In lupus nephritis (LuN) renal biopsies are used to assess the extent of renal involvement, assign prognosis and to aid in making therapeutic decisions. While current classification criteria focus on glomerular disease we and other groups have demonstrated that the degree of tubulointerstitial inflammation (TII) and scarring, and not glomerular injury1, predict progression to renal failure. During the last funding cycle, we demonstrated that lupus TII has many of the features of tertiary lymphoid neogenesis (TLN), including the propagation of in situ antigen-driven humoral immune responses. Therefore, LuN may arise from both systemic (GN) and organ- intrinsic (TII) autoimmune pathogenic mechanisms. As demonstrated, we have cloned and characterized a full panel of in situ expressed antibodies. Surprisingly, the predominant antigen driving in situ humoral selection was vimentin. Vimentin was highly expressed by infiltrating inflammatory cells and in situ selected antibodies preferentially bound to inflamed renal tissue. Furthermore, high-titers of serum anti-vimentin antibodies (AVAs) were highly specific for severe lupus TII. For B cell activation, second signals are necessary that, in SLOs are provided by T follicular helper cells (TFH). In preliminary data, we demonstrate that TFH cells are a common feature of severe lupus TII. Furthermore, using laser capture microscopy, and novel computational tools that we have developed, we demonstrated that these TFH cells provide cognate help to most infiltrating B cells. These findings suggest a general model in which coordination between antigen-related T cells and antigen presenting cells drives in situ adaptive immunity and amplifies inflammation. We will test this model in the following Specific Aims:
Aim 1. To define the prevalence, origin, and clinical significance of anti-vimentin antibodies.
Aim 2. Understand the functional importance of anti-vimentin antibodies.
Aim 3. To elucidate the network of cognate interactions between T cell and antigen presenting cell populations in TII.
In human lupus nephritis, inflammation of the tubulointerstitium of the kidney is a strong predictor of who progresses to renal failure. In this grant proposal, we are developing and applying novel analytical tools to understand how immune responses are propagated within the tubulointerstitium of human lupus nephritis. Such studies may reveal new therapeutic targets or biomarkers of severe disease.
|Henault, Jill; Riggs, Jeffrey M; Karnell, Jodi L et al. (2016) Self-reactive IgE exacerbates interferon responses associated with autoimmunity. Nat Immunol 17:196-203|
|Ko, Kichul; Wang, Jianing; Perper, Stuart et al. (2016) Bcl-2 as a Therapeutic Target in Human Tubulointerstitial Inflammation. Arthritis Rheumatol 68:2740-2751|
|Trotter, Kimberly; Clark, Marcus R; Liarski, Vladimir M (2016) Overview of pathophysiology and treatment of human lupus nephritis. Curr Opin Rheumatol 28:460-7|
|Clark, Marcus R; Trotter, Kimberly; Chang, Anthony (2015) The Pathogenesis and Therapeutic Implications of Tubulointerstitial Inflammation in Human Lupus Nephritis. Semin Nephrol 35:455-64|
|Liarski, Vladimir M; Kaverina, Natalya; Chang, Anthony et al. (2014) Cell distance mapping identifies functional T follicular helper cells in inflamed human renal tissue. Sci Transl Med 6:230ra46|
|Chang, Anthony; Ko, Kichul; Clark, Marcus R (2014) The emerging role of the inflammasome in kidney diseases. Curr Opin Nephrol Hypertens 23:204-10|
|Kinloch, Andrew J; Chang, Anthony; Ko, Kichul et al. (2014) Vimentin is a dominant target of in situ humoral immunity in human lupus tubulointerstitial nephritis. Arthritis Rheumatol 66:3359-70|
|Hsieh, Christine; Chang, Anthony; Brandt, Daniel et al. (2011) Predicting outcomes of lupus nephritis with tubulointerstitial inflammation and scarring. Arthritis Care Res (Hoboken) 63:865-74|
|Chang, Anthony; Henderson, Scott G; Brandt, Daniel et al. (2011) In situ B cell-mediated immune responses and tubulointerstitial inflammation in human lupus nephritis. J Immunol 186:1849-60|