atherosclerosis. RMT1‐10 treatment selectively doubled peritoneal B1a cells, tripled TIM‐1+ B1a cells and increased TIM‐1+IgM+interleukin (IL)‐10+ by 3‐fold and TIM‐1+IgM+IL‐10− B1a cells by 2.5‐fold. Similar expansion of B1a B cells was observed in spleens. These effects reduced atherosclerotic lesion size, increased plasma IgM and lesion IgM deposits, and decreased oxidatively modified low‐density lipoproteins in lesions. Lesion CD4+ and CD8+ T cells, macrophages and monocyte chemoattractant protein‐1, vascular cell adhesion molecule‐1, expression of proinflammatory cytokines monocyte chemoattractant protein‐1, vascular cell adhesion molecule‐1, IL1β, apoptotic cell numbers and necrotic cores were also reduced. RMT1‐10 treatment failed to expand peritoneal B1a cells and reduce atherosclerosis after splenectomy that reduces B1a cells, indicating that these effects are B1a cell‐dependent. Apolipoprotein E‐KO mice fed a high‐fat diet for 6 weeks before treatment with RMT1‐10 also increased TIM‐1+IgM+ IL‐10+ and TIM‐1+IgM+ IL‐10− B1a cells and IgM levels and attenuated progression of established atherosclerosis.Conclusions RMT1‐10 treatment attenuates atherosclerosis development and progression by selectively expanding IgM producing atheroprotective B1a cells. Antibody‐based in vivo expansion of B1a cells could be an attractive approach for treating atherosclerosis.

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The role of IgM antibodies in the recognition and clearance of apoptotic cells

Cited by 94 publications

References 48 publications

Apoptotic lymphocytes treated with IgG from Trypanosoma cruzi infection increase TNF‐α secretion and reduce parasite replication in macrophages

Apoptotic lymphocytes treated with IgG from Trypanosoma cruzi infection increase TNF‐α secretion and reduce parasite replication in macrophages

Irf4 is a positional and functional candidate gene for the control of serum IgM levels in the mouse

Anti‐TIM‐1 Monoclonal Antibody (RMT1‐10) Attenuates Atherosclerosis By Expanding IgM‐producing B1a Cells

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