Abstract: TH-PO821
T-Follicular Like Helper Cells Enhance IgA Secretion in IgA Nephropathy
Session Information
- Glomerular Diseases: Immunology and Inflammation - I
October 25, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1202 Glomerular Diseases: Immunology and Inflammation
Authors
- Steers, Nicholas J., Columbia University, New York, New York, United States
- Wold, Jaclyn L., Columbia University Medical Center, New York, New York, United States
- Marasa, Maddalena, Columbia University, New York, New York, United States
- Gharavi, Ali G., Columbia University, New York, New York, United States
Background
Dysregulated IgA1 response is a central defect in the development of IgA Nephropathy (IgAN), but is it not clear if the altered IgA1 response is attributed to excessive self-proliferation of IgA+ B-cells or an imbalance in the B-cell-T-cell interactions. We investigated the mechanism of IgA production, focusing on the function of T-follicular helper (Tfh) cells, which have recently been shown to play an essential role in antibody response.
Methods
We studied 15 IgAN patients and 20 healthy controls (HC). IgA antibody secreting cells (ASC) were measured by flow cytometry. Naive B-cells, Naïve CD4+ T-cells and T-follicular like helper cells were sorted from the PBMC of patients, and IgA was measured from the B-cell-T-cell co-cultures.
Results
We detected a 3.6 fold increase in IgA ASC numbers and 1.6-fold increase in Tfh like cells in the peripheral blood of IgAN patients compared to HC. Both IgA ASC and Tfh like cell numbers were strongly correlated with the increased IgA and IgA1 levels in the plasma. To distinguish whether enhanced IgA production is dependent on B-cells or Tfh like cells, we performed co-culture experiments. Autologous co-culture experiments of Tfh like cells with naïve B-cells resulted in significantly increased IgA production in cells derived from IgAN patients (172.9 + 60.9 ng/ml), compared to HC (58.4 + 13.3 ng/ml). Next, we performed co-culture experiments with cells derived from two pairs of monozygotic twins who are discordant for IgAN. Co-culture of Tfh like- and naïve B-cells from monozygotic twins with IgAN and one self-declared healthy control, and as expected yielded significantly higher lgA production compared to co-culture of cells from their corresponding healthy twins. In addition, Tfh like cells from the IgAN twins significantly increased IgA production from the naïve B-cells from the healthy twins (169.5 + 31.9 ng/ml) but Tfh like cells from the one healthy twin only elicited baseline IgA production from naïve B-cells from the IgAN twins (59.3 ng/ml).
Conclusion
Our data demonstrate an independent role of T-follicular like helper cells in enhanced generation of IgA in IgAN, identifying a new important step in IgAN pathogenesis. Future studies will be directed towards identification of molecular programs leading to enhanced Tfh like cell count and activity in IgAN.
Funding
- NIDDK Support