Tonsillar IF-Tfh Cells Linked to IgA Nephropathy Activity
Key Takeaways
- Tonsils removed from patients with IgAN at two Japanese hospitals had a higher IF-Tfh fraction than tonsils from recurrent tonsillitis, palmoplantar pustulosis, or obstructive sleep apnea syndrome donors.
- Greater tonsillar IF-Tfh frequency in IgAN was associated with lower eGFR, higher BUN, and higher qualitative urine-protein levels.
- IF-Tfh frequency tracked with class-switched memory B-cell frequency, while their cocultures increased antibody secretion in IgAN but not recurrent tonsillitis.
- IgAN tonsillar IF-Tfh cells showed an effector-memory-like transcriptional pattern distinct from that in recurrent tonsillitis, without establishing kidney causation.
For their Frontiers in Immunology study, Sugaya and colleagues examined tonsillectomy specimens from Sapporo Medical University Hospital and JR Sapporo Hospital in Japan. Donors included 54 patients with IgAN and patients with recurrent tonsillitis, palmoplantar pustulosis, or obstructive sleep apnea syndrome. Flow cytometry characterized interfollicular T follicular helper (IF-Tfh) cells among memory helper T cells and class-switched memory B cells by their surface markers. Investigators related tonsillar cell frequencies to renal measurements and cocultured sorted autologous T-cell and memory B-cell subsets from IgAN and recurrent tonsillitis donors for 10 days. They measured galactose-deficient immunoglobulin A1 (Gd-IgA1) and immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies against Thomsen-nouveau (Tn) antigen in culture supernatants. They also compared IF-Tfh transcriptional profiles and separately assessed circulating helper T-cell subsets.
IF-Tfh cells accounted for 34.3% ± 5.7% of tonsillar cluster of differentiation 4–positive (CD4+) T cells in IgAN, versus 27.3% ± 8.4% in recurrent tonsillitis; frequencies in the other two comparator groups were also lower. Within IgAN, greater IF-Tfh frequency correlated with lower estimated glomerular filtration rate (eGFR) and higher blood urea nitrogen (BUN); it was also associated with higher qualitative urine-protein levels, and its creatinine association was weaker. Germinal-center T follicular helper-cell frequencies were lower than in recurrent tonsillitis and obstructive sleep apnea syndrome and showed the opposite renal-function pattern. Unswitched memory B cells were less frequent across IgAN tonsils than comparator tonsils. Yet within IgAN, greater unswitched-cell frequency correlated with lower eGFR and higher BUN and creatinine.
In IgAN tonsils, IF-Tfh frequency correlated specifically with class-switched memory B-cell frequency, although the B-cell frequency itself did not significantly correlate with renal measures. Autologous IgAN IF-Tfh and class-switched memory B-cell cocultures increased Gd-IgA1 and anti-Tn IgG and IgM secretion relative to tested T-cell comparators; corresponding recurrent tonsillitis cocultures did not show that effect. IF-Tfh cells did not increase anti-Tn IgM secretion by unswitched memory B cells under the tested conditions. IgAN-derived IF-Tfh cells also had a distinct, effector-memory-like transcriptional profile compared with recurrent tonsillitis cells.
Selection for tonsillectomy across several indications limits how broadly these Japanese tonsillar findings apply. Cell frequencies and renal measures were assessed as associations, while coculture tested antibody production outside patients; smaller culture and blood subsets further constrain interpretation. Neither tonsillectomy benefit nor the efficacy of IF-Tfh-directed treatment was assessed. These measurements do not establish that IF-Tfh activity causes progressive kidney injury.
Sugaya and colleagues interpreted the expanded tonsillar IF-Tfh compartment as a possible contributor to abnormal antibody responses in IgAN through interaction with class-switched memory B cells. That interaction was tested in vitro, while its relationship to kidney injury remains observational.
Clinician Questions
Which patients with IgA nephropathy were excluded from the tonsillar IF-Tfh and kidney-function correlation analyses?
Sugaya and colleagues excluded patients with IgAN who were younger than 18 years or had eGFR below 30 mL/min/1.73 m² from the renal correlation analyses, limiting the population to which the tonsillar IF-Tfh associations apply.
Do circulating CD4+ T-cell patterns mirror tonsillar IF-Tfh activity in IgA nephropathy?
Among patients with IgAN assessed in blood, tonsillar IF-Tfh frequencies correlated positively with circulating conventional, peripheral-helper, and follicular-helper CD4+ T-cell subset frequencies. Only the circulating conventional subset correlated inversely with eGFR, and overall circulating subset frequencies were similar to those in healthy controls. These associations were not established as a monitoring test.
Where do tonsillar IF-Tfh cells interact with class-switched memory B cells in IgA nephropathy?
The precise location of IF-Tfh and class-switched memory B-cell interactions in IgAN tonsils was not established. The authors discussed interfollicular or perifollicular regions as possible sites; coculture did not locate the interaction within tonsillar tissue.
Recommended Reading
- For more on IgAN disease pathways: Decoding IgA Nephropathy: From Suspicion to Solution
- For more on B-cell biology in IgAN: Targeting BAFF and APRIL in IgA Nephropathy