This is a project to test the basic idea that T cells reacting to somatically generated sequences in autoantibody variable regions mediate the development of pathology in lupus nephritis (LN). Many years of research into the immunobiology of LN have demonstrated the pathologic capacity of B cells, infiltrating T cells, and immune complexes in the glomerular endothelium. Inflammatory kidney-infiltrating T cells, both IFN3-secreting Th1 and IL-17-secreting Th17 cells, recruit innate effector cells, which inflict damage upon glomerular cells. However, the mechanisms by which T cells are primed, the specificity of renal T cells, and how autoantibodies are initially elicited are still large unanswered questions. I hypothesize that these questions can be explained by T cells that react to MHC II-presented peptides derived from autoantibodies and that differentiate into inflammatory mediators of kidney pathology. The significance of this hypothesis applies not only to genesis of disease but also to its treatment, as human anti-chimera antibodies (HACA) driven by antibody peptide-specific T cells may play a role in the unexpectedly variable response of LN to monoclonal antibody therapy. To test this hypothesis, I will use an adoptive transfer model of SLE with nephritis in which T cells specific for a V: peptides are introduced into a mouse expressing a corresponding Ig: transgene in B cells. I will determine whether nephritogenic Th1 and Th17 T cells that later arise in mice with LN are V: peptide-specific or instead are derived from an endogenous population via determinant spreading. Both V: peptide-specific and endogenous CD4 T cells will be assessed for microanatomical localization and for their participation in conjugate formation with Ig: transgenic B cells in the kidney. I will extend this analysis to anti-glomerular basement membrane (GBM) models of LN, in which T cell populations in the kidneys may be responsive to either autologous or heterologous antibodies. Finally, I will test the hypothesis that IgG in immune complexes is immunogenic and proinflammatory for V: peptide-specific T cells, and that this is dependent upon Ig glycan content. In contrast, I predict that IgM is immunogenic but noninflammatory. The results of this work will reveal important information about potential antigenic specificities of nephritogenic T cells and provide insight into mechanisms that promote HACA responses in patients that receive monoclonal Ab therapy.
T lymphocytes are major inducers of kidney disease (lupus nephritis) in systemic lupus erythematosus (SLE). While it is commonly assumed that these nephrotigenic T cells are reacting to self-antigens located in kidney tissue, this has never been formally demonstrated. This deficiency in our knowledge severely limits the development of novel and specific therapeutic strategies for treating lupus nephritis. The project proposed in this application will test the idea that T cells react with components of immunoglobulins that deposit within the kidney rather than with kidney antigens themselves. This could explain why it has been so difficult to define the antigens to which nephritogenic T cells react. We will utilize a novel mouse model of SLE that permits us to examine this problem at a high level of definition. In addition, we will confirm our findings in the context of a well-established induced model of lupus nephritis. Testing this hypothesis will advance our understanding how kidney disease develops in SLE. It will also shed light on patient reactions to therapeutic monoclonal antibodies used to treat SLE. Therefore, the results of this study will provide a framework to develop novel therapies for lupus nephritis and optimize current therapeutic antibodies that are used to treat it.
| Kirchenbaum, Greg A; St Clair, James B; Detanico, Thiago et al. (2014) Functionally responsive self-reactive B cells of low affinity express reduced levels of surface IgM. Eur J Immunol 44:970-82 |
| Detanico, Thiago; St Clair, James B; Aviszus, Katja et al. (2013) Somatic mutagenesis in autoimmunity. Autoimmunity 46:102-14 |
| Aviszus, Katja; Macleod, Megan K L; Kirchenbaum, Greg A et al. (2012) Antigen-specific suppression of humoral immunity by anergic Ars/A1 B cells. J Immunol 189:4275-83 |
| Heiser, Ryan A; Snyder, Christopher M; St Clair, James et al. (2011) Aborted germinal center reactions and B cell memory by follicular T cells specific for a B cell receptor V region peptide. J Immunol 187:212-21 |
