Table 1.
Studies of Tph cells in patients with autoimmune diseases.
| Disease | Ref | Year | Patient cohort | Molecular phenotype | Main findings |
|---|---|---|---|---|---|
| RA | (7) | 2017 | Synovial tissue (n = 10), synovial fluid (n = 9), and blood (n = 42) from seropositive RA patients. | PD-1hi
CXCR5− CD4+ |
Tph↑, PD-1hiMHC II+CXCR5−↑, and PD-1hiCXCR5−ICOS+↑ in seropositive RA patients. And these cells decreased in patients whose disease activity decreased after treatment escalation. |
| (52) | 2019 | Synovial tissues from leukocyte-rich RA (n = 19) or leukocyte-poor RA (n = 17). | CD4+
PD-1+ ICOS+ |
CXCL13↑ in leukocyte-rich RA. | |
| (6) | 2013 | Synovial tissue cells from 2 patients and synovial fluid mononuclear cells from 8 patients. | CD4+
PD-1+ CXCR5− |
Synovial Tph cells expressed CXCL13. TCR induced CXCL13 production, and proinflammatory cytokines supported the long-term production of CXCL13. | |
| (48) | 2019 | Fifty-six DMARD-naïve early RA patients including seropositive RA (n = 38) and seronegative RA (n = 18). | CD4+
CXCR5− PD-1hi |
cTph↑, and they were decreased with clinical improvement. | |
| (53) | 2021 | Thirty-four seropositive RA patients, and 11 seronegative RA patients. | PD-1hi
CXCR5− CD4+ |
cTph↑, and HLA−DR+cTph↑ in seropositive RA patients. HLA−DR− Tph cells reflected the disease activity. | |
| (54) | 2020 | Synovial samples from 11 patients on anti-TNF therapy. | PD-1hi
CXCR5− CD4+ |
A lower abundance of synovial Tph cells was associated with a better response to anti-TNF therapy. | |
| SLE | (55) | 2019 | Sixty-eight SLE patients including the active group (n = 22) and the inactive group (n = 46). | PD-1+
CXCR5− CD4+ |
cTph↑, CD38+ cTph1↑, and Tph cells were correlated with lupus disease activity index and plasma cells. |
| (56) | 2019 | Patients with SLE (n = 9). | CD3+
CD4+ CD45RA− PD-1high CXCR5− |
cTph↑, cTph1↑, cTph were associated with lupus disease activity, and Tph1 cells were correlated with plasmablasts. | |
| (26) | 2019 | Lupus nephritis kidney biopsies (n = 13), lupus nephritis patients (n = 27), and PBMCs from SLE patients (n = 6). | PD-1hi
CXCR5– CD4+ |
cTph↑, and they were correlated with disease activity and CD11c+ B cells. Tph promoted B cell responses in lupus via MAF and IL-21. | |
| (57) | 2019 | SLE patients displaying class II (n = 4), III (n = 9), class IV (n = 8) lupus nephritis. | CXCR5−
CXCR3+ PD1hi CD4+ |
cTph↑, Tph↑ in the tubulointerstitial areas of patients with proliferative lupus nephritis. Tph cells provided B cell help through IL-10 and succinate. | |
| (58) | 2019 | N = 10 patients with SLE. | PD-1+
CXCR5− CD4+ |
cTph↑ in 4/10 patients. | |
| (59) | 2015 | The blood of patients with SLE (n = 49). | CD4+
TCRβ+ CD45RA− CXCR5lo |
cTph↑, and they were correlated with disease activity and plasmablasts. | |
| (60) | 2022 | PBMCs from 52 SLE patients. | CD4+
PD-1+ CXCR5− |
cTph↑, cTph/cTfh↑, and cTph cells were correlated with disease activity, serum levels of IFN-α, and renal involvement. | |
| (61) | 2022 | Ten lupus nephritis and 5 non-lupus nephritis SLE patients. | CD4+
PD-1+ CXCR5− |
cTph and cTfh did not change after rituximab. | |
| SS | (62) | 2020 | Blood and labial salivary glands biopsies from patients with SS (n = 83) and SS parotids with low-grade MALT-L (n = 15). | CD4+CD25+
CXCR5− CD4+PD1hi ICOS+ Foxp3− |
cTph↑, SG Tph↑, and they frequently coexpressed IL-21/IFN-γ, especially in parotid MALT-L. |
| (63) | 2017 | Patients with early and active primary SS (n = 15). | CD4+
CXCR5− PD-1high |
cTph↑, and they were decreased after abatacept treatment. | |
| (64) | 2018 | Blood specimens from patients with SS (n = 16). | PD-1+
CXCR5− CD4+ |
The percentage of cTph↑, but the absolute number of cTph-. | |
| (65) | 2022 | Blood specimens (n = 60) and labial gland tissue biopsy specimens (n = 10) from patients with SS. | PD-1+
CXCR5– CD4+ |
cTph↑, Tph↑ in labial gland, and cTph cells were correlated with disease activity and plasmablasts. | |
| (66) | 2021 | Blood specimens from 2 SS cohorts (n = 29 and n = 15). | CD4+
CXCR5– PD-1hi |
cTph↑, cTfh↑, but there was no correlation between ESSDAI and cTph or activated cTph cells. cTph cells were correlated with circulating plasmablasts. | |
| IgG4-RD | (64) | 2018 | Blood specimens from patients with IgG4-RD (n = 53). | PD-1+
CXCR5− CD4+ |
cTph↑, GZMA+cTph↑, cTph cells were positively correlated with serum IgG4, ratio of IgG4/IgG, number of organs involved, and sIL-2R. |
| (67) | 2021 | Patients with IgG4-RD (n = 17). | PD-1+
CXCR5− CD4+ |
CX3CR1+ cTph↑, and they were positively correlated with IgG4-RD responder index, number of organs involved, and serum level of sIL-2R. | |
| T1D | (68) | 2020 | Abatacept administration, n = 34 patients. | CXCR5−
ICOS+ PD-1+ |
cTph↑ in individuals with new-onset T1D, and they were strongly reduced after abatacept treatment. |
| (69) | 2019 | Forty-four children with newly diagnosed T1D. | CXCR5−
PD-1hi CD4+ |
cTph↑, especially in those who are seropositive for multiple autoantibodies. cTph↑ in autoantibody-positive at-risk children who later progressed to T1D. | |
| PBC | (70) | 2021 | Twenty PBC patients. | CD4+
CXCR5− PD-1+ |
cTph↑, ICOS+ cTph↑, CD28+ cTph↑, and ICOS+ cTph cells were positively correlated with AMA-M2, IgM, and plasma cell levels. |
| IgAN | (71) | 2020 | Patients with IgAN (n = 37). | CD3+CD4+
PD1hi CXCR5− |
cTph↑, and they were correlated with disease severity. cTph cells reduced after treatment. |
| JIA | (72) | 2022 | Fifty-three patients with active JIA, in whom joint puncture had been performed for intraarticular steroid injection. | PD-1high
CXCR5– HLA–DR+ CD4+ |
SF Tph cells differentiate B cell toward a CD21low/–CD11c+ phenotype in vitro, and frequencies of SF Tph cells were correlated with the appearance of SF CD21low/–CD11c+CD27–IgM– double-negative B cells in situ. |
| AIH | (73) | 2020 | Patients with AIH with (SLA-pos; n = 8) and without (SLA-neg; n = 8) anti-SLA autoantibodies. | PD-1+
CXCR5− CD4+ |
Memory Tph↑, CD45RA−PD-1+CD38+CXCR5−CD127−CD27+ subset was correlated with AIH activity. |
| DM | (74) | 2021 | Twenty-six newly diagnosed DM patients, and 15 patients were reanalyzed in remission during follow-up. | PD-1hi
CXCR5− CD4+ |
cTph↓, cTfh↓, muscular Tph↑, and cTph↑ after treatment. cTph cells were negatively correlated with inflammation levels. |
| CeD | (58) | 2019 | Patients with untreated CeD (n = 8). | PD-1+
CXCR5− CD4+ |
cTph↑ in 7/8 patients. |
| SSc | (58) | 2019 | Patients with SSc (n = 10). | PD-1+
CXCR5− CD4+ |
cTph↑ in 8/10 patients. |
| IBD | (75) | 2019 | CD flare (n = 13); CD remission (n = 11); UC flare (n = 10); UC remission (n = 10). | CD3+CD4+CD45RO+
CXCR5− PD-1+ |
Tissue Tph > cTph, Tph abundance in CD = that in UC. |
| PV | (76) | 2021 | Peripheral blood samples from 27 patients with PV. | CXCR3−
CCR6+ PD-1+ CXCR5− CD4+ |
cTph17 cells had an activated, proliferative phenotype, and the quantity of cTph17 cells were positively correlated with disease severity, plasma CXCL13 levels, and cTfh cells. |
Frequencies of Tph and Tfh cells were compared; ↓, lower level compared with controls; ↑, higher level compared with controls; -, no statistically significant difference between patients and controls; >, more than; =, no statistically significant difference between two groups.
Tph, T peripheral helper; ref, reference; RA, rheumatoid arthritis; PD-1, programmed cell death protein 1; CXCR, C‐X‐C chemokine receptor; MHC, major histocompatibility complex; ICOS, inducible T cell co-stimulator; CXCL13, C‐X‐C motif chemokine ligand 13; TCR, T-cell receptor; DMARD, disease-modify anti-rheumatic drug; cTph, circulating T peripheral helper; HLA, human leucocyte antigen; TNF, tumor-necrosis factor; SLE, systemic lupus erythematosus; PBMCs, peripheral blood mononuclear cells; IL, interleukin; IFN, interferon; cTfh, circulating follicular helper T; SS, sjögren syndrome; MALT-L, mucosa-associated lymphoid tissue lymphomas; SG, salivary gland; cTfh, circulating follicular helper T; ESSDAI, EULAR Sjogren’s syndrome disease activity index; IgG, immunoglobulin G; IgG4-RD, IgG4-related disease; GZMA, granzyme A; sIL-2R, soluble IL-2 receptor; T1D, type 1 diabetes; PBC, primary biliary cholangitis; AMA-M2, anti-mitochondrial antibodies against M2 antigen; IgAN, immunoglobulin A nephropathy; JIA, juvenile idiopathic arthritis; SF, synovial fluid; AIH, autoimmune hepatitis; SLA, anti-soluble liver antigen; DM, dermatomyositis; CeD, celiac disease; SSc, systemic sclerosis; IBD, autoimmune bowel disease; CD, Crohn’s disease; UC, ulcerative colitis; PV, psoriasis vulgaris.