The development of B cells is dependent on the sequential DNA rearrangement of immunoglobulin loci that encode subunits of the B cell receptor. The pathway navigates a crucial checkpoint that ensures expression of a signalling-competent immunoglobulin heavy chain before commitment to rearrangement and expression of an immunoglobulin light chain. The checkpoint segregates proliferation of pre-B cells from immunoglobulin light chain recombination and their differentiation into B cells. Recent advances have revealed the molecular circuitry that controls two rival signalling systems, namely the interleukin-7 (IL-7) receptor and the pre-B cell receptor, to ensure that proliferation and immunoglobulin recombination are mutually exclusive, thereby maintaining genomic integrity during B cell development.

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 molecular crosstalk between the interkeukin-7 receptor (IL-7R) and pre-BCR in B lymphopoiesis has been enigmatic. We demonstrate that in pre-B cells, the IL-7R, but not the pre-BCR, was coupled to the phosphatidylinositol-3-OH kinase (PI(3)K)–Akt module, signaling by which prevents Rag expression. Attenuation of IL-7 signaling resulted in up-regulation of Foxo1 and Pax5, which co-activated many pre-B cell genes, including Rag1,2 and Blnk. Induction of the latter gene enabled pre-BCR signaling via the Syk-BLNK module and promoted immunoglobulin light chain rearrangement. BLNK signaling also antagonized Akt activation, thereby augmenting Foxo1 and Pax5 accumulation. This self-reinforcing molecular circuit appears to sense limiting concentrations of IL-7 and functions to control the expansion and differentiation of pre-B cells.

Objective In lupus nephritis, glomerular injury correlates poorly with progression to renal failure. While the tubulointerstitium is also commonly involved, the importance of such involvement is not well defined. Therefore, we developed a simple method to assess the prognostic utility of measuring tubulointerstitial inflammation (TI). Methods Sixty-eight SLE patients with lupus nephritis were enrolled. Tubulointerstitial lymphocytic infiltrates were quantitated both by anti-CD45 antibody staining and standard histochemical staining. Follow-up data was obtained and survival analysis carried out to determine which histologic features were predictive of subsequent renal failure. Results By CD45 staining TI was a common pathological finding, with 72% of biopsies having moderate or severe involvement. The extent of TI correlated with serum creatinine, but not with dsDNA antibodies, serum C3, or glomerular inflammation. TI severity, but not glomerular injury, identified patients at greater risk for renal failure (p=0.02). A high NIH chronicity index also identified patients at risk for renal failure. However, when the glomerular and tubulointerstitial subcomponents of the NIH chronicity index were separated in a bivariate model, only tubulointerstitial chronicity provided prognostic information (HR 2.2, 95% C.I. 1.3, 3.6, p=0.002 vs. HR 1.0, 95% C.I. 0.7, 1.5. p=0.97 for glomerular chronicity). Conclusion TI identifies lupus nephritis patients at greatest risk for progression to renal failure. The immunological mechanisms underlying TI may provide novel targets for therapeutic intervention.

HS1, the leukocyte-specific homolog of cortactin, regulates F-actin in vitro and is phosphorylated in response to TCR ligation, but its role in lymphocyte activation has not been addressed. We demonstrate that HS1-deficient T cells fail to accumulate F-actin at the immune synapse (IS) and, upon TCR ligation, form actin-rich structures that are disordered and unstable. Early TCR activation events are intact in these cells, but Ca2+ influx and IL-2 gene transcription are defective. Importantly, HS1 tyrosine phosphorylation is required for its targeting to the IS and for its function in regulating actin dynamics and IL-2 promoter activity. Phosphorylation also links HS1 to multiple signaling proteins, including Lck, PLCgamma1, and Vav1, and is essential for the stable recruitment of Vav1 to the IS. Taken together, our studies show that HS1 is indispensable for signaling events leading to actin assembly and IL-2 production during T cell activation.