In Situ B Cell-Mediated Immune Responses and Tubulointerstitial Inflammation in Human Lupus Nephritis

Abstract

The most prevalent severe manifestation of systemic lupus erythematosus (SLE) is nephritis which is characterized by immune complex deposition, inflammation, and scarring in both glomeruli and in the tubulointerstitium. Numerous studies indicate that glomerulonephritis results from a systemic break in B cell tolerance resulting in the local deposition of immune complexes containing antibodies reactive with ubiquitous self-antigens. However, the pathogenesis of SLE tubulointerstitial disease is not known. Herein, we demonstrate that in over half of a cohort of 68 lupus nephritis biopsies, the tubulointerstitial infiltrate was organized into either well-circumscribed T:B cell aggregates or germinal centers (GCs) containing follicular dendritic cells. Sampling of the in situ expressed immunoglobulin repertoire revealed that both histological patterns were associated with intrarenal B cell clonal expansion and ongoing somatic hypermutation. However, in the GC histology the proliferating cells were CD138−CD20+ centroblasts while in T:B aggregates, they were CD138+CD20low/− plasmablasts. The presence of either GCs or T:B aggregates was strongly associated with tubular basement membrane immune complexes. These data implicate tertiary lymphoid neogenesis in the pathogenesis of lupus tubulointerstitial inflammation.

The darker side of follicular helper T cells: from autoimmunity to immunodeficiency

“…[25][26][27] T FH cells in human autoimmune diseases Although less clearer than that in murine models, the implications of T FH cells in the development of human autoimmune diseases have started to be appreciated. 6,32 Earlier studies have provided indirect evidence to indicate the role of T FH cells in promoting human autoimmunity, e.g., production of pathogenic autoantibodies in SLE patients caused by dysregulated GC reactions, 31,48 presence of the aggregates of T and B cells containing plasmablasts in the kidneys of patients with lupus nephritis 49 and reduced GC reactions upon blocking CD40L-CD40 interactions in patients with active SLE. 50 Recent studies have further provided clearer evidence on the role of T FH cells in promotion of both systemic and organ-specific autoimmune diseases in humans.…”

The immune cell landscape in kidneys of lupus nephritis patients

“…7, 2018; B cells are found in more than half of the lupus biopsies but not in healthy samples 45 . The organization of B cell infiltrates can vary from scattered cells, to B-T cell clusters and, rarely, fully formed germinal centers 46,47 . Clonal expansions of B cells are common, with antigenic specificity frequently directed to local renal antigens 48 , suggesting that immune responses to damaged tissue are being driven in situ 49 Tissue resident myeloid cells have considerable developmental and functional differences from circulating subsets 6,51 and their gene expression profile is shaped by their microenvironment 51,52,53 .…”

The Pathogenesis of Lupus Nephritis

“…70 Infiltrating leukocytes form de novo perivascular tertiary lymphoid organs inside the kidney, which involve the clonal expansion and ongoing somatic hypermutation of B cells in proximity to T cell aggregates. 71 Such B cells undergo intrarenal proliferation and activation, which contributes to local inflammation and tissue pathology in addition to their role for systemic and intrarenal autoantibody production. 26,72,73 These data provide a rationale for B celltargeted therapies in LN.…”