Systemic lupus erythematosus (SLE) is a complex autoimmune disease, characterized by considerable changes in peripheral lymphocyte structure and function, that plays a critical role in commencing and reviving the inflammatory and immune signaling pathways. In healthy individuals, B lymphocytes have a major role in guiding and directing defense mechanisms against pathogens. Certain changes in B lymphocyte phenotype, including alterations in surface and endosomal receptors, occur in the presence of SLE and lead to dysregulation of peripheral B lymphocyte subpopulations. Functional changes are characterized by loss of self-tolerance, intra- and extrafollicular activation, and increased cytokine and autoantibody production. T lymphocytes seem to have a supporting, rather than a leading, role in the disease pathogenesis. Substantial aberrations in peripheral T lymphocyte subsets are evident, and include a reduction of cytotoxic, regulatory, and advanced differentiated subtypes, together with an increase of activated and autoreactive forms and abnormalities in follicular T cells. Up-regulated subpopulations, such as central and effector memory T cells, produce pre-inflammatory cytokines, activate B lymphocytes, and stimulate cell signaling pathways. This review explores the pivotal roles of B and T lymphocytes in the pathogenesis of SLE and Lupus Nephritis, emphasizing the multifaceted mechanisms and interactions and their phenotypic and functional dysregulations.

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.

Lupus nephritis (LN), a chronic inflammatory disease, is characterized by the substantial disruption of immune homeostasis. This study examines its effects on the T lymphocyte phenotype and, particularly, its senescence- and exhaustion-related immune alterations. T cell subpopulations were determined with flow cytometry in 30 LN patients and 20 healthy controls (HCs), according to the expression of senescence- (CD45RA, CCR7, CD31, CD28, CD57), and exhaustion- (PD1) related markers. The immune phenotype was associated with disease activity and renal histology. LN patients were characterized by pronounced lymphopenia, mainly affecting the CD4 compartment, with a concurrent reduction in the naïve, central and effector memory subsets compared to the HCs. In the CD8 compartment, the naïve subsets were significantly lower than that of the HCs, but a shift in the T cells occurred towards the central memory population. CD4+PD1+ and CD8+PD1+ cells were increased in the LN patients compared to the HCs. However, in CD4 T cells, the increase was limited to CD45RA+, whereas in CD8 T cells, both CD45RA+ and CD45RA− subsets were affected. Disease activity was correlated with CD4+PD1+ and highly differentiated CD4+CD28-CD57+ cells. Histology was only associated with CD4 T cell disturbances, with stage IV presenting reduced naïve and increased senescent subsets. Exhausted T lymphocyte subpopulations predominate within LN patients, while the T cell phenotype varies depending on disease activity.

Immunosenescence encompasses a spectrum of lymphocyte phenotypic alterations. The aim of the study was to evaluate immunosenescent effect of two different forms of chronic inflammation, Systemic Lupus Erythematosous (SLE), a systemic autoimmune disease, and End-Stage Kidney Disease (ESKD), a chronic inflammatory disorder. Certain lymphocyte surface molecules, including CD31, CD45RA, CCR7, CD28, CD57, for T, and IgD, CD27 for B lymphocytes, were analyzed by flow cytometry in 30 SLE and 53 ESKD patients on hemodialysis (HD), and results were compared to 31 healthy controls (HC) of similar age, gender, and nationality. Significant Lymphopenia was evident in both SLE and ESKD-HD patients, compared to HC, affecting B cells 75.4 (14.4–520.8), 97 (32–341), and 214 (84–576) cells/μL, respectively, p < 0.0001, and CD4 cells 651.2 (71.1–1478.2), 713 (234–1509), and 986 (344–1591) cells/μL, respectively, p < 0.0001. The allocation of B cell subpopulations was remarkably different between SLE and ESKD-HD patients. SLE showed a clear shift to senescence (CD19IgD-CD27−) cells, compared to ESKD-HD and HC, 11.75 (10)% vs. 8 (6) vs. 8.1 (10), respectively. Regarding T lymphocytes, Central Memory CD8 cells predominated in both SLE and ESKD-HD patients compared to HC, 53 (50)%, 52 (63), and 24 (64)%, respectively, while ESKD-HD but not SLE patients also had increased expression of CD4CD28− and CD8CD28− cells. In conclusion, both diseases are followed by significant lymphopenia; however, the senescent phenomenon affects the B lymphocyte compartment in SLE patients and T lymphocytes in ESKD-HD patients.

The recommendations in the Kidney Disease: Improving Global Outcomes (KDIGO) 2021 guidelines regarding Idiopathic Membranous Nephropathy (IMN) management include significant changes as compared to those published in 2012. According to the recent guidelines, a biopsy is not always needed for IMN diagnosis; since diagnosis can be allowed for by the detection of circulating antibodies against the M-type transmembrane phospholipase A2 receptor (anti-PLA2R). Moreover, alterations in anti-PLA2R concentrations, along with other serum and urinary markers, may guide further follow-up. The findings of numerous recent studies which compared different immunosuppressive treatments resulted in substantial changes in treatment indications in the KDIGO 2021 guidelines, suggesting the stratification of patients into four risk categories. The definition of resistant cases and relapses was likewise modified. All the above will lead to a more granular and personalized approach, whose results need to be tested over time. In this commentary, we discuss the changes in the 2012 and 2021 guidelines, adding information from the most recent literature. Graphical

Background: The response to vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) varies depending on comorbidities. This study evaluated the clinical and immunological factors affecting the humoral response of patients with end stage renal disease (ESRD) to the BNT162b2 vaccine. Methods: Humoral immunity was evaluated in 54 ESRD patients using serum levels of anti-receptor-binding domain (RBD) and neutralizing antibodies (NAbs), measured by chemiluminescent immunoassay 30 (T1), 60 (T2), and 120 (T3) days after the second vaccine dose. The results were correlated to baseline patient T-and B-lymphocyte sub populations determined by flow cytometry. Results: The proportion of seroconverted patients based on the NAb titer decreased from 83.3% at tau 1 to 53.7% at tau 3. Age was negatively correlated to the NAb titer at T1 and tau 2. Patients receiving hemodiafiltration had higher NAb titers at T3. Diabetes was associated with a lower response rate at T3. Univariate analysis revealed a positive correlation be-tween the naive CD4 T-lymphocyte population and RBD titer at T1 and the NAb titer at T3, with no association observed with naive CD8 T lymphocytes. NAb titers at T3 were significantly correlated with late-differentiated CD4 T lymphocytes and terminally differen-tiated effector memory cells re-expressing CD45RA (TEMRA) CD8 T lymphocytes. RBD levels were positively correlated with naive and memory B-lymphocyte counts at T3. Conclusions: Age, diabetes, and hemodialysis prescription had significant impacts on the response to vaccination. T-and B-lymphocyte phenotypes are major determinants of the humoral response potency to SARS-CoV-2 vaccination with BNT162b2 in patients with ESRD.