Objective
To better define the immunologic character of the T cell infiltrate in lupus nephritis.
Methods
We performed double immunohistochemical staining and clonotypic T cell receptor (TCR) beta-chain sequencing in multiple anatomic regions isolated by laser-capture microdissection from renal biopsies.
Results
SLE kidneys have a variably patterned and often extensive infiltrate of predominantly clonally expanded T cells of CD4 and CD8 lineages. CD4 T cells were prominent in nearly two-thirds of SLE biopsies, and distributed as broad periglomerular aggregates or intermixed with CD8 T cells forming periglomerular caps. Sequencing of the T cell TCR from periglomerular regions showed a predominance of clonally expanded T cells. The CD8 T cells, which were present in all biopsies, often adhered to Bowman's capsule and infiltrated the tubular epithelium. They exhibited features that suggest participation in an adaptive immune response: differentiation into CD28null memory-effector phenotype, trafficking of the same expanded clonotype to different regions of the kidney and to the peripheral blood, and clonal persistence for years in repeat biopsies. CD8 T cell tubulitis was especially associated with progressive changes.
Conclusions
The immunological characteristics of the infiltrating CD4 and CD8 T cells in the lupus kidney indicate they have the potential to mediate injury, which may be relevant to development of progressive renal failure. Whereas the oligoclonality of the CD4 T cell infiltrate is consistent with the paradigm of SLE as a class II-associated autoimmune disease, the finding of CD8 T cell clonality and trafficking implies participation in a distinct systemic adaptive immune response.
Giant cell tumor (GCT) of bone is a unique bone lesion that is characterized by an excessive number of multinucleated osteoclasts. GCT consists of neoplastic stromal cells, multinucleated osteoclasts and their precursors, thus serving as a naturally occurring human disease model for the study of osteoclastogenesis. It still remains unclear how stromal cells of GCT recruit osteoclast precursors. In the present study, we characterized the cellular components of GCT and confirmed the presence of C D 14+-monocytes/CD68'-macrophages and CD34+-heniatopoetic stem cells that express CXCR4, a specific receptor for SDF-1; SDF-1 gene expression and presence of SDF-1 protein were confirmed by real time RT-PCR, in situ hybridization, and immunohistochemistry in the GCT tissue and cultured cells. SDF-1 was present at 25-50ng/ml in the conditioned media from the GCT cultures, which is in the range of physiological chemotactic concentration. Migration of osteoclast precursors was 2.5-fold higher in response to GCT conditioned media compared to the control media; and migration was inhibited by an average of 36% with anti-SDF-1 neutralizing antibody or competing recombinant SDF-1. These results suggest that SDF-1 is one of the significant chemoattractant factors involved in the recruitment of hematopoietic osteoclast precursor cells during tumor-induced osteoclastogenesis.
We sought to delineate further the immunological significance of T lymphocytes infiltrating the valve leaflets in calcific aortic stenosis (CAS) and determine whether there were associated alterations in circulating T cells. Using clonotypic TCR β-chain length and sequence analysis we confirmed the repertoire of tricuspid CAS valves contains numerous expanded T cell clones with varying degrees of additional polyclonality, which was greatest in cases with severe calcification. We now report a similar proportion of clonal expansions in the much younger bicuspid valve CAS cases. Peripheral blood flow cytometry revealed elevations in HLA-DR+ activated CD8 cells and in the CD8+CD28nullCD57+ memory-effector subset that were significantly greater in both bicuspid and tricuspid CAS cases with more severe valve calcification. Lesser increases of CD4+CD28null T cells were identified, principally in cases with concurrent atherosclerotic disease. Upon immunostaining the CD8 T cells in all valves were mainly CD28null, and CD8 T cell percentages were greatest in valves with oligoclonal repertoires. T cell clones identified by their clonotypic sequence as expanded in the valve were also found expanded in the circulating blood CD28nullCD8+ T cells and to a lesser degree in the CD8+CD28+ subset, directly supporting the relationship between immunologic events in the blood and the valve. The results suggest that an ongoing systemic adaptive immune response is occurring in cases with bicuspid and tricuspid CAS, involving circulating CD8 T cell activation, clonal expansion and differentiation to a memory-effector phenotype, with trafficking of T cells in expanded clones between blood and the valve.
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