...even if significant findings or clinical anecdotes support the use of racially tailored practices, they should be rigorously critiqued and mediating variables, such as structural conditions, ...should be analysed accordingly. ...it should be taught that racial health disparities are a consequence of structural racism. ...resolutions denouncing race-based medicine across clinical leadership should be adopted. ...clinical research should be used to examine structural barriers, rather than using race as a proxy for biology.
T cell regeneration after immunological injury Velardi, Enrico; Tsai, Jennifer J; van den Brink, Marcel R M
Nature reviews. Immunology,
05/2021, Letnik:
21, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Following periods of haematopoietic cell stress, such as after chemotherapy, radiotherapy, infection and transplantation, patient outcomes are linked to the degree of immune reconstitution, ...specifically of T cells. Delayed or defective recovery of the T cell pool has significant clinical consequences, including prolonged immunosuppression, poor vaccine responses and increased risks of infections and malignancies. Thus, strategies that restore thymic function and enhance T cell reconstitution can provide considerable benefit to individuals whose immune system has been decimated in various settings. In this Review, we focus on the causes and consequences of impaired adaptive immunity and discuss therapeutic strategies that can recover immune function, with a particular emphasis on approaches that can promote a diverse repertoire of T cells through de novo T cell formation.
Little is known about the maintenance of intestinal stem cells (ISCs) and progenitors during immune-mediated tissue damage or about the susceptibility of transplant recipients to tissue damage ...mediated by the donor immune system during graft versus host disease (GVHD). We demonstrate here that deficiency of recipient-derived IL-22 increased acute GVHD tissue damage and mortality, that ISCs were eliminated during GVHD, and that ISCs as well as their downstream progenitors expressed the IL-22 receptor. Intestinal IL-22 was produced after bone marrow transplant by IL-23-responsive innate lymphoid cells (ILCs) from the transplant recipients, and intestinal IL-22 increased in response to pretransplant conditioning. However, ILC frequency and IL-22 amounts were decreased by GVHD. Recipient IL-22 deficiency led to increased crypt apoptosis, depletion of ISCs, and loss of epithelial integrity. Our findings reveal IL-22 as a critical regulator of tissue sensitivity to GVHD and a protective factor for ISCs during inflammatory intestinal damage.
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► Intestinal stem cells (ISCs) and progenitors express the IL-22 receptor ► Intestinal IL-22 increases after radiation injury but is decreased in GVHD ► Recipient innate lymphoid cells make IL-22 post-BMT, but they are eliminated by GVHD ► Recipient IL-22 deficiency increases crypt apoptosis, loss of ISC, and GVHD mortality
Mycobacterium tuberculosis (Mtb) mutants lacking rv1411c, which encodes the lipoprotein LprG, and rv1410c, which encodes a putative efflux pump, are dramatically attenuated for growth in mice. Here ...we show that loss of LprG-Rv1410 in Mtb leads to intracellular triacylglyceride (TAG) accumulation, and overexpression of the locus increases the levels of TAG in the culture medium, demonstrating a role of this locus in TAG transport. LprG binds TAG within a large hydrophobic cleft and is sufficient to transfer TAG from donor to acceptor membranes. Further, LprG-Rv1410 is critical for broadly regulating bacterial growth and metabolism in vitro during carbon restriction and in vivo during infection of mice. The growth defect in mice is due to disrupted bacterial metabolism and occurs independently of key immune regulators. The in vivo essentiality of this locus suggests that this export system and other regulators of metabolism should be considered as targets for novel therapeutics.
Treatment with methadone or buprenorphine is the current standard of care for opioid use disorder. Given the paucity of research identifying which patients will respond best to which medication, both ...medications should be accessible to all patients so that patients can determine which works best for them. However, given differences in the historical contexts of their initial implementation, access to each of these medications may vary along racial/ethnic lines.
To examine the extent to which capacity to provide methadone and buprenorphine vary with measures of racial/ethnic segregation.
This cross-sectional study included all counties and county-equivalent divisions in the US in 2016. Data on racial/ethnic population distribution were derived from the American Community Survey, and data on locations of facilities providing methadone and buprenorphine were obtained from Substance Abuse and Mental Health Services Administration databases. Data were analyzed from August 22, 2018, to September 11, 2019.
Two county-level measures of racial/ethnic segregation, including dissimilarity (representing the proportion of African American or Hispanic/Latino residents who would need to move census tracts to achieve a uniform spatial distribution of the population by race/ethnicity) and interaction (representing the probability that an African American or Hispanic/Latino resident will interact with a white resident and vice versa, assuming random mixing across census tracts).
County-level capacity to provide methadone or buprenorphine, defined as the number of facilities providing a medication per 100 000 population.
Among 3142 US counties, there were 1698 facilities providing methadone (0.6 facilities per 100 000 population) and 18 868 facilities providing buprenorphine (5.9 facilities per 100 000 population). Each 1% decrease in probability of interaction of an African American resident with a white resident was associated with 0.6 more facilities providing methadone per 100 000 population. Similarly, each 1% decrease in probability of interaction of a Hispanic/Latino resident with a white resident was associated with 0.3 more facilities providing methadone per 100 000 population. Each 1% decrease in the probability of interaction of a white resident with an African American resident was associated with 8.17 more facilities providing buprenorphine per 100 000 population. Similarly, each 1% decrease in the probability of interaction of a white resident with a Hispanic/Latino resident was associated with 1.61 more facilities providing buprenorphine per 100 000 population.
These findings suggest that the racial/ethnic composition of a community was associated with which medications residents would likely be able to access when seeking treatment for opioid use disorder. Reforms to existing regulations governing the provisions of these medications are needed to ensure that both medications are equally accessible to all.
Endogenous thymic regeneration is a crucial function that allows for renewal of immune competence after stress, infection, or immunodepletion. However, the mechanisms governing this regeneration ...remain poorly understood. We detail such a mechanism, centered on interleukin-22 (IL-22) and triggered by the depletion of CD4⁺CD8⁺ double-positive thymocytes. Intrathymic levels of IL-22 were increased after thymic insult, and thymic recovery was impaired in IL-22—deficient mice. IL-22, which signaled through thymic epithelial cells and promoted their proliferation and survival, was up-regulated by radio-resistant RORy(t)⁺CCR6⁺NKp46⁻ lymphoid tissue inducer cells after thymic injury in an IL-23-dependent manner. Administration of IL-22 enhanced thymic recovery after total body irradiation. These studies reveal mechanisms of endogenous thymic repair and offer innovative regenerative strategies for improving immune competence.
Understanding the cell-type composition and spatial organization of brain regions is crucial for interpreting brain computation and function. In the thalamus, the anterior thalamic nuclei (ATN) are ...involved in a wide variety of functions, yet the cell-type composition of the ATN remains unmapped at a single-cell and spatial resolution. Combining single-cell RNA sequencing, spatial transcriptomics, and multiplexed fluorescent in situ hybridization, we identify three discrete excitatory cell-type clusters that correspond to the known nuclei of the ATN and uncover marker genes, molecular pathways, and putative functions of these cell types. We further illustrate graded spatial variation along the dorsomedial-ventrolateral axis for all individual nuclei of the ATN and additionally demonstrate that the anteroventral nucleus exhibits spatially covarying protein products and long-range inputs. Collectively, our study reveals discrete and continuous cell-type organizational principles of the ATN, which will help to guide and interpret experiments on ATN computation and function.
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•The cell-type landscape of the ATN is investigated with spatial transcriptomics•Sharp spatial delineations in gene expression are found across nucleus boundaries•Graded transcriptomic heterogeneity is present within all individual nuclei•Graded transcriptomic properties spatially covary with proteins and inputs
Kapustina et al. investigate the cell-type composition and spatial organization of the anterior thalamic nuclei (ATN) of the mouse brain. They find that the three nuclei forming the ATN are comprised of distinct excitatory cell types and that additional spatially patterned graded heterogeneity is present within each nucleus.
Intestinal bacteria may modulate the risk of infection and graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Allo-HSCT recipients often develop ...neutropenic fever, which is treated with antibiotics that may target anaerobic bacteria in the gut. We retrospectively examined 857 allo-HSCT recipients and found that treatment of neutropenic fever with imipenem-cilastatin and piperacillin-tazobactam antibiotics was associated with increased GVHD-related mortality at 5 years (21.5% for imipenem-cilastatin-treated patients versus 13.1% for untreated patients, P = 0.025; 19.8% for piperacillin-tazobactam-treated patients versus 11.9% for untreated patients, P = 0.007). However, two other antibiotics also used to treat neutropenic fever, aztreonam and cefepime, were not associated with GVHD-related mortality (P = 0.78 and P = 0.98, respectively). Analysis of stool specimens from allo-HSCT recipients showed that piperacillin-tazobactam administration was associated with perturbation of gut microbial composition. Studies in mice demonstrated aggravated GVHD mortality with imipenem-cilastatin or piperacillin-tazobactam compared to aztreonam (P < 0.01 and P < 0.05, respectively). We found pathological evidence for increased GVHD in the colon of imipenem-cilastatin-treated mice (P < 0.05), but no difference in the concentration of short-chain fatty acids or numbers of regulatory T cells. Notably, imipenem-cilastatin treatment of mice with GVHD led to loss of the protective mucus lining of the colon (P < 0.01) and the compromising of intestinal barrier function (P < 0.05). Sequencing of mouse stool specimens showed an increase in Akkermansia muciniphila (P < 0.001), a commensal bacterium with mucus-degrading capabilities, raising the possibility that mucus degradation may contribute to murine GVHD. We demonstrate an underappreciated risk for the treatment of allo-HSCT recipients with antibiotics that may exacerbate GVHD in the colon.
Pladienolide, herboxidiene and spliceostatin have been identified as splicing modulators that target SF3B1 in the SF3b subcomplex. Here we report that PHF5A, another component of this subcomplex, is ...also targeted by these compounds. Mutations in PHF5A-Y36, SF3B1-K1071, SF3B1-R1074 and SF3B1-V1078 confer resistance to these modulators, suggesting a common interaction site. RNA-seq analysis reveals that PHF5A-Y36C has minimal effect on basal splicing but inhibits the global action of splicing modulators. Moreover, PHF5A-Y36C alters splicing modulator-induced intron-retention/exon-skipping profile, which correlates with the differential GC content between adjacent introns and exons. We determine the crystal structure of human PHF5A demonstrating that Y36 is located on a highly conserved surface. Analysis of the cryo-EM spliceosome B
complex shows that the resistance mutations cluster in a pocket surrounding the branch point adenosine, suggesting a competitive mode of action. Collectively, we propose that PHF5A-SF3B1 forms a central node for binding to these splicing modulators.
Bone marrow transplantation (BMT) offers curative potential for patients with high-risk hematologic malignancies, but the post-transplantation period is characterized by profound immunodeficiency. ...Recent studies indicate that the intestinal microbiota not only regulates mucosal immunity, but can also contribute to systemic immunity and hematopoiesis. Using antibiotic-mediated microbiota depletion in a syngeneic BMT mouse model, here we describe a role for the intestinal flora in hematopoietic recovery after BMT. Depletion of the intestinal microbiota resulted in impaired recovery of lymphocyte and neutrophil counts, while recovery of the hematopoietic stem and progenitor compartments and the erythroid lineage were largely unaffected. Depletion of the intestinal microbiota also reduced dietary energy uptake and visceral fat stores. Caloric supplementation through sucrose in the drinking water improved post-BMT hematopoietic recovery in mice with a depleted intestinal flora. Taken together, we show that the intestinal microbiota contribute to post-BMT hematopoietic reconstitution in mice through improved dietary energy uptake.
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•Intestinal microbiota depletion impairs hematopoiesis after bone marrow transplantation•Intestinal flora depletion decreases energy harvest and reduces visceral adipose tissue•Caloric supplementation rescues impaired hematopoiesis in microbiota-depleted mice•The effects of intestinal flora disruption are dose dependent
Intestinal bacteria can exert effects on systemic hematopoiesis. Staffas et al. show that the intestinal flora contributes to hematopoietic recovery after bone marrow transplantation (BMT) through improved dietary energy uptake. The findings suggest possible clinical intervention strategies for improved BMT outcomes.
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