T-follicular helper (Tfh) cells, a specialized subset of CD4⁺ cells, are the immune mediators connecting cellular and humoral immunity, as they lead B-cell proliferation within germinal centers, and orchestrate their response, including activation, class switching, and production of a diverse array of high-affinity antibodies. Their interactions with B cells is regulated by a wide complex of transcriptional and cytokine-driven pathways. A major contribution of Tfh cells to autoimmune diseases is through their production of cytokines, particularly IL-21, which supports the proliferation and differentiation of autoreactive B cells. Elevated levels of circulating Tfh-like cells and IL-21 have been observed in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) correlating strongly with disease severity and autoantibody levels. The feedback loop between Tfh cells and IL-21 or other signal pathways, such as Bcl-6, ICOS, and PD-1, not only sustains Tfh cell function but also drives the continuous expansion of autoreactive B cells, leading to chronic inflammation through the production of high-affinity pathogenic autoantibodies. By understanding these interactions, Tfh pathways may serve as potential therapeutic targets, with IL-21, ICOS, and PD1 blockades emerging as promising innovative therapeutic strategies to manage autoimmune diseases. Although a variety of studies have been conducted investigating the role of Tfh cells in SLE and RA, this review aims to reveal the gap in the literature regarding the role of such subpopulations in the pathogenesis of other autoimmune diseases, such as Anca-associated vasculitis (AAV), and express the need to conduct similar studies. Tfh cell-related biomarkers can be used to assess disease activity and transform autoimmune disease treatment, leading to more personalized and effective care for patients with chronic autoimmune conditions.

Kidney transplantation stands as the preferred treatment for end-stage kidney disease, significantly improving both the quality and longevity of life compared to dialysis. In recent years, the survival rates for patients and grafts have markedly increased thanks to innovative strategies in desensitization protocols for incompatible transplants and advancements in immunosuppressive therapies. For kidney transplant recipients, preventing allograft rejection is of paramount importance, necessitating the use of immunosuppressive medications. Regular follow-up appointments are essential, as monitoring the function of the kidney allograft is critical. Currently, established biomarkers such as serum creatinine, estimated Glomerular Filtration Rate (eGFR), proteinuria, and albuminuria are commonly employed to assess allograft function. However, these biomarkers have limitations, as elevated levels often indicate significant allograft damage only after it has occurred, thereby constraining treatment options and the potential for restoring graft function. Additionally, kidney biopsies, while considered the gold standard for diagnosing rejection, are invasive and carry associated risks. Consequently, the identification and development of new, sensitive, and specific biomarkers like dd-cfDNA, microRNAs (e.g., miR-21, miR-155), and sCD30 for allograft rejection are crucial. To tackle this challenge, intensive ongoing research employing cutting-edge technologies, including “omics” approaches, like genomic techniques, proteomics, or metabolomics, is uncovering a variety of promising new biomarkers.

Protocol biopsies are a fundamental component in the management of kidney transplant recipients, offering critical insights into graft health by detecting subclinical pathological changes undetectable through routine clinical and laboratory assessments. Conducted at predetermined intervals, these biopsies enable early identification of subclinical rejection, chronic allograft nephropathy, drug-induced toxicities, viral infections such as BK polyomavirus nephropathy, and recurrence of primary glomerular diseases. Early detection facilitates timely therapeutic interventions, including immunosuppressive regimen adjustments, which are pivotal in preserving graft function and improving long-term outcomes. While the optimal timing and frequency of protocol biopsies vary, early post-transplant biopsies within the first year are widely advocated. High-risk groups, including ABO- and HLA-incompatible recipients and those with recurrent primary nephropathies, particularly benefit from surveillance biopsies. Despite the invasive nature and associated risks of biopsy procedures, most experts agree that the benefits outweigh the risks in selected populations. However, the role of routine protocol biopsies in low-risk patients remains debated due to unclear long-term outcome improvements and resource considerations. Retrospective observational studies have demonstrated the ability of protocol biopsies to detect subclinical pathological changes such as rejection, drug toxicity, viral infections, and recurrent diseases before clinical or laboratory abnormalities appear. These studies also highlight the impact of biopsy-guided interventions on graft survival and management in high-risk groups (e.g., HLA- and ABO-incompatible recipients, and patients at risk for disease recurrence). Furthermore, randomized controlled trials provide higher-level evidence showing that protocol biopsy-guided interventions improve graft function, reflected by better serum creatinine levels and glomerular filtration rates, compared to indicated biopsies alone. They also emphasize the importance of both early and late surveillance biopsies for predicting long-term outcomes. Expert opinion and consensus acknowledge the benefits of protocol biopsies for early detection and tailored management but also highlight ongoing debates regarding their routine use in low-risk patients due to risks, costs, and resource considerations. Overall, protocol biopsies represent a valuable tool for personalized graft monitoring and management, aiding in early detection of complications, guiding immunosuppressive therapy, and enhancing graft longevity. Further multicenter randomized trials are needed to refine guidelines and optimize their clinical utility.

T-follicular helper (Tfh) cells, a specialized subset of CD4+ cells, are the immune mediators connecting cellular and humoral immunity, as they lead B cell proliferation within germinal centers, and orchestrate their response, including activation, class switching, and production of a diverse array of high affinity antibodies. Their interactions with B cells is regulated by a wide complex of transcriptional and cytokine-driven pathways. A major contribution of Tfh cells to autoimmune diseases is through their production of cytokines, particularly IL-21, which supports the proliferation and differentiation of autoreactive B cells. Elevated levels of circulating Tfh-like cells and IL-21 have been observed in patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) correlating strongly with disease severity and autoantibody levels. The feedback loop between Tfh cells and IL-21 or other signal pathways, such as Bcl-6, ICOS and PD-1, not only sustains Tfh cell function but also drives the continuous expansion of autoreactive B cells, leading to chronic inflammation through production of high affinity pathogenic autoantibodies. By understanding these interactions, Tfh pathways may serve as potential therapeutic targets, with IL-21, ICOS, PD1 blockade emerging as promising innovative therapeutic strategies to manage autoimmune diseases. Although a variety of studies have been conducted investigating the role of Tfh cells in SLE and RA, this review is an aim to reveal the gap in the literature regarding the role of such subpopulations in the pathogenesis of other autoimmune diseases such as Anca-Associated vasculitis (AAV) and also express the need for conducting similar studies. Tfh cell-related biomarkers can be used to assess disease activity and transform autoimmune disease treatment, leading to more personalized and effective care for patients with chronic autoimmune conditions.

Kidney transplantation stands as the preferred treatment for end-stage kidney disease, significantly improving both the quality and longevity of life compared to dialysis. In recent years, the survival rates for patients and grafts have markedly increased thanks to innovative strategies in desensitization protocols for incompatible transplants and advancements in immunosuppressive therapies. Although the initial expenses associated with transplantation may exceed those of dialysis, it proves to be more cost-effective in the long run. Despite its numerous benefits, the widespread adoption of kidney transplantation faces several challenges, notably a scarcity of donated organs, financial limitations, and unequal access among various populations. Additionally, there is a shortage of healthcare professionals equipped with the requisite expertise. For kidney transplant recipients, preventing allograft rejection is of paramount importance, necessitating the use of immunosuppressive medications. Regular follow-up appointments are essential, as monitoring the function of the kidney allograft is critical. Currently, established biomarkers such as serum creatinine, estimated Glomerular Filtration Rate (eGFR), proteinuria, and albuminuria are commonly employed to assess allograft function. However, these biomarkers have limitations, as elevated levels often indicate significant allograft damage only after it has occurred, thereby constraining treatment options and the potential for restoring graft function. Additionally, kidney biopsies, while considered the gold standard for diagnosing rejection, are invasive and carry associated risks. Consequently, the identification and development of new, sensitive, and specific biomarkers for allograft rejection are crucial. To tackle this challenge, intensive ongoing research employing cutting-edge technologies, including “omics” approaches, is uncovering a variety of promising new biomarkers.