The most frequent severe manifestation of SLE is lupus nephritis (LN). Pathologically, lupus nephritis (LN) is characterized by immune complex deposition and inflammation in both glomeruli and tubuluointersitium that, if left untreated, can result in scarring and irreversible organ failure. Of the pathological manifestations of LN, glomerulonephritis (GN) is both the best studied and the feature most often replicated in murine models of autoimmune disease. However, tubulointerstitial inflammation is also a usual feature of LN that contributes to overall disease activity and determines long-term prognosis. Myriad studies indicate that GN results from a systemic break in B cell tolerance and the local deposition of immune complexes containing antibodies reactive with ubiquitous self-antigens. However, the pathogenesis of SLE tubulointerstitial disease is not known. In this grant application, we demonstrate that in over half of patients, the tubulointerstitial inflammatory infiltrate is organized into either well-circumscribed T:B cell aggregates or germinal centers (GCs) containing follicular dendritic cells. Sampling of in situ expressed immunoglobulins using laser capture microscopy coupled to RT-PCR revealed a restricted repertoire in both histological patterns that likely arose from local clonal expansion. Furthermore, the pattern of somatic hypermutations in GC expressed immunoglobulins was consistent with ongoing antigen-driven selection. The presence of either T:B aggregates or GCs was strongly associated with more severe tubulointerstitial inflammation and the deposition of immune complexes in tubular basement membranes. These observations raise the novel possibility that lupus tubulointerstitial nephritis is not a manifestation of systemic autoimmunity to ubiquitous autoantigens. Rather, it might result from a break in tolerance to locally expressed antigens. In this grant application, we hypothesize that in lupus nephritis, in situ selected B cells secrete autoreactive antibodies which deposit in the tubulointerstitium and contribute to local inflammation. This hypothesis will be tested in the following Specific Aims:
Aim 1. To characterize in situ B cell responses in lupus nephritis biopsies manifesting the diffuse, T:B aggregate and GC histological patterns.
Aim 2 : To determine the origin of the in situ B cell repertoire in lupus nephritis.
In Aim 3 : To identify the antigenic specificities of in situ expressed antibodies in SLE nephritis.
The most prevalent, severe manifestation of systemic lupus erythematosus is nephritis. Recently, we have demonstrated that tertiary lymphoid neogenesis is a common feature of lupus nephritis that is associated with severe tubulointerstitial inflammation. In this application, we will determine if tubulointerstitial nephritis results from a local break in tolerance and the development of in situ immune responses.
|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|