The four Janus kinase (JAK) proteins and seven signal transducer and activator of transcription (STAT) transcription factors mediate intracellular signal transduction downstream of cytokine ...receptors, which are implicated in the pathology of autoimmune, allergic and inflammatory diseases. Development of targeted small-molecule therapies such as JAK inhibitors, which have varied selective inhibitory profiles, has enabled a paradigm shift in the treatment of diverse disorders. JAK inhibitors suppress intracellular signalling mediated by multiple cytokines involved in the pathological processes of rheumatoid arthritis and many other immune and inflammatory diseases, and therefore have the capacity to target multiple aspects of those diseases. In addition to rheumatoid arthritis, JAK inhibition has potential for treatment of autoimmune diseases including systemic lupus erythematosus, spondyloarthritis, inflammatory bowel disease and alopecia areata, in which stimulation of innate immunity activates adaptive immunity, leading to generation of autoreactive T cells and activation and differentiation of B cells. JAK inhibitors are also effective in the treatment of allergic disorders, such as atopic dermatitis, and can even be used for the COVID-19-related cytokine storm. Mechanism-based treatments targeting JAK-STAT pathways have the potential to provide positive outcomes by minimizing the use of glucocorticoids and/or non-specific immunosuppressants in the treatment of systemic immune-mediated inflammatory diseases.
Treatment of difficult-to-treat rheumatoid arthritis (D2T RA) is one of the greatest unmet needs in rheumatology. This study aims to find out preferable treatment options for a group of D2T RA ...patients who are refractory to multiple biologic and targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs).
Data were obtained from patients enrolled in the FIRST Registry who started either TNF inhibitor (TNFi), interleukin-6 receptor inhibitor, cytotoxic T-lymphocyte-associated antigen-4 immunoglobulin, or Janus-kinase inhibitor (JAKi) in the period of August 2013 to December 2020. Those who failed to ≥ 2 and ≥ 3 b/tsDMARDs were categorised as D2T RA and very D2T RA (vD2T RA), respectively. Change in Clinical Disease Activity Index (CDAI) and Health Assessment Questionnaire Disability Index were compared among the groups using propensity-based inverse probability treatment weighted (IPTW) method.
Of 2128 cases included, 353 were categorised as D2T RA. Among the D2T RA, 106 were identified as vD2T RA. JAKi showed a significant improvement in CDAI in the patients with D2T RA and vD2T RA, compared to IPTW-adjusted patients treated with the other 3 regimens. Latent class analysis of the trajectories of treatment response revealed that the proportion of a group of patients who showed poor response was lower among the JAKi subgroup than among those with other subgroups. This superiority of JAKi was more apparent among methotrexate- and glucocorticoid-free individuals. The hazard ratio of severe adverse events was comparable among the four treatment subgroups in both the D2T RA and b/tsDMARD-naïve groups.
This study compared responsiveness to different classes of b/tsDMARDs among D2T RA and vD2T RA patients who were refractory to multiple b/tsDMARDs. The results suggest JAKi is a preferable treatment choice for this type of D2T RA.
B cells play a crucial role in the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus (SLE). However, the relevance of the metabolic pathway in the differentiation of human B ...cell subsets remains unknown. In this article, we show that the combination of CpG/TLR9 and IFN-α markedly induced the differentiation of CD27
IgD
unswitched memory B cells into CD27
CD38
plasmablasts. The response was accompanied by mammalian target of rapamycin complex 1 (mTORC1) activation and increased lactate production, indicating a shift to glycolysis. However, CpG alone induced the differentiation of unswitched memory B cells into CD27
IgD
memory B cells with high cytokine production, but such differentiation was suppressed by IFN-α. AMP-activated protein kinase activation enhanced the differentiation to CD27
IgD
B cells, but it attenuated mTORC1 activation and differentiation into plasmablasts. High mTORC1 activation was noted in CD19
B cells of patients with SLE and correlated with plasmablast differentiation and disease activity. Taken together, differential metabolic reprogramming commits the differentiation of human unswitched memory B cells into plasmablasts (the combination of CpG and IFN-α amplifies mTORC1-glycolysis pathways) or CD27
IgD
memory B cells (CpG alone amplifies the AMP-activated protein kinase pathway). The former metabolic pathway may play a pivotal role in SLE.
ABSTRACT
IgG4-related disease (IgG4-RD) is a systemic disease characterized by high serum IgG4 levels, infiltration of lymphocytes and IgG4-positive plasma cells into affected tissues, and subsequent ...fibrosis, forming mass, nodular, and thickened lesions in organs. Although glucocorticoids (GCs) are the first-line treatment for IgG4-RD, the disease often relapses during dose reduction or after discontinuation of GC. Long-term treatment with GC is associated with adverse effects such as infection, osteoporosis, and atherosclerosis. Therefore, there is an urgent need to develop a treatment strategy that specifically addresses the pathogenesis of IgG4-RD. As immunocompetent cells and immune-related molecules involved in the pathogenesis of IgG4-RD are increasingly being identified, there is a growing demand for new molecular-targeted drugs that target them. In particular, favourable results have been reported for drugs that target B cells, such as anti-cluster of differentiation (CD)20 and anti-CD19 antibodies. In addition, clinical trials are underway for new therapeutic agents, such as anti-signalling lymphocytic activation molecule family 7 antibodies that target T cells and other cells.
Abstract
Cytokines are critical mediators of diverse immune and inflammatory diseases. Targeting cytokines and cytokine receptors with biologics has revolutionized the treatment of many of these ...diseases, but targeting intracellular signalling with Janus kinase (JAK) inhibitors (jakinibs) now represents a major new therapeutic advance. We are still in the first decade since these drugs were approved and there is still much to be learned about the mechanisms of action of these drugs and the practical use of these agents. Herein we will review cytokines that do, and just as importantly, do not signal by JAKs, as well as explain how this relates to both efficacy and side effects in various diseases. We will review new, next-generation selective jakinibs, as well as the prospects and challenges ahead in targeting JAKs.
T follicular helper (Tfh) cells participate in humoral immune by promoting inflammation and aiding B cells survival, proliferation, maturation, and generation autoantibodies. The plasticity of Tfh ...cells enables the immune system to adjust the direction of differentiation according to the degree of the immune response, regulate the germinal center (GC) response and maintain homeostasis. Tfh differentiation involves several signaling factors, including multiple cytokines, receptors, transcription factors and genes. The signal transducer and activator of transcription (STAT) family signaling pathways are crucial for Tfh formation. However, because of the multi-factorial and multi-stage features of Tfh differentiation, every STAT member plays a role in Tfh differentiation, but is not completely depended on. With the gradual recognition of different Tfh subsets (Tfh1, Tfh2, Tfh17), the process of Tfh differentiation can no longer be explained by straight-line derivation models. In this review, we summarize the roles of different STATs in mediating Tfh subsets, analyze the contributions of mutual restraint and cooperation among cytokine-STAT signals to terminal Tfh differentiation, and clarify the multi-source pathways of Tfh differentiation with a three-dimensional illustration.
The treatment of rheumatoid arthritis was revolutionized with the use of molecular-targeted drugs that target immunoregulatory molecules. The success of treatment with these drugs prompted the ...development of molecular-targeted drugs for systemic lupus erythematosus. However, systemic lupus erythematosus is a disease with high heterogeneous immune abnormalities, and diverse cells or molecules can be treatment targets. Thus, the identification of subpopulations based on immune abnormalities is essential for the development of effective treatment. One analytical method used to identify subpopulations is the immunophenotyping of peripheral blood samples of patients. This analysis evaluates the validity of target molecules for peripheral blood immune cell subsets, which are expected to be developed as biomarkers for precision medicine in which appropriate treatment targets are set for each subpopulation.
Human mesenchymal stem cells (MSCs) are multipotent and exert anti-inflammatory effects, but the underlying mechanism remains to be elucidated. In the current study, we investigated the regulatory ...mechanism of regulatory T cell (Treg) induction through the growth factors released by human MSCs. Human naive CD4
T cells were stimulated with anti-CD3/28 Abs and cocultured with human MSC culture supernatant for 48 h. The proliferation and cytokine production of CD4
T cells and surface molecule expression on CD4
T cells were evaluated. The proliferation of anti-CD3/28 Abs-stimulated CD4
T cells was suppressed by the addition of human MSC culture supernatant; in addition, the production of IL-10 and IL-4 increased. The human MSC culture supernatant induced CD4
FOXP3
Tregs that expressed CD25, CTLA-4, glucocorticoid-induced TNFR-related protein, insulin-like growth factor (IGF)-1R, and IGF-2R, showing antiproliferative activity against CD4
T cells. In addition, the induction of Tregs by human MSC culture supernatant was enhanced by the addition of IGF and suppressed by the inhibition of IGF-1R. In contrast, a significant amount of IGF binding protein (IGFBP)-4, an inhibitor of IGF action, was detected in the human MSC culture supernatant. After neutralization of IGFBP-4 in the human MSC culture supernatant by anti-IGFBP-4 Ab, Treg numbers increased significantly. Thus, our results raise the possibility that human MSC actions also involve a negative-regulatory mechanism that suppresses Treg proliferation by releasing IGFBP-4. The results of this study suggest that regulation of IGF may be important for treatments using human MSCs.
T follicular helper cells participate in stimulating germinal center (GC) formation and supporting B cell differentiation and autoantibody production. However, T follicular regulatory (Tfr) cells ...suppress B cell activation. Since changes in the number and functions of Tfr cells lead to dysregulated GC reaction and autoantibody response, targeting Tfr cells may benefit the treatment of autoimmune diseases. Differentiation of Tfr cells is a multistage and multifactorial process with various positive and negative regulators. Therefore, understanding the signals regulating Tfr cell generation is crucial for the development of targeted therapies. In this review, we discuss recent studies that have elucidated the roles of Tfr cells in autoimmune diseases and investigated the modulators of Tfr cell differentiation. Additionally, potential immunotherapies targeting Tfr cells are highlighted.
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