Dendritic cells,T cells and their interaction in rheumatoid arthritis

Dendritic cells (DCs) are the key professional antigen-presenting cells which bridge innate and adaptive immune responses, inducing the priming and differentiation of naive to effector CD4⁺ T cells, the cross-priming of CD8⁺ T cells and the promotion of B cell antibody responses. DCs also play a critical role in the maintenance of immune homeostasis and tolerance. DC–T cell interactions underpin the generation of an autoimmune response in rheumatoid arthritis (RA). Here we describe the function of DCs and review evidence for DC and T cell involvement in RA pathogenesis, in particular through the presentation of self-peptide by DCs that triggers differentiation and activation of autoreactive T cells. Finally, we discuss the emerging field of targeting the DC–T cell interaction for antigen-specific immunotherapy of RA.     

Autophagy plays a protective role as an anti‐oxidant system in human T cells and represents a novel strategy for induction of T‐cell apoptosis

Autophagy is an intracellular degradation system that plays an important role in T‐cell survival. However, the precise mechanism linking autophagy and cell death in primary human T cells is unclear because methods for monitoring autophagy in small numbers of primary human cells remain controversial. We established a novel method for assessing autophagy in activated human T cells using a retroviral GFP–LC3 expression system. We found that autophagy was induced after TCR stimulation and that autophagy‐defective naïve CD4⁺ T cells were susceptible to apoptosis through the intrinsic apoptotic pathway. Enhanced apoptosis of autophagy‐defective T cells resulted from accumulation of ROS due to impaired mitophagy. We also demonstrated that effector memory CD4⁺ T cells had lower autophagic activity than naïve CD4⁺ T cells, which contributed to their enhanced apoptosis due to increased ROS. Moreover, blocking autophagy increased intracellular mitochondrial volume and ROS levels in activated T cells. These results suggest a protective role of autophagy as an anti‐oxidant system in activated human T cells. The combination of an autophagy blocker and a mitochondrial electron transport chain inhibitor has a synergistic effect on T‐cell death, which could be a novel strategy for induction of T‐cell apoptosis.     

Lymph node biopsy analysis reveals an altered immunoregulatory balance already during the at‐risk phase of autoantibody positive rheumatoid arthritis

The balance between proinflammatory and regulatory CD4⁺ T cells is tightly controlled in lymphoid organs. In autoimmune diseases this balance is altered in the periphery and target tissue of patients. However, not much is known about the balance initiated in lymphoid organs during the development of disease. Since systemic autoimmunity is present years before the clinical manifestations of rheumatoid arthritis (RA), it is possible to study the immunoregulatory balance during the earliest (preclinical) phases of disease. Here, we report for the first time the frequency and phenotype of proinflammatory and regulatory CD4⁺ T cells in lymph node biopsies obtained from autoantibody positive individuals at risk for developing RA, patients with established disease and healthy controls. The frequency of proinflammatory LN Th1 cells was increased in RA patients compared with HCs, while the frequency of regulatory T cells was lower in LN biopsies of RA‐risk individuals. Upon in vitro stimulation LN CD4⁺ T cells produced lower levels of proinflammatory cytokines, IFN‐γ and IL‐17A, in both RA‐risk individuals and early RA patients. This study shows that already during the earliest phases of systemic autoimmunity the immunoregulatory balance between proinflammatory and regulatory CD4⁺ T cells is altered in LN tissue.     

A preliminary study on the characterization of follicular helper T (Tfh) cells in rheumatoid arthritis synovium

Rheumatoid arthritis (RA) is a chronic and systematic autoimmune inflammatory disease. Recently, a novel T cell subset, follicular helper CD4 T cell (Tfh cells) was found in relation to the pathogenesis and progression of RA, and increased numbers of circulating Tfh cells were found in RA patients. However, there is little evidence regarding the localization of Tfh cells in synovium tissues from RA patients, owing to the lack of an available method to characterize their localization in tissue. The aim of our present study was to characterize the Tfh cells in rheumatoid synovium tissues from RA patients by using immunohistochemistry and triple-fluorescence immunostaining methods. Our results showed that specific staining of CD4, CXCR5 and ICOS could be found on infiltrating immune cells in rheumatoid synovium tissues. The use of triple-fluorescence immunostaining and confocal laser scanning showed immunolocalization of CD4⁺CXCR5⁺ICOS⁺T cells (Tfh cells) in the rheumatoid synovium tissues, whereas these signals were absent in osteoarthritis (OA) synovium and in normal synovium tissues. Thus the data from our present preliminary study support the notion that CD4⁺CXCR5⁺ICOS⁺Tfh cells could be found in rheumatoid synovium tissues from RA patients, indicating the possibility that this T cell subset in synovium tissues may have important roles in the pathogenesis and progression of RA.     

Activating NK‐cell receptors co‐stimulate CD4+CD28− T cells in patients with rheumatoid arthritis

Effector T‐cell responses can be modulated by competing positive or negative signals transduced by NK‐cell receptors (NKR). In the CD4⁺ T‐cell population, the expression of NKR is primarily found in the CD4⁺CD28⁻ T‐cell subset, also known as CD28^null T cells. These T cells are frequently found in rheumatoid arthritis (RA) and other inflammatory disorders, suggesting that signaling through NKR may play a role in the autoimmune reaction. Here we aimed to dissect the phenotype and function of NKR‐expressing CD4⁺CD28⁻ T cells in patients with RA. By analyzing a broad array of NKR on CD4⁺CD28⁻ T cells we found a significant expression of the co‐activating receptors 2B4 (CD244), DNAM‐1 (CD226), and CRACC. Pair‐wise ligations of 2B4 with DNAM‐1 and/or NKG2D lead to increased effector functions of primary CD4⁺CD28⁻ T cells to suboptimal levels of anti‐CD3 stimulation. Using multi‐parameter flow cytometry, we demonstrate that such co‐ligation led to an increased magnitude in overall responsiveness without changing qualitative aspects of the response. Altogether these results demonstrate a pattern of additive effects in NKR‐mediated functional modulation of CD4⁺CD28⁻ T cells in RA. This may have consequences for the inflammatory responses imposed by these cells, thus influencing disease manifestations.     

Elevated circulating Th17 and follicular helper CD4+ T cells in patients with rheumatoid arthritis

It remains not fully elucidated the potential functions of Th17 cells and follicular helper T (Tfh) cells and secreting cytokines in the pathogenesis of rheumatoid arthritis (RA) and their association with disease activity. In this study, the frequencies of Th17 and Tfh cells were determined by flow cytometry, and the levels of interleukin (IL)‐17, IL‐21, and IL‐22 were measured by ELISA in RA patients with different disease activities. The dynamic changes of cell subsets were also detected in response to disease‐modify antirheumatic drugs (DMARDs) therapy. The percentages of CD3⁺CD4⁺IL‐17A⁺ (Th17) cells and CD3⁺CD4⁺CXCR5⁺ICOS^high (Tfh) cells, as well as the concentrations of IL‐17, IL‐21, and IL‐22 were significantly elevated in RA patients than those in healthy individuals. Furthermore, Tfh cells, IL‐21, and IL‐22 in the serum was positively correlated with the values of disease activity score. Concentrations of IL‐21 and IL‐22 in the serum were remarkably reduced following the DMARDs therapies. Our data suggested that Th17 cells, Tfh cells as well as the secreting cytokines may be involved in the pathogenesis of RA. The frequency of circulating Tfh cells and the productions of IL‐21 and IL‐22 were associated with the disease activity of RA patients, and might be potential therapeutic targets for treatment of RA.     

Relationship of CD146 expression to secretion of interleukin (IL)‐17, IL‐22 and interferon‐γ by CD4+ T cells in patients with inflammatory arthritis

Expression of the adhesion molecule, CD146/MCAM/MelCAM, on T cells has been associated with recent activation, memory subsets and T helper type 17 (Th17) effector function, and is elevated in inflammatory arthritis. Th17 cells have been implicated in the pathogenesis of rheumatoid arthritis (RA) and spondyloarthritides (SpA). Here, we compared the expression of CD146 on CD4⁺ T cells between healthy donors (HD) and patients with RA and SpA [ankylosing spondylitis (AS) or psoriatic arthritis (PsA)] and examined correlations with surface markers and cytokine secretion. Peripheral blood mononuclear cells (PBMC) were obtained from patients and controls, and synovial fluid mononuclear cells (SFMC) from patients. Cytokine production [elicited by phorbol myristate acetate (PMA)/ionomycin] and surface phenotypes were evaluated by flow cytometry. CD146⁺CD4⁺ and interleukin (IL)‐17⁺CD4⁺ T cell frequencies were increased in PBMC of PsA patients, compared with HD, and in SFMC compared with PBMC. CD146⁺CD4⁺ T cells were enriched for secretion of IL‐17 [alone or with IL‐22 or interferon (IFN)‐γ] and for some putative Th17‐associated surface markers (CD161 and CCR6), but not others (CD26 and IL‐23 receptor). CD4⁺ T cells producing IL‐22 or IFN‐γ without IL‐17 were also present in the CD146⁺ subset, although their enrichment was less marked. Moreover, a majority of cells secreting these cytokines lacked CD146. Thus, CD146 is not a sensitive or specific marker of Th17 cells, but rather correlates with heterogeneous cytokine secretion by subsets of CD4⁺ helper T cells.     

CD147 modulates the differentiation of T‐helper 17 cells in patients with rheumatoid arthritis

The role of CD147 in regulation of rheumatoid arthritis (RA) is not fully elucidated. The aim of this study was to investigate the effect of cell‐to‐cell contact of activated CD14⁺ monocytes with CD4⁺ T cells, and the modulatory role of CD147 on T‐helper 17 (Th17) cells differentiation in patients with RA. Twenty confirmed active RA patients and twenty normal controls were enrolled. CD4⁺ T cells and CD14⁺ monocytes were purified by magnetic beads cell sorting. Cells were cultured under different conditions in CD4⁺ T cells alone, direct cell‐to‐cell contact co‐culture of CD4⁺ and CD14⁺ cells, or indirect transwell co‐culture of CD4⁺/CD14⁺ cells in response to LPS and anti‐CD3 stimulation with or without anti‐CD147 antibody pretreatments. The proportion of IL‐17‐producing CD4⁺ T cells (defined as Th17 cells) was determined by flow cytometry. The levels of interleukin (IL)‐17, IL‐6, and IL‐1β in the supernatants of cultured cells were measured by ELISA. The optimal condition for in vitro induction of Th17 cells differentiation was co‐stimulation with 0.1 μg/mL of LPS and 100 ng/mL of anti‐CD3 for 3 days under direct cell‐to‐cell contact co‐culture of CD4⁺ and CD14⁺ cells. Anti‐CD147 antibody reduced the proportion of Th17 cells, and also inhibited the productions of IL‐17, IL‐6, and IL‐1β in PBMC culture from RA patients. The current results revealed that Th17 differentiation required cell‐to‐cell contact with activated monocytes. CD147 promoted the differentiation of Th17 cells by regulation of cytokine production, which provided the evidence for pathogenesis and potential therapeutic targets for RA.     

类风湿关节炎CD4+CD28-T细胞与淋巴细胞凋亡的相关性研究

目的: 研究类风湿关节炎(RA)患者外周血CD4⁺CD28^-T细胞比例与淋巴细胞凋亡异常的相关性。方法: 采用流式细胞术三色分析法检测50例患者和50例健康志愿者的外周血淋巴细胞中CD4⁺CD28^-T细胞比例;通过加入PHA孵育检测RA病人外周淋巴细胞和正常对照的淋巴细胞对激活诱导细胞死亡(AICD)易感性差异;分析CD4⁺CD28^-T细胞比例与外周血淋巴细胞凋亡率的相关性。结果: RA组CD4⁺CD28^-T细胞比例的均数明显高于健康对照组(7.79%±3.52% vs 1.89%±1.78%,P<0.05)。RA组病人外周血淋巴细胞的AICD凋亡率低于健康对照组(11.38%±5.73% vs 19.46%±6.32%,P<0.05)。Spearman相关分析结果显示CD4⁺CD28^-T细胞比例与外周血淋巴细胞AICD凋亡率负相关(r=-0.433,P<0.01)。结论: RA患者外周血中CD4⁺CD28^-T细胞比例增多,活化淋巴细胞生存期延长,这可能参与RA的发病机制。     

Rheumatoid arthritis fibroblast‐like synoviocytes co‐cultured with PBMC increased peripheral CD4+CXCR5+ICOS+ T cell numbers

‘Circulating’ T follicular helper cells (Tfh), characterized by their surface phenotypes CD4⁺chemokine receptor 5 (CXCR5)⁺ inducible co‐stimulatory molecule (ICOS)⁺, have been identified as the CD4⁺ T cell subset specialized in supporting the activation, expansion and differentiation of B cells. Fibroblast‐like synoviocytes (FLS) are critical in promoting inflammation and cartilage destruction in rheumatoid arthritis (RA), and the interaction between FLS and T cells is considered to facilitate FLS activation and T cell recruitment. However, it remains unknown whether RA‐FLS co‐cultured with activated peripheral blood mononuclear cells (PBMC) has immunoregulatory effects on peripheral Tfh. In the present study, we co‐cultured RA‐FLS with or without anti‐CD3/CD28‐stimulated PBMC. The results showed that RA‐FLS co‐cultured with stimulated PBMC could increase the numbers of CD4⁺CXCR5⁺ICOS⁺ T cells of RA PBMC possibly via the production of interleukin (IL)‐6, a critical cytokine involved in the differentiation of Tfh cells. We also observed increased reactive oxygen species (ROS) levels in the co‐culture system of RA‐FLS and PBMC. The percentage of CD4⁺CXCR5⁺ICOS⁺ T cells was decreased when ROS production was inhibited by N‐acetyl‐L‐cysteine (NAC), a specific inhibitor which can decrease ROS production. In addition, we showed that the higher levels of tumour necrosis factor (TNF)‐α and IL‐1β in the co‐culture system and the blocking of TNF receptor 2 (TNF‐R2) and IL‐1β receptor (IL‐1βR) both decreased the numbers of CD4⁺CXCR5⁺ICOS⁺ T cells. Our study reveals a novel mechanistic insight into how the interaction of RA‐FLS and PBMC participates in the RA pathogenesis, and also provides support for the biologicals application for RA.     

Antigen‐specific over‐expression of human cartilage glycoprotein 39 on CD4+CD25+ forkhead box protein 3+ regulatory T cells in the generation of glucose‐6‐phosphate isomerase‐induced arthritis

Human cartilage gp‐39 (HC gp‐39) is a well‐known autoantigen in rheumatoid arthritis (RA). However, the exact localization, fluctuation and function of HC gp‐39 in RA are unknown. Therefore, using a glucose‐6‐phosphate isomerase (GPI)‐induced model of arthritis, we investigated these aspects of HC gp‐39 in arthritis. The rise in serum HC gp‐39 levels was detected on the early phase of GPI‐induced arthritis (day 7) and the HC gp‐39 mRNA was increased significantly on splenic CD4⁺T cells on day7, but not on CD11b⁺cells. Moreover, to identify the characterization of HC gp‐39⁺CD4⁺T cells, we assessed the analysis of T helper (Th) subsets. As a result, HC gp‐39 was expressed dominantly in CD4⁺CD25⁺ forkhead box protein 3 (FoxP3)⁺ refulatory T cells (T_reg), but not in Th1, Th2 or Th17 cells. Furthermore, to investigate the effect of HC gp‐39 to CD4⁺T cells, T cell proliferation assay and cytokine production from CD4⁺T cells using recombinant HC gp‐39 was assessed. We found that GPI‐specific T cell proliferation and interferon (IFN)‐γ or interleukin (IL)‐17 production were clearly suppressed by addition of recombinant HC gp‐39. Antigen‐specific over‐expression of HC gp‐39 in splenic CD4⁺CD25⁺ FoxP3⁺ T_reg cells occurs in the induction phase of GPI‐induced arthritis, and addition of recombinant HC gp‐39 suppresses antigen‐specific T‐cell proliferation and cytokine production, suggesting that HC gp‐39 in CD4⁺ T cells might play a regulatory role in arthritis.     

Autoimmune arthritis induces paired immunoglobulin‐like receptor B expression on CD4+ T cells from SKG mice

The chronic, destructive autoimmune arthritis in SKG mice, which closely resembles human rheumatoid arthritis, is the result of self‐reactive T cells escaping thymic deletion. Since the inhibitory receptor LIR‐1 is up‐regulated on auto‐reactive T cells in human rheumatoid arthritis, the role of its murine ortholog PIR‐B was investigated. Peripheral CD4⁺ T cells from SKG mice were found to frequently express PIR‐B, and this population produces more frequently IL‐17 upon in vitro stimulation compared to PIR‐B^? cells. A much larger fraction of PIR‐B⁺ T cells, however, was found to secret no IL‐17, but IFN‐γ. With regards to the clinical course of the disease, high frequencies of PIR‐B⁺ CD4⁺ T cells were found to be associated with a milder course of arthritis, suggesting that the net effect of PIR‐B expression is suppression of autoreactive T cells. Our results indicate that overexpression of PIR‐B on IL‐17‐producing SKG CD4⁺ T cells might represent an effective counter‐regulatory mechanism against the destructive potential of those cells. More importantly, a major population of PIR‐B⁺ T cells in SKG mice appears to play an inhibitory role by way of their IFN‐γ production, since high frequencies of those cells ameliorate the disease.     

Upregulated BclGL expression enhances apoptosis of peripheral blood CD4 T lymphocytes in patients with systemic lupus erythematosus

Increased lymphocyte apoptosis has been suggested to contribute to the development of systemic lupus erythematosus (SLE), but the critical factors involved in the apoptotic pathways are still unknown. By long serial analysis of gene expression (LongSAGE) profiles and microarray analyses, a novel apoptosis-related gene BclG_L expression was found significantly increased in peripheral blood CD4⁺ T cells of SLE patients, which was correlated with the enhanced CD4⁺ T cells apoptosis, anti-nuclear antibody (ANA) titer and proteinuria. In vitro, BclG_L expression could be specially upregulated by SLE serum stimulation and positively correlated with induced CD4⁺ T cell apoptosis. Enforcing BclG_L overexpression by lentivirus could directly enhance CD4⁺ T cell apoptosis, but these apoptosis-inducing effects could be partially inhibited by knockdown of BclG_L expression. Collectively, these results indicate that increased BclG_L expression may contribute to the aberrant CD4⁺ T cell apoptosis which causes an inappropriate immune response and impaired homeostasis in SLE.     

Tofacitinib treatment of rheumatoid arthritis increases senescent T cell frequency in patients and limits T cell function in vitro

Unraveling the immune signatures in rheumatoid arthritis (RA) patients receiving various treatment regimens can aid in comprehending the immune mechanisms’ role in treatment efficacy and side effects. Given the critical role of cellular immunity in RA pathogenesis, we sought to identify T-cell profiles characterizing RA patients under specific treatments. We compared 75 immunophenotypic and biochemical variables in healthy donors (HD) and RA patients, including those receiving different treatments as well as treatment-free patients. Additionally, we conducted in vitro experiments to evaluate the direct effect of tofacitinib on purified naïve and memory CD4⁺ and CD8⁺ T cells. Multivariate analysis revealed that tofacitinib-treated patients segregated from HD at the expense of T-cell activation, differentiation, and effector function-related variables. Additionally, tofacitinib led to an accumulation of peripheral senescent memory CD4⁺ and CD8⁺ T cells. In vitro, tofacitinib impaired the activation, proliferation, and effector molecules expression and triggered senescence pathways in T-cell subsets upon TCR-engagement, with the most significant impact on memory CD8⁺ T cells. Our findings suggest that tofacitinib may activate immunosenescence pathways while simultaneously inhibiting effector functions in T cells, both effects likely contributing to the high clinical success and reported side effects of this JAK inhibitor in RA.     

Elevated Th22 Cells Correlated with Th17 Cells in Patients with Rheumatoid Arthritis

Background

T-helper (Th) 22 and Th17 cells are implicated in the pathogenesis of autoimmune diseases. The roles of Th22 cells in the pathophysiology of rheumatoid arthritis (RA) remain unsettled.

Materials and Methods

CD4⁺IFN??^?IL17^?IL-22⁺ T cells (Th22 cells), CD4⁺IFN??^?IL-22^?IL17⁺ T cells (pure Th17 cells), CD4⁺IL17⁺ T cells (Th17 cells), and CD4⁺IFN??⁺ T cells (Th1 cells) in RA, osteoarthritis patients, and healthy controls were examined by flow cytometry. Plasma IL-22 and IL-17 levels were examined by enzyme-linked immunosorbent assay.

Results

Th22 cells, pure Th17 cells, Th17 cells, and interleukin-22 were significantly elevated in RA patients compared with osteoarthritis and healthy controls, but there were no significant differences regarding Th1 cells and interleukin-17. Th22 cells showed a positive correlation with interleukin-22 as well as pure Th17 cells or Th17 cells in RA patients. Additionally, the percentages of Th22 cells, pure Th17 cells as well as Th17 cells correlated positively with both C-reactive protein levels and 28-joints disease activity score.

Conclusion

Together, our results indicated a possible role of Th22 pure Th17 cells and Th17 cells in RA, and blockade of the interleukin-22 may be a reasonable therapeutic strategy for RA.     

Carbon monoxide‐treated dendritic cells decrease β1‐integrin induction on CD8+ T cells and protect from type 1 diabetes

Carbon monoxide (CO) treatment improves pathogenic outcome of autoimmune diseases by promoting tolerance. However, the mechanism behind this protective tolerance is not yet defined. Here, we show in a transgenic mouse model for autoimmune diabetes that ex vivo gaseous CO (gCO)‐treated DCs loaded with pancreatic β‐cell peptides protect mice from disease. This protection is peptide‐restricted, independent of IL‐10 secretion by DCs and of CD4⁺ T cells. Although no differences were observed in autoreactive CD8⁺ T‐cell function from gCO‐treated versus untreated DC‐immunized groups, gCO‐treated DCs strongly inhibited accumulation of autoreactive CD8⁺ T cells in the pancreas. Interestingly, induction of β1‐integrin was curtailed when CD8⁺ T cells were primed with gCO‐treated DCs, and the capacity of these CD8⁺ T cells to lyse isolated islet was dramatically impaired. Thus, immunotherapy using CO‐treated DCs appears to be an original strategy to control autoimmune disease.     

Effects of type II collagen epitope carbamylation and citrullination in human leucocyte antigen (HLA)‐DR4+ monozygotic twins discordant for rheumatoid arthritis

The aim of this study is to investigate the effect of the native, citrullinated or carbamylated type II human collagen T cell‐ and B cell‐epitopes on the adaptive immune response in rheumatoid arthritis (RA). Peripheral blood T and B cells obtained from a human leucocyte D4‐related (antigen DR4^? HLA‐DR4)⁺ woman with early RA, her healthy monozygotic twin and an unrelated HLA‐DR3⁺ woman with early RA were analysed for activation (CD154/CD69), apoptosis (annexin/7‐aminoactinomycin), cytokine production [interferon (IFN)γ/interleukin (IL)?17/IL‐4/IL‐10/IL‐6] and functional phenotype (CD45Ra/CCR7) after stimulation with the collagen native T cell epitope (T261‐273), the K264 carbamylated T cell epitope (carT261–273), the native B cell epitope (B359–369) or the R360 citrullinated B cell epitope (citB359–369), and the combinations of these. The T cell memory compartment was activated by T cell epitopes in both discordant DR4⁺ twins, but not in the DR3⁺ RA. The collagen‐specific activation of CD4⁺ T cells was induced with both the native and carbamylated T cell epitopes only in the RA twin. Both T cell epitopes also induced IL‐17 production in the RA twin, but a greater IL‐4 and IL‐10 response in the healthy twin. The citrullinated B cell epitope, particularly when combined with the carbamylated T cell epitope, induced B cell activation and an increased IL‐6/IL‐10 ratio in the RA twin compared to a greater IL‐10 production in the healthy twin. Our data suggest that circulating collagen‐specific T and B cells are found in HLA‐DR4⁺ subjects, but only RA activated cells express co‐stimulatory molecules and produce proinflammatory cytokines. Carbamylation and citrullination further modulate the activation and cytokine polarization of T and B cells.     

The potential of CD38 protein as a target for autoimmune diseases

Cluster of differentiation 38 (CD38) is a multifunctional cell surface protein involved in nicotinamide adenine dinucleotide (NAD⁺) homeostasis in types of cells and tissues, which can be found in many immune cells and non-immune cells. Previous studies have shown that CD38 plays an important role in regulating innate immunity. Recently, many studies have revealed the importance of CD38 in autoimmune diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), type 1 diabetes (T1D) and inflammatory bowel disease, among others. In this report, we will briefly discuss the complex immunological functions of CD38 and focus on recent advances in the role of CD38 in the development and pathogenesis of autoimmune diseases, as well as their potential as therapeutic targets for systemic diseases, intending to make a comprehensive understanding of CD38 and its promising therapeutic potential in these systemic diseases.