Biomedical subjects

Susan A Boackle

Publications and source records attributed to Susan A Boackle.

6 recordsLinked to original sources

PubMed2004

CR1/CR2 deficiency alters IgG3 autoantibody production and IgA glomerular deposition in the MRL/lpr model of SLE.

CR1 and CR2 expression is decreased by approximately 50% on B cells of patients with systemic lupus erythematosus (SLE). Expression is also decreased in the MRL/lpr murine model of SLE prior to the development of clinical disease, suggesting that this alteration may play a role in pathogenesis. To determine whether the decrease in receptor levels affects the development of SLE, we analyzed MRL/lpr mice in which CR1/CR2 expression was altered by gene targeting. Mice from each cohort (Cr2+/+, Cr2+/-, and Cr2-/-) were analyzed biweekly for the development of proteinuria and autoantibodies. Kidneys were examined at 12 and 16 weeks for evidence of immune complex deposition and renal disease. Deficiency of CR1/CR2 did not affect survival or development of renal disease as measured by proteinuria. Mice deficient in CR1/CR2 had significantly lower levels of IgG3 rheumatoid factor (RF) and total serum IgG3, suggesting a specific defect in production of IgG3 in response to endogenous autoantigens. Since IgG3 RF has been associated with the development of vasculitis in this model, we examined the mice for alterations in development of this clinical manifestation. Although there was no difference in the development of ear necrosis among the three groups, renal arteritis was not identified in any of the Cr2+/- mice, whereas it was present in 20% of the Cr2+/- and 40% of the Cr2+/+ mice. Finally, significantly higher levels of IgA were seen in the glomeruli of Cr2+/- mice compared to Cr2+/- or Cr2+/+ mice, suggesting that CR1/CR2 are involved in either the regulation of IgA production or the clearance of IgA immune complexes. Together these data support the concept that alterations in CR1/CR2 expression or function affect the regulation of autoantibody production and/or clearance and may have clinical consequences.

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PubMed2004

Complement receptor 2 and autoimmunity.

Complement receptor 2 (CR2/CD21) plays a major role in the immune response by linking innate and adaptive immunity to foreign pathogens and proteins. In addition, several lines of evidence strongly support a role for CR2 in the maintenance of tolerance to self-antigens. Both the absence of CR2 expression (along with the alternatively spliced gene product CR1) and the presence of a dysfunctional CR2 protein are tightly associated with the development of autoreactivity to nuclear antigens. Altered levels of expression of CR2 in patients with systemic lupus erythematosus support a clinically relevant role for this phenotype. Several possible mechanisms could underlie the loss of self-tolerance related to CR2, but the effect is most likely related to the failure of one or more specific checkpoints that limit autoreactivity during B cell development and immune reactions.

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PubMed2003

Complement and autoimmunity.

The complement system is comprised of a number of serum and membrane-bound proteins that play an important role in the elimination of foreign microorganisms while protecting the host organism from complement-related damage. Complement has also been shown to participate in the generation of normal humoral immune responses to foreign antigens. Recent studies suggest that the functions of complement may be extended to include the maintenance of B cell tolerance. Complement receptor 2 (CR2/CD21) has been implicated in lupus susceptibility in both humans and animal models of disease. Located primarily on B cells and follicular dendritic cells, CR2 binds C3 degradation products that have become covalently bound to antigen or immune complexes in the process of complement activation. The mechanism by which CR2 might regulate B cell reactivity to autoantigens has not been elucidated, but may involve direct effects on B cell tolerance or indirect effects on T cell tolerance.

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PubMed2003

Role of complement in the development of autoimmunity.

B cell complement receptors have been shown to be important in the generation of normal humoral immune responses, and they likely also participate in the development of autoimmunity. Complement component and receptor deficiencies have been associated with SLE in both animal models and patients with disease. Recent data suggest that Cr2 is a lupus susceptibility gene in the NZM2410 mouse model for lupus, as it generates complement receptors that are structurally and functionally altered. Complement deficiency may result in autoimmune disease because of the inability to appropriately clear immune complexes or apoptotic cells or by the impaired generation of C3-coated autoantigens for CR1/CR2. In turn, CR1/CR2 may participate in the maintenance of B cell tolerance by lowering the threshold for negative selection of autoreactive B cells, by targeting autoantigen to FDCs in secondary lymphoid organs, or by regulating autoreactive T cell function. The effect of CR2 has not been dissected from that of CR1 in the animal studies performed to date. Furthermore, the effects of CR1/CR2 dysfunction or partial deficiency, which are found in the NZM2410 mouse model and in patients with SLE respectively, have not been delineated from those of complete deficiency, which has been studied in several animal models of autoimmunity and tolerance. Although CR1/CR2 dysfunction or deficiency may confer only a modest phenotype in isolation, it is likely that when combined with other disease susceptibility genes it will result in a fully penetrant end-stage disease phenotype. Understanding the mechanisms by which these receptors participate in the maintenance of B cell tolerance will be critical in developing appropriate therapeutic interventions for patients with autoimmune diseases such as SLE.

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PubMed2002

Transgenic expression of a soluble complement inhibitor protects against renal disease and promotes survival in MRL/lpr mice.

To investigate the role of complement in lupus nephritis, we used MRL/lpr mice and a transgene overexpressing a soluble complement regulator, soluble CR1-related gene/protein y (sCrry), both systemically and in kidney. Production of sCrry in sera led to significant complement inhibition in Crry-transgenic mice relative to littermate transgene negative controls. This complement inhibition with sCrry conferred a survival advantage to MRL/lpr mice. In a total of 154 animals, 42.5% transgene-negative animals had impaired renal function (blood urea nitrogen > 50 mg/dl) compared with 16.4% mice with the sCrry-producing transgene (p < 0.001). In those animals that died spontaneously, MRL/lpr mice with the sCrry-producing transgene did not die of renal failure, while those without the transgene did (blood urea nitrogen values of 46.6 +/- 9 and 122 +/- 29 mg/dl in transgene-positive and transgene-negative animals, respectively; p < 0.001). Albuminuria was reduced in those transgenic animals in which sCrry expression was maximally stimulated (urinary albumin/creatinine = 12.4 +/- 4.3 and 36.9 +/- 7.7 in transgene-positive and transgene-negative animals, respectively; p < 0.001). As expected in the setting of chronic complement inhibition, there was less C3 deposition in glomeruli of sCrry-producing transgenic mice compared with transgene-negative animals. In contrast, there was no effect on glomerular IgG deposition, levels of anti-dsDNA Ab and rheumatoid factor, or spleen weights between the two groups. Thus, long-term complement inhibition reduces renal disease in MRL/lpr mice, which translates into improved survival. MRL/lpr mice in which complement is inhibited still have spontaneous mortality, yet this is not from renal disease.

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PubMed2002

Arthritis critically dependent on innate immune system players.

K/BxN T cell receptor transgenic mice are a model of inflammatory arthritis, similar to rheumatoid arthritis. Disease in these animals is focused specifically on the joints but stems from autoreactivity to a ubiquitously expressed antigen, glucose-6-phosphate isomerase (GPI). T and B cells are both required for disease initiation, but anti-GPI immunoglobulins (Igs), alone, can induce arthritis in lymphocyte-deficient recipients. Here, we show that the arthritogenic Igs act through both Fc receptors (in particular, FcgammaRIII) and the complement network (C5a). Surprisingly, the alternative pathway of complement activation is critical, while classical pathway components are entirely dispensable. We suggest that autoimmune disease, even one that is organ specific, can occur when mobilization of an adaptive immune response results in runaway activation of the innate response.

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