Daratumumab, a human monoclonal antibody that targets CD38, depletes plasma cells and is approved for the treatment of multiple myeloma. Long-lived plasma cells are implicated in the pathogenesis of ...systemic lupus erythematosus because they secrete autoantibodies, but they are unresponsive to standard immunosuppression. We describe the use of daratumumab that induced substantial clinical responses in two patients with life-threatening lupus, with the clinical responses sustained by maintenance therapy with belimumab, an antibody to B-cell activating factor. Significant depletion of long-lived plasma cells, reduction of interferon type I activity, and down-regulation of T-cell transcripts associated with chronic inflammation were documented. (Supported by the Deutsche Forschungsgemeinschaft and others.).
For targeted intervention in coronavirus disease 2019 (COVID‐19), there is a high medical need for biomarkers that predict disease progression and severity in the first days after symptom onset. This ...study assessed the utility of early transforming growth factor β (TGF‐β) serum levels in COVID‐19 patients to predict disease severity, fatality, and response to dexamethasone therapy. Patients with severe COVID‐19 had significantly higher TGF‐β levels (416 pg/mL) as compared to patients with mild (165 pg/mL, p < 0.0001) or moderate COVID‐19 (241 pg/mL; p < 0.0001). Receiver operating characteristics area under the curve values were 0.92 (95% confidence interval CI 0.85–0.99, cut‐off: 255 pg/mL) for mild versus severe COVID‐19, and 0.83 (95% CI 0.65–1.0, cut‐off: 202 pg/mL) for moderate versus severe COVID‐19. Patients who died of severe COVID‐19 had significantly higher TGF‐β levels (453 pg/mL) as compared to convalescent patients (344 pg/mL), and TGF‐β levels predicted fatality (area under the curve: 0.75, 95% CI 0.53–0.96). TGF‐β was significantly reduced in severely ill patients treated with dexamethasone (301 pg/mL) as compared to untreated patients (416 pg/mL; p < 0.05). Early TGF‐β serum levels in COVID‐19 patients predict, with high accuracy, disease severity, and fatality. In addition, TGF‐β serves as a specific biomarker to assess response to dexamethasone treatment.
Serum TGF‐β concentrations within 14 days after symptom onset predicted severe COVID‐19 requiring intensive care treatment (cut‐off 255 pg/mL, AUC: 0.92). TGF‐β levels at that time also predicted mortality (cut‐off 455 pg/mL, AUC: 0.75). Serum TGF‐β is the first biomarker predicting severe COVID‐19 allowing early intervention and individual risk stratification.
In humans and mice, mucosal immune responses are dominated by IgA antibodies and the cytokine TGF‐β, suppressing unwanted immune reactions but also targeting Ig class switching to IgA. It had been ...suggested that eosinophils promote the generation and maintenance of mucosal IgA‐expressing plasma cells. Here, we demonstrate that not eosinophils, but specific bacteria determine mucosal IgA production. Co‐housing of eosinophil‐deficient mice with mice having high intestinal IgA levels, as well as the intentional microbiota transfer induces TGF‐β expression in intestinal T follicular helper cells, thereby promoting IgA class switching in Peyer's patches, enhancing IgA+ plasma cell numbers in the small intestinal lamina propria and levels of mucosal IgA. We show that bacteria highly enriched for the genus Anaeroplasma are sufficient to induce these changes and enhance IgA levels when adoptively transferred. Thus, specific members of the intestinal microbiota and not the microbiota as such regulate gut homeostasis, by promoting the expression of immune‐regulatory TGF‐β and of mucosal IgA.
Microbiota containing Anaeroplasma enhances TGF‐β expression in Tfh cells of the PP. This leads to the increased class switch to IgA during GC reaction, resulting in enhanced numbers of IgA+ plasma cells and fecal IgA levels.
MicroRNAs (miRNAs) are endogenously encoded ∼22 nt small non‐coding RNAs. They function as key players of many cellular processes by base pairing with target mRNAs and thereby impairing gene ...expression at the post‐transcriptional level. Recent findings demonstrate a critical role of many miRNAs in immune cell differentiation and immune responses, which is also associated with the development and progression of many tumor and non‐tumor diseases. Here we review the multifaceted miRNA‐148/‐152 family members consisting of miR‐148a, miR‐148b and miR‐152. Next to regulation mechanisms that control the expression of this miRNA family, we will focus on (i) the role of miR‐148a in regulating B and T lymphocyte function and its role in associated diseases and (ii) the importance of miR‐148/‐152 family members for cancer initiation, tumor growth and metastasis formation. In addition, this review aims to highlight some selected targets of the miRNA‐148/‐152 family members, which are involved in the biology of cancer and maintenance of epigenetic patterns. In conclusion, members of the miR‐148/‐152 family might represent prognostic markers and/or potential therapeutic targets for treatment of autoimmune disorders, chronic inflammatory diseases and multiple types of cancer.
The article reviews the multifaceted miR‐148/‐152 family in human and mice. Besides regulation mechanisms including an epigenetic feedback loop, we highlight important functions of miR‐148a, miR‐148b and miR‐152 in controlling B and T cell differentiation as well as the process of tumorigenesis.
Clonal expansion of cells with somatically diversified receptors and their long-term maintenance as memory cells is a hallmark of adaptive immunity. Here, we studied pathogen-specific adaptation ...within the innate immune system, tracking natural killer (NK) cell memory to human cytomegalovirus (HCMV) infection. Leveraging single-cell multiomic maps of ex vivo NK cells and somatic mitochondrial DNA mutations as endogenous barcodes, we reveal substantial clonal expansion of adaptive NK cells in HCMV
individuals. NK cell clonotypes were characterized by a convergent inflammatory memory signature enriched for AP1 motifs superimposed on a private set of clone-specific accessible chromatin regions. NK cell clones were stably maintained in specific epigenetic states over time, revealing that clonal inheritance of chromatin accessibility shapes the epigenetic memory repertoire. Together, we identify clonal expansion and persistence within the human innate immune system, suggesting that these mechanisms have evolved independent of antigen-receptor diversification.
Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic condition in childhood. The disease etiology remains largely unknown; however, a key role in JIA pathogenesis is surely ...mediated by T cells. T‐lymphocytes activity is controlled via signals, known as immune checkpoints. Delivering an inhibitory signal or blocking a stimulatory signal to achieve immune suppression is critical in autoimmune diseases. However, the role of immune checkpoints in chronic inflammation and autoimmunity must still be deciphered. In this study, we investigated at the single‐cell level the feature of T cells in JIA chronic inflammation, both at the transcriptome level via single‐cell RNA sequencing and at the protein level by flow cytometry. We found that despite the heterogeneity in the composition of synovial CD4+ and CD8+ T cells, those characterized by PD‐1 expression were clonally expanded tissue‐resident memory (Trm)‐like cells and displayed the highest proinflammatory capacity, suggesting their active contribution in sustaining chronic inflammation in situ. Our data support the concept that novel therapeutic strategies targeting PD‐1 may be effective in the treatment of JIA. With this approach, it may become possible to target overactive T cells regardless of their cytokine production profile.
T cells expressing PD‐1 are enriched in synovial fluid of juvenile idiopathic arthritis patients. Interestingly, PD‐1 positive cells exhibit markers of tissue residency, display a high proinflammatory capacity, and are clonally expanded cells, suggesting their active contribution in sustaining chronic inflammation in situ.
At present, it is not clear how memory B lymphocytes are maintained over time, and whether only as circulating cells or also residing in particular tissues. Here we describe distinct populations of ...isotype-switched memory B lymphocytes (Bsm) of murine spleen and bone marrow, identified according to individual transcriptional signature and B cell receptor repertoire. A population of marginal zone-like cells is located exclusively in the spleen, while a population of quiescent Bsm is found only in the bone marrow. Three further resident populations, present in spleen and bone marrow, represent transitional and follicular B cells and B1 cells, respectively. A population representing 10-20% of spleen and bone marrow memory B cells is the only one qualifying as circulating. In the bone marrow, all cells individually dock onto VCAM1
stromal cells and, reminiscent of resident memory T and plasma cells, are void of activation, proliferation and mobility.
It has been 25 years since we first described long‐lived memory plasma cells of the bone marrow, 13 years since we identified bone marrow resident memory T cells and 2 years since we showed that the ...bone marrow is also a preferred location of resident memory B cells. The bone marrow is increasingly recognized as a fundamental component of long‐lasting immunological memory, not only providing protective immunity but also fuelling chronic inflammation. We now understand that the bone marrow functions as the ‘backbone’ of immunological memory, hosting the memory plasma cells which provide not only humoral immunity but also memory B and T cells, which constitute ‘reactive memory’. This knowledge now allows us to define true cellular ‘correlates of protection’ for systemic immunity, its quality and duration, as induced by infection and vaccination, something that has never been more important given the recent SARS‐CoV‐2 pandemic. While memory plasma cells of the bone marrow indicate long‐lasting humoral protection, memory T (and B) cells mobilized into the blood in secondary immune reactions indicate the strength of reactive memory. In this review, we have contextualized many of our own findings from the last two decades that have contributed to our understanding of how bone marrow‐resident memory cells provide local and systemic immunity.
It is current belief that numbers of CD8+ memory T lymphocytes in the memory phase of an immune response are maintained by homeostatic proliferation. Here, we compare the proliferation of CD8+ memory ...T lymphocytes, generated by natural infections and by intentional immunization, in spleen and bone marrow (BM). Fifty percent of CD8+ memory T lymphocytes in the spleen are eliminated by cyclophosphamide within 14 days, indicating that numbers of at least 50% of splenic CD8+ memory T lymphocytes are maintained by proliferation. The numbers of CD8+ memory T lymphocytes in the BM, however, were not affected by cyclophosphamide. This stability was independent of circulating CD8+ memory T cells, blocked by FTY720, showing that BM is a privileged site for the maintenance of memory T lymphocytes, as resident cells, resting in terms of proliferation.
Cyclophosphamide does not eliminate CD8+ memory T cells of the bone marrow, demonstrating that they do not proliferate, and their numbers are maintained in the presence of FTY720, demonstrating that they are resident.
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