Spontaneous class switching and B cell hyperactivity increase autoimmunity against intracellular self antigen in Lyn‐deficient mice

Silver, Karlee; Bouriez-Jones, Tiphaine; Crockford, Tanya L.; Ferry, Helen; Tang, Hao; Cyster, Jason G.; Cornall, Richard J.

doi:10.1002/eji.200636462

Cited by 6 publications

(7 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Under these circumstances, some of the factors causing a breakdown in tolerance could be antigen independent. Lyn-deficient B cells expressing Ig transgenes for hen egg lysozyme show increased differentiation to plasma cells even in the absence of lysozyme, which is consistent with a polyclonal B cell activation [29,54]. This process could be driven to affinity maturation and isotype class switching by antigen and TLR-dependent signals or by nonspecific activation of DC and hypersecretion of cytokines, such as IL-6.…”

Section: Discussionsupporting

confidence: 61%

“…Serum antibody titers were measured by ELISA as previously described [29], except coating antibodies were anti-mouse IgM, II/41; IgG 1 , A85-3; IgG 2a , RII-89 (2 lg/mL; BD Pharmingen), and antibodies were detected with biotinylated antibody [IgM a , DS-1-Bi; IgM b , AF6-78-Bi; IgG1, A85-1-Bi; IgG1 a , 10.9-Bi; IgG1 b , B68-2-Bi; IgG2a a , 8.3-Bi; IgG2a b , 5.7-Bi (BD Pharmingen)] followed by avidin-alkaline phosphatase (AP), or with IgM-AP (Sigma) or IgG2a-AP (Southern Biotech). IgM-secreting plasma cells were measured by spot ELISA as described previously [4], except plates were coated with purified anti-mouse IgM and detected with IgM-AP.…”

Section: Measurement Of Serum Antibody Titers and Plasma Cell Numbersmentioning

confidence: 99%

“…The evidence for involvement of TLR in autoimmunity and the fact that transgenic Lyn-deficient B cells are able to class switch to IgG isotypes by a mechanism that does not obviously require the presence of self antigen [29] has now led us to explore the requirement for TLR signaling in the Lyn-deficient lupus model. To do this, we generated Lyn-deficient (lyn -/-) mice that were also deficient in MyD88 on a uniform C57BL/6 (B6) genetic background and analyzed these mice alongside lyn -/-and WT littermates.…”

Section: Introductionmentioning

confidence: 99%

“…These in vivo results provide a strong basis for the hypothesis that pathogenic antibodies in SLE become targeted to nuclear antigens because the nuclear antigens are themselves stimulators of the immune system via TLR [24,25]. This is further supported by evidence in vitro that chromatin-containing IC directly stimulate autoreactive B cell proliferation via TLR9 [26,27], and that RNA-associated proteins cause DC and monocyte secretion of type I IFN, TNF-a and IL-12 via TLR7 and TLR8 [28]-The evidence for involvement of TLR in autoimmunity and the fact that transgenic Lyn-deficient B cells are able to class switch to IgG isotypes by a mechanism that does not obviously require the presence of self antigen [29] has now led us to explore the requirement for TLR signaling in the Lyn-deficient lupus model. To do this, we generated Lyn-deficient (lyn -/-) mice that were also deficient in MyD88 on a uniform C57BL/6 (B6) genetic background and analyzed these mice alongside lyn -/-and WT littermates.…”

mentioning

confidence: 99%

See 3 more Smart Citations

MyD88‐dependent autoimmune disease in Lyn‐deficient mice

et al. 2007

Self Cite

View full text Add to dashboard Cite

Recent evidence suggests that systemic autoimmune disease depends on signals from TLR ligands, but little is known about how TLR-dependent pathways lead to the loss of self tolerance in vivo. To address this, we have examined the role of TLR signaling in Lyndeficient mice, which develop an autoimmune disease similar to SLE. We found that absence of the TLR signaling adaptor molecule MyD88 suppresses plasma cell differentiation of switched and unswitched B cells, and prevents the generation of antinuclear IgG antibodies and glomerulonephritis. In mixed chimeras the increased IgM and IgG antibody secretion in Lyn-deficient mice is at least partially due to B cellindependent effects of Lyn. We now show that MyD88 deficiency blocks the expansion and activation of DC in which Lyn is also normally expressed, and prevents the hypersecretion of proinflammatory cytokines IL-6 and IL-12 by Lyn-deficient DC. These findings further highlight the important role of TLR-dependent signals in both lymphocyte activation and autoimmune pathogenesis. IntroductionOur understanding of the pathways leading to autoantibody (autoAb) production in systemic lupus erythematosus (SLE) has been greatly enhanced by studies of murine SLE models, including mice with single targeted mutations to negative regulators of BCR signaling, e.g., the src-family protein tyrosine kinase Lyn [1][2][3], phosphatase SHP-1 [4] and coreceptor CD22 [5, 6]. Lyn deficiency manifests as the hypersecretion of IgM, IgA and IgG autoAb, which, by 17-20 weeks of age, develop specificity to nuclear components such as dsDNA, are deposited as immune complexes (IC) in the kidneys and lead to lethal proliferative glomerulonephritis [1][2][3]. Following BCR stimulation, Lyn-deficient B cells have greater and more prolonged intracellular calcium flux, more MAPK activation and hyperproliferate in comparison to WT B cells [1, 7, 8]. These findings, together with the fact that the expression of Lyn is limited to B, NK and myeloid cells [9], have led to the suggestion that B cell intrinsic effects are the main cause of SLE-like autoimmune disease. Growing support for the central role B cells play in the development of autoimmune disease (reviewed in [10]) and the discovery of lower levels of Lyn in B cells of human SLE patients have helped strengthen this idea [11].However, the development of high-affinity pathogenic autoAb, which are targeted at nuclear antigens and potentially damaging to organs including kidneys, depends on somatic hypermutation in the germinal center and collaboration between cells of the adaptive and innate immune systems. T cells play an important role in this process and autoantigen-specific T cells are required for secretion of IgG autoAb specific for nuclear components and end-organ damage in the spontaneous murine models, MRL-lpr/lpr and (NZBÂNZW)F 1 [18]. Disease in the gp96 transgenic mice is dependent on MyD88, an adaptor molecule required for signaling by all TLR except TLR3, which binds dsRNA, and TLR4, which also signals by a MyD88-independent pa...

show abstract

Section: Discussionsupporting

confidence: 61%

Section: Measurement Of Serum Antibody Titers and Plasma Cell Numbersmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

MyD88‐dependent autoimmune disease in Lyn‐deficient mice

et al. 2007

Self Cite

View full text Add to dashboard Cite

show abstract

“…In the situations described above, loss of CD22 function is associated with autoimmunity, presumably as a consequence of altered BCR signalling thresholds and B‐cell dysregulation. In lyn ‐deficient mice, reduced BCR signalling thresholds and B‐cell hyperactivity predispose to the development of autoimmunity through spontaneous B‐cell activation, class switch recombination and antibody hypersecretion 110,111 . In a similar fashion, altered BCR signalling in CD22‐deficient mice might have similar effects, especially when combined with defects in other components of the inhibitory pathway, for example haploinsufficiency in Lyn and SHP‐1, 28 or with as yet unidentified 129‐derived genes 49,89 .…”

Section: Autoimmunitymentioning

confidence: 99%

CD22: an inhibitory enigma

2008

View full text Add to dashboard Cite

SummaryCD22 is an inhibitory coreceptor of the B-cell receptor (BCR), and plays a critical role in establishing signalling thresholds for B-cell activation. Like other coreceptors, the ability of CD22 to modulate B-cell signalling is critically dependent upon its proximity to the BCR, and this in turn is governed by the binding of its extracellular domain to a2,6-linked sialic acid ligands. Manipulation of CD22 ligand binding in various experimental settings has profound effects on B-cell signalling, but as yet there is no complete model for how ligand binding in vivo controls normal CD22 function. Several elegant studies have recently shed light on this issue, although the results appear to suggest two mutually exclusive models for the role of ligand binding; in either promoting or inhibiting, CD22 function. We shall therefore discuss these results in detail, and suggest possible approaches by which these conflicting experimental findings might be reconciled. We shall also consider a second important issue in CD22 biology, which relates to the role that defects in this receptor might play in mediating autoimmune disease. We review the current evidence for this, and discuss the importance of genetic background in modifying CD22 function and predisposition to autoimmunity.Keywords: autoimmunity; B cell; CD22; inhibitory receptor; sialic acid Abbreviations: a2,6Sia, a2,6-linked sialic acid; sIgM, cell surface immunoglobulin M; HEL, hen egg lysozyme.

show abstract