Background/Purpose: Inflammatory infiltrates contain multiple cell types that could interact in myriad ways to amplify in situ immune responses. However, there currently are no methods available to quantitatively assess such interactions in human tissue.

Methods: Therefore, we developed a novel computational approach which we term cell distance mapping (CDM) that, when coupled to confocal microscopy, enabled us to quantitatively assess the spatial relationships between different cell populations.

Results: When applied to human lupus nephritis (LuN), CDM revealed that T follicular helper (T_FH)-like cells commonly infiltrated the renal tubulointerstitium with almost half in cognate pairs with B cells. Furthermore, in the absence of evident germinal center (GCs), the overall spatial organization of B cells and T_FH cells in LuN was similar to that observed in tonsil GC light zones. T_FH-like cells (CD4⁺ICOS⁺PD-1⁺) were also observed in T cell-mediated renal transplant rejection (TCMR) cases. However, the T_FH-like cells in TCMR infrequently formed cognate pairs with B cells. Furthermore, the TCMR T_FH-like cells did not organize the B cells around them. Finally, while IL-21 expression was high in tonsil GC and LuN T_FH-like cells, it was barely detectable in the T_FH-like cells infiltrating the tubulointerstitium in TCMR.

Conclusion: These results suggest that even in areas of diffuse inflammation, CDM reveals cellular organizations and inter-cell interactions associated with in situ adaptive immunity. Furthermore, we propose that CDM can discriminate between functional and non-functional T_FH cells in situ.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/quantitative-cell-distance-mapping-in-human-nephritis-reveals-organization-of-in-situ-adaptive-immune-responses/