. 2023 Apr 28;14:1178792. doi: 10.3389/fimmu.2023.1178792

Table 2.

Human autoimmune diseases associated with aberrant Tfh-cell function. .

Autoimmune diseases	Tfh-cell subsets	Correlated pathology
Rheumatoid arthritis	Increased CXCR5⁺PD-1⁺ Tfh cells (54–56); cTfh2 and cTfh17 cells (57); CXCR5⁻PD-1^hi Tph cells (48, 58); Decreased CXCR5⁺CD25⁺CD127^lo cTfr cells (59–61); Decreased Tfr/Tfh ratio (59–61).	Tph cells contribute to chronic autoimmune phenomena at the inflammatory foci (48, 58); Tfr/Tfh ratio is negatively correlated with CRP, ESR, ACPA, and DAS28 index (59–61).
Systemic lupus erythematosus	Increased NLRP3 active Tfh cells (62); CXCR5⁻PD-1^hi Tph cells (26, 63, 64); CXCX5⁻PD-1^hiCXCR3⁺ Tfh-like cells in blood and the tubulointerstitial areas (65); CCR6⁺IL7R⁺IL-10⁺ Tfh-like cells in peripheral blood and LN (66); CXCR5⁺FOXP3⁺ Tfr cells (67); expression of PD-1 on CXCR5⁺FOXP3⁺ Tfr cells (68); Decreased CXCR5⁺CD25⁺CD127^lo Tfr cells (69); expression of Foxp3, CTLA4, and IL-2 receptor on CXCR5⁺FOXP3⁺ Tfr cells; Increased/Decreased Tfr/Tfh ratio (69).	Tfh cells with active NLRP3 inflammasome are essential for optimal humoral responses and GC formation (62); Tph cells contribute to B-cell responses via IL-21 (26, 63, 64); CXCX5⁻PD-1^hiCXCR3⁺ Tfh-like cells provide B-cell help, independently of IL-21, by producing IL-10 and succinate (65). IL-10-producing CCR6⁺IL7R⁺ Tfh-like cells are associated with anti-dsDNA antibodies and promoted B-cell IgG production (66). Tfr cell frequency and Tfr/Tfh ratio are negatively correlated with serum IL-21 concentration, anti-dsDNA antibody levels and disease activity (69).
Sjögren’s syndrome	Increased CXCR5⁺ICOS⁺PD-1⁺ Tfh cells (70, 71); CCR7^loPD-1^hi cTfh cells (72); Tfh1, Tfh2, and Tfh17 cells in SG (71, 73); CCR9⁺ Tfh-like cells in peripheral blood and LSG (74); CXCR5⁺PD1⁺ICOS⁺Foxp3⁻ Tfh cells and CXCR5⁻PD1^hiICOS⁺Foxp3⁻ Tph cells in peripheral blood and SG (75, 76); FoxP3⁺CXCR5⁺ Tfr cells (71, 77); Decreased CXCR5⁺FoxP3⁺CD25⁺ Tfr cells (78); Decreased Tfr/Tfh ratio (78).	IL-21⁺ or ICOS⁺ Tfh cells are positively correlated with transitional B cells, plasmablasts, and plasma cells (70, 79); cTfh cells are positively correlated with disease activity scores and plasma cell percentages (72). CCR9⁺ Tfh-like cells promote IgG production and display higher levels of IFN-γ, IL-17, IL-4, and IL-21 than CXCR5⁺ Tfh cells with antigen or IL-7 stimulation (74).
Granulomatosis with polyangiitis	Increased CXCR5⁺PD-1⁺ cTfh cells (80), CD4⁺IL-21⁺, CD4⁺IL-21⁺IL-17A⁺, and CD4⁺BCL6⁺ T cells (81).	CD4⁺IL-21⁺ and CD4⁺BCL6⁺ T cells are elevated only in ANCA-positive GPA patients (81).
Multiple sclerosis	Increased cTfh1 and CXCR3⁺CCR6⁺ cTfh17.1 cells in CNS (46); CD4⁺IL-21⁺ T cells in the lesions (82), CCR7⁺ICOS⁺ cTfh cells, cTfh17 cells and cTfh17.1 cells (83–87); CXCR5⁺PD-1⁺ Tfh cells in CSF (88); Decreased cTfh1 cells and cTfh2 cells (83–87); CXCR5⁺CD25⁺PD-1⁺ FoxP3⁺/CD127⁻ or CXCR5⁺CD25^hi/+ CD127^dim/− Tfr cells in blood and CSF (85–87, 89); Decreased Tfr/Tfh ratio (87, 90).	cTfh cells secrete high level of IL-21 (85); CCR7⁺ICOS⁺ cTfh cells are positively correlated with disease activity scores, the levels of IL-21and IgG in plasma and CSF (86); cTfr cells secrete low level of IL-10 (85); Tfr cells exhibit reduced suppressive capacity in blood and CSF (85–87, 89); Tfr/Tfh ratio are negatively correlated with the levels of IgG in serum and CSF (87, 90).
Type 1 diabetes	Increased Tfh cells; Tph cells (91–95); Tfh1 cells in pancreas (96); Decreased Tfr cells in the peripheral blood, spleen and pancreatic lymph nodes (97, 98); Decreased Tfr/Tfh ratio (97, 98).	Tfh and Tph cells are associated with T1D progression by producing IL-21 and recruiting and activating B cells (91–95). Tfh1 cells promote T1D development (96). Tfr cells show attenuate suppressive ability (97, 98).

GC, germinal centers; Tfh, T follicular helper; cTfh, circulating Tfh; Tph, T peripheral helper; Tfr, T follicular regulatory; ICOS, inducible T cell co-stimulator; PD-1, programmed cell death protein-1; Foxp3, forkhead box P3; Bcl6, B-cell lymphoma 6; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; ACPA, serum anti-cyclic citrullinated peptide antibodies; DAS28, disease activity score-28; Ig, immunoglobulin; LN, lymph nodes; SG, salivary glands; LSG, labial salivary glands; ANCA, antineutrophilic cytoplasmic autoantibody; CNS, central nervous system; CSF, cerebrospinal fluid; T1D, type 1 diabetes.