Immunological memory in rheumatic inflammation — a roadblock to tolerance induction

Maschmeyer, Patrick; Chang, Hyun‐Dong; Cheng, Qingyu; Mashreghi, Mir‐Farzin; Hiepe, Falk; Radbruch, Andreas

doi:10.1038/s41584-021-00601-6

Cited by 27 publications

(25 citation statements)

References 198 publications

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“…Future studies will show if this new ACPA also has functional capacities. Plasma cell survival niches in the joint were found present already at time of RA diagnosis supporting the notion that such structures are attractive therapeutic targets in RA 45 or even individuals at risk of developing RA 46,47 .…”

Section: Discussionmentioning

confidence: 74%

Integrated single cell and spatial transcriptomics reveal autoreactive differentiated B cells in joints of early rheumatoid arthritis

Hardt

Carlberg

Klint

et al. 2022

Sci Rep

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B cells play a significant role in established Rheumatoid Arthritis (RA). However, it is unclear to what extent differentiated B cells are present in joint tissue already at the onset of disease. Here, we studied synovial biopsies (n = 8) captured from untreated patients at time of diagnosis. 3414 index-sorted B cells underwent RNA sequencing and paired tissue pieces were subjected to spatial transcriptomics (n = 4). We performed extensive bioinformatics analyses to dissect the local B cell composition. Select plasma cell immunoglobulin sequences were expressed as monoclonal antibodies and tested by ELISA. Memory and plasma cells were found irrespective of autoantibody status of the patients. Double negative memory B cells were prominent, but did not display a distinct transcriptional profile. The tissue architecture implicate both local B cell maturation via T cell help and plasma cell survival niches with a strong CXCL12–CXCR4 axis. The immunoglobulin sequence analyses revealed clonality between the memory B and plasma cell pools further supporting local maturation. One of the plasma cell-derived antibodies displayed citrulline autoreactivity, demonstrating local autoreactive plasma cell differentiation in joint biopsies captured from untreated early RA. Hence, plasma cell niches are not a consequence of chronic inflammation, but are already present at the time of diagnosis.

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Section: Discussionmentioning

confidence: 74%

Integrated single cell and spatial transcriptomics reveal autoreactive differentiated B cells in joints of early rheumatoid arthritis

Hardt

Carlberg

Klint

et al. 2022

Sci Rep

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show abstract

“…Further, CD4 + effector T cells invade the affected tissues and mediate tissue inflammation and damage by cell-cell interactions and by the production of inflammatory and cytotoxic cytokines such as interferon (IFN)-γ and IL-17 ( 6 , 7 ). In addition, chronic activation of CD4 + T cells and the generation of a robust autoimmune T cell memory may contribute to the recurrence of disease flares, the persistence of tissue inflammation and damage accrual and to treatment refractory disease states ( 6 , 8 ). Despite the controlled deletion of most autoreactive T cells during T cell maturation in the thymus, T cells that can recognize autoantigens are still abundantly present in the healthy organism, but those do not become pathogenic when kept under check by intact mechanisms of peripheral self-tolerance ( 9 ).…”

Section: Introductionmentioning

confidence: 99%

Dysregulation and chronicity of pathogenic T cell responses in the pre-diseased stage of lupus

et al. 2022

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In the normal immune system, T cell activation is tightly regulated and controlled at several levels to ensure that activation occurs in the right context to prevent the development of pathologic conditions such as autoimmunity or other harmful immune responses. CD4+FoxP3+ regulatory T cells (Treg) are crucial for the regulation of T cell responses in the peripheral lymphatic organs and thus for the prevention and control of autoimmunity. In systemic lupus erythematosus (SLE), a prototypic systemic autoimmune disease with complex etiology, a disbalance between Treg and pathogenic effector/memory CD4+ T cells develops during disease progression indicating that gradual loss of control over T cell activation is an important event in the immune pathogenesis. This progressive failure to adequately regulate the activation of autoreactive T cells facilitates chronic activation and effector/memory differentiation of pathogenic T cells, which are considered to contribute significantly to the induction and perpetuation of autoimmune processes and tissue inflammation in SLE. However, in particular in humans, little is known about the factors which drive the escape from immune regulation and the chronicity of pathogenic T cell responses in an early stage of autoimmune disease when clinical symptoms are still unapparent. Here we briefly summarize important findings and discuss current views and models on the mechanisms related to the dysregulation of T cell responses which promotes chronicity and pathogenic memory differentiation with a focus on the early stage of disease in lupus-prone individuals.

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“…The commitment of Th cells to a specific effector state is one of the key decision-making processes at the beginning of an immune reaction and has far-reaching consequences regarding the type and strength of the response. That decision can have severe consequences in the context of diseases including autoimmune disorders ( 35 , 36 ), cancer ( 37 ), or viral infections including SARS-CoV-2 ( 38 ). Here, kinetic gene expression analysis at high temporal resolution especially in the very early phase of cell differentiation allowed us to derive a full picture of the transcriptional landscape during Th1, Th2, and Th1/2 cell differentiation, and to achieve a detailed classification of the kinetically changing genes.…”

Section: Discussionmentioning

confidence: 99%

Dissecting the dynamic transcriptional landscape of early T helper cell differentiation into Th1, Th2, and Th1/2 hybrid cells

et al. 2022

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Selective differentiation of CD4+ T helper (Th) cells into specialized subsets such as Th1 and Th2 cells is a key element of the adaptive immune system driving appropriate immune responses. Besides those canonical Th-cell lineages, hybrid phenotypes such as Th1/2 cells arise in vivo, and their generation could be reproduced in vitro. While master-regulator transcription factors like T-bet for Th1 and GATA-3 for Th2 cells drive and maintain differentiation into the canonical lineages, the transcriptional architecture of hybrid phenotypes is less well understood. In particular, it has remained unclear whether a hybrid phenotype implies a mixture of the effects of several canonical lineages for each gene, or rather a bimodal behavior across genes. Th-cell differentiation is a dynamic process in which the regulatory factors are modulated over time, but longitudinal studies of Th-cell differentiation are sparse. Here, we present a dynamic transcriptome analysis following Th-cell differentiation into Th1, Th2, and Th1/2 hybrid cells at 3-h time intervals in the first hours after stimulation. We identified an early bifurcation point in gene expression programs, and we found that only a minority of ~20% of Th cell-specific genes showed mixed effects from both Th1 and Th2 cells on Th1/2 hybrid cells. While most genes followed either Th1- or Th2-cell gene expression, another fraction of ~20% of genes followed a Th1 and Th2 cell-independent transcriptional program associated with the transcription factors STAT1 and STAT4. Overall, our results emphasize the key role of high-resolution longitudinal data for the characterization of cellular phenotypes.

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Immunological memory in rheumatic inflammation — a roadblock to tolerance induction

Cited by 27 publications

References 198 publications

Integrated single cell and spatial transcriptomics reveal autoreactive differentiated B cells in joints of early rheumatoid arthritis

Integrated single cell and spatial transcriptomics reveal autoreactive differentiated B cells in joints of early rheumatoid arthritis

Dysregulation and chronicity of pathogenic T cell responses in the pre-diseased stage of lupus

Dissecting the dynamic transcriptional landscape of early T helper cell differentiation into Th1, Th2, and Th1/2 hybrid cells

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