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Type III-A CRISPR-Cas systems are prokaryotic RNA-guided adaptive immune systems that use a protein-RNA complex, Csm, for transcription-dependent immunity against foreign DNA. Csm can cleave RNA and single-stranded DNA (ssDNA), but whether it targets one or both nucleic acids during transcription elongation is unknown. Here, we show that binding of a Thermus thermophilus (T . thermophilus ) Csm (TthCsm) to a nascent transcript in a transcription elongation complex (TEC) promotes tethering but not direct contact of TthCsm with RNA polymerase (RNAP). Biochemical experiments show that both TthCsm and Staphylococcus epidermidis ( S. epidermidis ) Csm (SepCsm) cleave RNA transcripts, but not ssDNA, at the transcription bubble. Taken together, these results suggest that Type III systems primarily target transcripts, instead of unwound ssDNA in TECs, for immunity against double-stranded DNA (dsDNA) phages and plasmids. This reveals similarities between Csm and eukaryotic RNA interference, which also uses RNA-guided RNA targeting to silence actively transcribed genes. Type III CRISPR-Cas systems are able to target transcriptionally active DNA sequences in phages and plasmids. Here, the authors reveal the mechanism of the target nucleic acid preference of Type III-A CRISPR-Cas complexes at the transcription bubble by a combination of structural and biochemical approaches.

PD-1, a negative coreceptor expressed on antigen-stimulated T cells and B cells, seems to serve as a 'rheostat' of the immune response. The molecular mechanisms of the functions of PD-1, in conjunction with the mild, chronic and strain-specific autoimmune phenotypes of PD-1-deficient mice, in contrast to the devastating fatal autoimmune disease of mice deficient in the immunomodulatory receptor CTLA-4, suggest that immunoregulation by PD-1 is rather antigen specific and is mainly cell intrinsic. Such unique properties make PD-1 a powerful target for immunological therapy, with highly effective clinical applications for cancer treatment.

Despite the presence of strategically positioned anatomical barriers designed to protect the central nervous system (CNS), it is not entirely isolated from the immune system 1 , 2 . In fact, it remains physically connected to, and can be influenced by, the peripheral immune system 1 . How the CNS retains such responsiveness while maintaining an immunologically unique status remains an outstanding question. Here, in searching for molecular cues that derive from the CNS and enable its direct communication with the immune system, we identified an endogenous repertoire of CNS-derived regulatory self-peptides presented on major histocompatibility complex class II (MHC-II) molecules in the CNS and at its borders. During homeostasis, these regulatory self-peptides were found to be bound to MHC-II molecules throughout the path of lymphatic drainage from the brain to its surrounding meninges and its draining cervical lymph nodes. However, in neuroinflammatory disease, the presentation of regulatory self-peptides diminished. After boosting the presentation of these regulatory self-peptides, a population of suppressor CD4 + T cells was expanded, controlling CNS autoimmunity in a CTLA-4- and TGFβ-dependent manner. CNS-derived regulatory self-peptides may be the molecular key to ensuring a continuous dialogue between the CNS and the immune system while balancing overt autoreactivity. This sheds light on how we conceptually think about and therapeutically target neuroinflammatory and neurodegenerative diseases. Central nervous system (CNS)-derived regulatory self-peptides are essential for maintaining a continuous dialogue between the CNS and the immune system while balancing overt autoreactivity.

Neuroimmunologists seek to understand the interactions between the central nervous system (CNS) and the immune system, both under homeostatic conditions and in diseases. Unanswered questions include those relating to the diversity and specificity of the meningeal T cell repertoire; the routes taken by immune cells that patrol the méninges under healthy conditions and invade the parenchyma during pathology; the opposing effects (beneficial or detrimental) of these cells on CNS function; the role of immune cells after CNS injury; and the evolutionary link between the two systems, resulting in their tight interaction and interdependence. This Review summarizes the current standing of and challenging questions related to interactions between adaptive immunity and the CNS and considers the possible directions in which these aspects of neuroimmunology will be heading over the next decade.

The enteric nervous system (ENS) is an extensive network comprising millions of neurons and glial cells contained within the wall of the gastrointestinal tract. The major functions of the ENS that have been most studied include the regulation of local gut motility, secretion, and blood flow. Other areas that have been gaining increased attention include its interaction with the immune system, with the gut microbiota and its involvement in the gut–brain axis, and neuro-epithelial interactions. Thus, the enteric circuitry plays a central role in intestinal homeostasis, and this becomes particularly evident when there are faults in its wiring such as in neurodevelopmental or neurodegenerative disorders. In this review, we first focus on the current knowledge on the cellular composition of enteric circuits. We then further discuss how enteric circuits detect and process external information, how these signals may be modulated by physiological and pathophysiological factors, and finally, how outputs are generated for integrated gut function.

Key Points Local inflammation includes elements — pain and vasodilation — that are neurally mediated. The systemic acute-phase response includes neurally mediated elements — fever and activation of the central hormonal stress response — that are mediated by the effects of immune factors on the hypothalamus. The cellular and molecular components of the innate immune system provide the first line of defence against invading pathogens, through recognition of pathogen-associated molecular patterns (PAMPs) and initial nonspecific cellular and humoral responses. Immune mediators and cytokines that are subsequently released by the innate immune system rapidly activate nonspecific neural responses that both amplify local immune responses to clear pathogens and trigger systemic neuroendocrine and regional neural responses that eventually return the system to a resting state. These neural responses include systemic hormonal responses (through the hypothalamic–pituitary–adrenal axis); regional neuronal responses (through the sympathetic and parasympathetic nervous systems) that innervate immune organs; and local neuronal responses (through the peripheral nervous system). Immune cells contain the molecular machinery to respond to neural signals, including receptors and signalling pathways. Neurotransmitters (including noradrenaline and acetylcholine), neuropeptides (including opioids, substance P, neuropeptide Y and calcitonin gene-related peptide and hormones (glucocorticoids) alter innate immune-cell function through these molecular mechanisms. The nervous system and innate immune system form a cohesive and integrated early host response to pathogens. This interplay constitutes an important feedback loop that optimizes innate inflammatory responses to invading pathogens. Prolonged or inappropriate central nervous system counter-regulatory responses could predispose the host to excess inflammation (in the context of inadequate hormonal suppression) or uncontrolled infection (in the context of excess or prolonged anti-inflammatory hormonal responses). Evidence for crosstalk between the central nervous system and innate immune cells is accumulating. As discussed by Esther Sternberg, neural factors that first amplify and then temper pro-inflammatory responses have a crucial role in pathogen defence and in preventing toxic shock. The central nervous system (CNS) regulates innate immune responses through hormonal and neuronal routes. The neuroendocrine stress response and the sympathetic and parasympathetic nervous systems generally inhibit innate immune responses at systemic and regional levels, whereas the peripheral nervous system tends to amplify local innate immune responses. These systems work together to first activate and amplify local inflammatory responses that contain or eliminate invading pathogens, and subsequently to terminate inflammation and restore host homeostasis. Here, I review these regulatory mechanisms and discuss the evidence indicating that the CNS can be considered as integral to acute-phase inflammatory responses to pathogens as the innate immune system.

Neuroinflammation is often associated with blood-brain-barrier dysfunction, which contributes to neurological tissue damage. Here, we reveal the pathophysiology of Susac syndrome (SuS), an enigmatic neuroinflammatory disease with central nervous system (CNS) endotheliopathy. By investigating immune cells from the blood, cerebrospinal fluid, and CNS of SuS patients, we demonstrate oligoclonal expansion of terminally differentiated activated cytotoxic CD8 + T cells (CTLs). Neuropathological data derived from both SuS patients and a newly-developed transgenic mouse model recapitulating the disease indicate that CTLs adhere to CNS microvessels in distinct areas and polarize granzyme B, which most likely results in the observed endothelial cell injury and microhemorrhages. Blocking T-cell adhesion by anti-α4 integrin-intervention ameliorates the disease in the preclinical model. Similarly, disease severity decreases in four SuS patients treated with natalizumab along with other therapy. Our study identifies CD8 + T-cell-mediated endotheliopathy as a key disease mechanism in SuS and highlights therapeutic opportunities. Susac syndrome is an inflammatory pathology of the brain endothelium. Here the authors show that the pathology is driven by CD8 T cells attacking the endothelium, and that blocking T cell-endothelial adhesion ameliorates the disease in a mouse model, and associates with improved clinical score in 4 patients.

A severe form of encephalitis associated with antibodies against NR1–NR2 heteromers of the NMDA receptor was recently identified. We aimed to analyse the clinical and immunological features of patients with the disorder and examine the effects of antibodies against NMDA receptors in neuronal cultures. We describe the clinical characteristics of 100 patients with encephalitis and NR1–NR2 antibodies. HEK293 cells ectopically expressing single or assembled NR1–NR2 subunits were used to determine the epitope targeted by the antibodies. Antibody titres were measured with ELISA. The effect of antibodies on neuronal cultures was determined by quantitative analysis of NMDA-receptor clusters. Median age of patients was 23 years (range 5–76 years); 91 were women. All patients presented with psychiatric symptoms or memory problems; 76 had seizures, 88 unresponsiveness (decreased conciousness), 86 dyskinesias, 69 autonomic instability, and 66 hypoventilation. 58 (59%) of 98 patients for whom results of oncological assessments were available had tumours, most commonly ovarian teratoma. Patients who received early tumour treatment (usually with immunotherapy) had better outcome (p=0·004) and fewer neurological relapses (p=0·009) than the rest of the patients. 75 patients recovered or had mild deficits and 25 had severe deficits or died. Improvement was associated with a decrease of serum antibody titres. The main epitope targeted by the antibodies is in the extracellular N-terminal domain of the NR1 subunit. Patients' antibodies decreased the numbers of cell-surface NMDA receptors and NMDA-receptor clusters in postsynaptic dendrites, an effect that could be reversed by antibody removal. A well-defined set of clinical characteristics are associated with anti-NMDA-receptor encephalitis. The pathogenesis of the disorder seems to be mediated by antibodies. National Institutes for Health, University of Pennsylvania Institute for Translational Medicine, Lankenau Institute for Medical Research, Foederer Foundation of the Children's Hospital of Philadelphia.

Women are at increased risk for developing depression and cardiovascular disease (CVD) across the lifespan and their comorbidity is associated with adverse outcomes that contribute significantly to rates of morbidity and mortality in women worldwide. Immune-system activity has been implicated in the etiology of both depression and CVD, but it is unclear how inflammation contributes to sex differences in this comorbidity. This narrative review provides an updated synthesis of research examining the association of inflammation with depression and CVD, and their comorbidity in women. Recent research provides evidence of pro-inflammatory states and sex differences associated with alterations in the hypothalamic–pituitary–adrenal axis, the renin–angiotensin–aldosterone system and the serotonin/kynurenine pathway, that likely contribute to the development of depression and CVD. Changes to inflammatory cytokines in relation to reproductive periods of hormonal fluctuation (i.e. the menstrual cycle, perinatal period and menopause) are highlighted and provide a greater understanding of the unique vulnerability women experience in developing both depressed mood and adverse cardiovascular events. Inflammatory biomarkers hold substantial promise when combined with a patient’s reproductive and mental health history to aid in the prediction, identification and treatment of the women most at risk for CVD and depression. However, more research is needed to improve our understanding of the mechanisms underlying inflammation in relation to their comorbidity, and how these findings can be translated to improve women’s health.

Tolebrutinib is an oral, CNS-penetrant, irreversible inhibitor of Bruton’s tyrosine kinase, an enzyme expressed in B lymphocytes and myeloid cells including microglia, which are major drivers of inflammation in multiple sclerosis. We aimed to determine the dose-response relationship between tolebrutinib and the reduction in new active brain MRI lesions in patients with relapsing multiple sclerosis. We did a 16-week, phase 2b, randomised, double-blind, placebo-controlled, crossover, dose-finding trial at 40 centres (academic sites, specialty clinics, and general neurology centres) in ten countries in Europe and North America. Eligible participants were adults aged 18–55 years with diagnosed relapsing multiple sclerosis (either relapsing-remitting or relapsing secondary progressive multiple sclerosis), and one or more of the following criteria: at least one relapse within the previous year, at least two relapses within the previous 2 years, or at least one active gadolinium-enhancing brain lesion in the 6 months before screening. Exclusion criteria included a diagnosis of primary progressive multiple sclerosis or a diagnosis of secondary progressive multiple sclerosis without relapse. We used a two-step randomisation process to randomly assign eligible participants (1:1) to two cohorts, then further randomly assign participants in each cohort (1:1:1:1) to four tolebrutinib dose groups (5, 15, 30, and 60 mg administered once daily as an oral tablet). Cohort 1 received tolebrutinib for 12 weeks, then matched placebo (ie, identical looking tablets) for 4 weeks; cohort 2 received 4 weeks of placebo followed by 12 weeks of tolebrutinib. Participants and investigators were masked for dose and tolebrutinib-placebo administration sequence; investigators, study team members, and study participants did not have access to unmasked data. MRI scans were done at screening and every 4 weeks over 16 weeks. The primary efficacy endpoint was the number of new gadolinium-enhancing lesions detected on the scan done after 12 weeks of tolebrutinib treatment (assessed at week 12 for cohort 1 and week 16 for cohort 2), relative to the scan done 4 weeks previously, and compared with the lesions accumulated during 4 weeks of placebo run-in period in cohort 2. Efficacy data were analysed in a modified intention-to-treat population, using a two-step multiple comparison procedure with modelling analysis. Safety was assessed for all participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT03889639), EudraCT (2018-003927-12), and WHO (U1111-1220-0572), and has been completed. Between May 14, 2019, and Jan 2, 2020, we enrolled and randomly assigned 130 participants to tolebrutinib: 33 to 5 mg, 32 to 15 mg, 33 to 30 mg, and 32 to 60 mg. 129 (99%) completed the treatment regimen and 126 were included in the primary analysis. At treatment week 12, there was a dose-dependent reduction in the number of new gadolinium-enhancing lesions (mean [SD] lesions per patient: placebo, 1·03 [2·50]; 5 mg, 1·39 [3·20]; 15 mg, 0·77 [1·48]; 30 mg, 0·76 [3·31]; 60 mg, 0·13 [0·43]; p=0·03). One serious adverse event was reported (one patient in the 60 mg group was admitted to hospital because of a multiple sclerosis relapse). The most common non-serious adverse event during tolebrutinib treatment was headache (in one [3%] of 33 in the 5 mg group; three [9%] of 32 in the 15 mg group; one [3%] of 33 in the 30 mg group; and four [13%] of 32 in the 60 mg group). No safety-related discontinuations or treatment-related deaths occurred. 12 weeks of tolebrutinib treatment led to a dose-dependent reduction in new gadolinium-enhancing lesions, the 60 mg dose being the most efficacious, and the drug was well tolerated. Reduction of acute inflammation, combined with the potential to modulate the immune response within the CNS, provides a scientific rationale to pursue phase 3 clinical trials of tolebrutinib in patients with relapsing and progressive forms of multiple sclerosis. Sanofi.