Synergistic roles of IgM and complement in antigen trapping and follicular localization

Youd, Michele E.; Ferguson, Andrew R.; Corley, Ronald B.

doi:10.1002/1521-4141(200208)32:8<2328::aid-immu2328>3.0.co;2-t

Cited by 67 publications

(75 citation statements)

References 43 publications

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“…Because MZ B cells express high levels of CD21 and low levels of CD23, whereas the reverse is true for FO B cells (44), it seems logical that IgE-Ag and IgM-C-Ag complexes bind to different B cells. An intact C system is vital for a normal Ab response (51) and one of the explanations is increased deposition of Ag on FDCs in B cell follicles, both in spleen (43,52,53) and lymph nodes (37). Our observations indicate that there exists an additional route for transport of Ag into splenic B cell follicles using IgE and CD23 ϩ B cells.…”

Section: Discussionmentioning

confidence: 99%

A Novel B Cell-Mediated Transport of IgE-Immune Complexes to the Follicle of the Spleen

Hjelm

Karlsson

Heyman

2008

The Journal of Immunology

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Ag administered i.v. to mice along with specific IgE or IgG2a induces higher Ab- and CD4+ T cell responses than Ag administered alone. The IgE effect is completely dependent on the low-affinity receptor for IgE, CD23, whereas the IgG2a effect depends on activating FcγRs. In vitro studies suggest that IgE/Ag is presented more efficiently than Ag alone to CD4+ T cells by CD23+ B cells and that IgG2a/Ag is presented by FcγR+ dendritic cells (DCs). In this study, we investigate in vivo the early events leading to IgE- and IgG2a-mediated enhancement of immune responses. OVA administered i.v. in PBS in combination with specific IgE binds circulating B cells after 5 min and is found in B cell follicles bound to follicular B cells (CD23high) after 30 min. This novel B cell-dependent route of entry is specific for IgE because IgG2a-Ag complexes were trapped in the marginal zone. OVA-specific CD4+ T cells were found at the T-B border in the T cell zones 12 h after immunization both with IgE/OVA or IgG2a/OVA and proliferated vigorously after 3 days. The findings suggest that IgE- and IgG2a-immune complexes are efficient stimulators of early CD4+ T cell responses and that Ag bound to IgE has a specific route for transportation into follicles.

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Section: Discussionmentioning

confidence: 99%

A Novel B Cell-Mediated Transport of IgE-Immune Complexes to the Follicle of the Spleen

Hjelm

Karlsson

Heyman

2008

The Journal of Immunology

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“…The splenic MZ is a barrier for blood-borne pathogens, T-independent antigens and IgM-IC [22,40,41], and it supports the humoral immune response in C4 null mice [22]. Here, we tested if additional endogenous DNA could be targeted to the spleen by i.v.…”

Section: An Elevated Intravascular Concentration Of Nuclear Antigens mentioning

confidence: 99%

“…The intravascular DNA may be from apoptotic bodies, which have been proposed to be a source of nuclear autoantigens [7]. It has been demonstrated that complement C1q [4,38] and C4 [5] deficient mice have impaired elimination of administered apoptotic bodies and accumulate these within tissues, although not all murine models with apoptotic cell clearing defects are prone to SLE [39], probably as a result of an abnormal B cell homeostasis.The splenic MZ is a barrier for blood-borne pathogens, T-independent antigens and IgM-IC [22,40,41], and it supports the humoral immune response in C4 null mice [22]. Here, we tested if additional endogenous DNA could be targeted to the spleen by i.v.…”

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confidence: 99%

Elevated levels of endogenous apoptotic DNA and IFN‐α in complement C4‐deficient mice: Implications for induction of systemic lupus erythematosus

et al. 2007

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Systemic lupus erythematosus (SLE), an autoimmune disease characterized by chronic nephritis, arthritis and dermatitis, and the presence of antinuclear autoantibodies, is associated with complement factor deficiencies in the classical activation pathway. In addition, IFN-a seems to be a key cytokine in SLE as an activated IFN-a system is regularly observed in patients with SLE. Here, we demonstrate that in lupus-susceptible, complement C4-deficient mice the lack of complement results in elevated intravascular levels of apoptotic DNA. The apoptotic DNA is targeted to the splenic marginal zone where it accumulates and induces IFN-a. As such, we present here a unifying hypothesis for the induction of SLE that incorporates the role of complement deficiency and elevated levels of IFN-a. IntroductionSystemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by autoantibodies against various nuclear antigens, as well as the generation of immune complexes (IC) leading to inflammatory responses in skin, kidneys, joints, the vasculature and the heart [1]. Susceptibility genes for SLE include those involved in the deficiency of early complement factors of the classical pathway (C1, C4, C2) [2], which has been confirmed in animal models for complement deficiency [3,4]. Current explanations for the loss of tolerance in states of complement deficiency include impaired elimination of apoptotic bodies [4,5] or dying cells [6] as a source of autoantigens [7,8], and inadequate regulation of follicular B cells via the complement receptor CD21/35 [3], although the absence of CD21, or its most important ligand (C3d), does not seem to be associated with SLE [9,10]. As such, neither model alone can adequately account for the association of complement deficiency and SLE [11].IFN-a is another important factor in the development of SLE, and elevated levels of this antiviral cytokine or IFN-a-induced genes are frequently observed in patients with SLE [12][13][14][15]. Activation of the class I IFN system has been confirmed by recent studies using microarray approaches [16][17][18][19]. Moreover, the administration of IFN-a for therapeutic purposes induces typical SLE autoantibodies as a side effect [20,21]. Both these phenomena are poorly understood and no unifying hypothesis, incorporating the role of complement deficiency and elevated IFN-a levels in the induction of SLE, exists. Recently, we described an unusual deposition of IgMcontaining immune complexes (IgM-IC) in the splenic marginal zone (MZ) of complement C4-deficient (C4 null ) mice. This IgM-IC deposition led to restoration of a humoral immune response against foreign antigens within those IC, when compared to mice receiving antigen only [22]. Murine MZ macrophages are known to produce IFN-a [23] and we hypothesized that intravascular nuclear antigen levels would be elevated as a result of complement deficiency and that natural IgM anti-DNA antibodies would mediate the IC deposition in the splenic MZ. Here, the nuclear antigens would induce IFN-a, which i...

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“…The multimeric structure makes IgM polyreactive to phylogenetically conserved repetitive structures such as lipopolysaccharide (LPS), peptidoglycan, lipoteichoic acids, lipoarabinomannan, mannans and lipoproteins, and to a potent activator of the complement system. Natural IgM and complement were shown to have a synergistic role in the first line of defense against invading microorganisms by mediating clearance of immune complexes from the circulation and their localization to liver and secondary lymphoid organs [2][3][4][5][6]. The spleen is the largest of the secondary lymphoid organs and is organized in the red pulp with its blood-filled sinuses and in the white pulp with the T and B cell zone [7].…”

Section: Introductionmentioning

confidence: 99%

The presence of MOMA‐2⁺ macrophages in the outer B cell zone and protection of the splenic micro‐architecture from LPS‐induced destruction depend on secreted IgM

et al. 2007

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The role secretory IgM has in protecting splenic tissue from LPS-induced damage was assessed in mice incapable of secreting IgM but able to express surface IgM and IgD. Within seconds after LPS challenge, 99% of the 131 I-labeled LPS was found in the liver and the spleen of both sIgM-deficient and wild-type mice. In the spleen FITC-labeled LPS was found on the surface of 2F8 + scavenger receptor macrophages localized in the outer marginal zone, while none of the labeled LPS could be detected on marginal zone ER-TR9 + and MOMA-1 + macrophages. An additional population of macrophages, MOMA-2 + , were capable of producing C3 locally in the T and B cell zone after LPS challenge. Local C3 production was regulated, as no C3 was found in splenic tissue of unchallenged mice. Interestingly, in the absence of circulating and locally produced secretory IgM, MOMA-2 + macrophages of the T and B cell zone failed to establish an additional ring of C3-producing macrophages in the outer B cell zone close to the marginal zone upon LPS challenge. The consequence was a massive destruction of the microarchitecture of the spleen where marginal zones disorganized, lymphoid follicles and T cell zones disrupted and follicular DC (FDC) networks disappeared.

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Synergistic roles of IgM and complement in antigen trapping and follicular localization

Cited by 67 publications

References 43 publications

A Novel B Cell-Mediated Transport of IgE-Immune Complexes to the Follicle of the Spleen

A Novel B Cell-Mediated Transport of IgE-Immune Complexes to the Follicle of the Spleen

Elevated levels of endogenous apoptotic DNA and IFN‐α in complement C4‐deficient mice: Implications for induction of systemic lupus erythematosus

The presence of MOMA‐2⁺ macrophages in the outer B cell zone and protection of the splenic micro‐architecture from LPS‐induced destruction depend on secreted IgM

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Synergistic roles of IgM and complement in antigen trapping and follicular localization

Cited by 67 publications

References 43 publications

A Novel B Cell-Mediated Transport of IgE-Immune Complexes to the Follicle of the Spleen

A Novel B Cell-Mediated Transport of IgE-Immune Complexes to the Follicle of the Spleen

Elevated levels of endogenous apoptotic DNA and IFN‐α in complement C4‐deficient mice: Implications for induction of systemic lupus erythematosus

The presence of MOMA‐2+ macrophages in the outer B cell zone and protection of the splenic micro‐architecture from LPS‐induced destruction depend on secreted IgM

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The presence of MOMA‐2⁺ macrophages in the outer B cell zone and protection of the splenic micro‐architecture from LPS‐induced destruction depend on secreted IgM