Mutations that prevent caspase cleavage of RIPK1 cause autoinflammatory disease.

RIPK1 is a key regulator of innate immune signalling pathways. To ensure an optimal inflammatory response, RIPK1 is regulated post-translationally by well-characterized ubiquitylation and phosphorylation events, as well as by caspase-8-mediated cleavage1-7. The physiological relevance of this cleavage event remains unclear, although it is thought to inhibit activation of RIPK3 and necroptosis8. Here we show that the heterozygous missense mutations D324N, D324H and D324Y prevent caspase cleavage of RIPK1 in humans and result in an early-onset periodic fever syndrome and severe intermittent lymphadenopathy-a condition we term 'cleavage-resistant RIPK1-induced autoinflammatory syndrome'. To define the mechanism for this disease, we generated a cleavage-resistant Ripk1D325A mutant mouse strain. Whereas Ripk1-/- mice died postnatally from systemic inflammation, Ripk1D325A/D325A mice died during embryogenesis. Embryonic lethality was completely prevented by the combined loss of Casp8 and Ripk3, but not by loss of Ripk3 or Mlkl alone. Loss of RIPK1 kinase activity also prevented Ripk1D325A/D325A embryonic lethality, although the mice died before weaning from multi-organ inflammation in a RIPK3-dependent manner. Consistently, Ripk1D325A/D325A and Ripk1D325A/+ cells were hypersensitive to RIPK3-dependent TNF-induced apoptosis and necroptosis. Heterozygous Ripk1D325A/+ mice were viable and grossly normal, but were hyper-responsive to inflammatory stimuli in vivo. Our results demonstrate the importance of caspase-mediated RIPK1 cleavage during embryonic development and show that caspase cleavage of RIPK1 not only inhibits necroptosis but also maintains inflammatory homeostasis throughout life.

NLRP3 mutation and cochlear autoinflammation cause syndromic and nonsyndromic hearing loss DFNA34 responsive to anakinra therapy.

The NLRP3 inflammasome is an intracellular innate immune sensor that is expressed in immune cells, including monocytes and macrophages. Activation of the NLRP3 inflammasome leads to IL-1ß secretion. Gain-of-function mutations of NLRP3 result in abnormal activation of the NLRP3 inflammasome, and cause the autosomal dominant systemic autoinflammatory disease spectrum, termed cryopyrin-associated periodic syndromes (CAPS). Here, we show that a missense mutation, p.Arg918Gln (c.2753G > A), of NLRP3 causes autosomal-dominant sensorineural hearing loss in two unrelated families. In family LMG446, hearing loss is accompanied by autoinflammatory signs and symptoms without serologic evidence of inflammation as part of an atypical CAPS phenotype and was reversed or improved by IL-1ß blockade therapy. In family LMG113, hearing loss segregates without any other target-organ manifestations of CAPS. This observation led us to explore the possibility that resident macrophage/monocyte-like cells in the cochlea can mediate local autoinflammation via activation of the NLRP3 inflammasome. The NLRP3 inflammasome can indeed be activated in resident macrophage/monocyte-like cells in the mouse cochlea, resulting in secretion of IL-1ß. This pathway could underlie treatable sensorineural hearing loss in DFNA34, CAPS, and possibly in a wide variety of hearing-loss disorders, such as sudden sensorineural hearing loss and Meniere's disease that are elicited by pathogens and processes that stimulate innate immune responses within the cochlea.

A unified metric of human immune health.

Immunological health has been challenging to characterize but could be defined as the absence of immune pathology. While shared features of some immune diseases and the concept of immunologic resilience based on age-independent adaptation to antigenic stimulation have been developed, general metrics of immune health and its utility for assessing clinically healthy individuals remain ill defined. Here we integrated transcriptomics, serum protein, peripheral immune cell frequency and clinical data from 228 patients with 22 monogenic conditions impacting key immunological pathways together with 42 age- and sex-matched healthy controls. Despite the high penetrance of monogenic lesions, differences between individuals in diverse immune parameters tended to dominate over those attributable to disease conditions or medication use. Unsupervised or supervised machine learning independently identified a score that distinguished healthy participants from patients with monogenic diseases, thus suggesting a quantitative immune health metric (IHM). In ten independent datasets, the IHM discriminated healthy from polygenic autoimmune and inflammatory disease states, marked aging in clinically healthy individuals, tracked disease activities and treatment responses in both immunological and nonimmunological diseases, and predicted age-dependent antibody responses to immunizations with different vaccines. This discriminatory power goes beyond that of the classical inflammatory biomarkers C-reactive protein and interleukin-6. Thus, deviations from health in diverse conditions, including aging, have shared systemic immune consequences, and we provide a web platform for calculating the IHM for other datasets, which could empower precision medicine.

Multiomics integration of 22 immune-mediated monogenic diseases reveals an emergent axis of human immune health.

Monogenic diseases are often studied in isolation due to their rarity. Here we utilize multiomics to assess 22 monogenic immune-mediated conditions with age- and sex-matched healthy controls. Despite clearly detectable disease-specific and "pan-disease" signatures, individuals possess stable personal immune states over time. Temporally stable differences among subjects tend to dominate over differences attributable to disease conditions or medication use. Unsupervised principal variation analysis of personal immune states and machine learning classification distinguishing between healthy controls and patients converge to a metric of immune health (IHM). The IHM discriminates healthy from multiple polygenic autoimmune and inflammatory disease states in independent cohorts, marks healthy aging, and is a pre-vaccination predictor of antibody responses to influenza vaccination in the elderly. We identified easy-to-measure circulating protein biomarker surrogates of the IHM that capture immune health variations beyond age. Our work provides a conceptual framework and biomarkers for defining and measuring human immune health.

Medical and environmental risk factors associated with frontotemporal dementia: a case-control study in a veteran population.

BACKGROUND: Compared with other major dementias, very little is known about the medical and environmental risk factors associated with frontotemporal dementia (FTD). In this study, we evaluated medical and environmental disorders associated with FTD in a veteran population. METHODS: The medical records of 845 consecutive veterans who were evaluated for cognitive and/or behavioral complaints at a cognitive disorders clinic in an academic medical center between March 1, 2003, and June 30, 2008, were reviewed and 554 patients received a diagnosis of dementia. Medical disorders and environmental risk factors in 63 patients with behavioral variant of FTD were compared with 491 patients with non-FTD dementias. RESULTS: The prevalence of traumatic brain injury (TBI) was significantly greater in patients with FTD versus those with non-FTD dementias (12.7% vs 3.5%; P < .05). The FTD group also had a lower prevalence of heart disease (19.0% vs 36.7%; P < .05) and cerebrovascular diseases (12.7% vs 26.1%; P < .05), although the prevalence of vascular risk factors was comparable between FTD and non-FTD dementia groups: hypertension (65.1% vs 68.2%), diabetes (31.7% vs 26.9%), hyperlipidemia (42.9% vs 48.9%), and tobacco use (7.9% vs 8.8%; P > .05 for all). In multivariate analysis, the risk for FTD was increased in patients with TBI (OR, 4.4; 95% CI, 1.6-11.8). The risk for FTD was marginally decreased in patients with heart disease (OR, 0.4; 95% CI, 0.3-0.96). CONCLUSIONS: In a clinical sample of veterans, risk of FTD was increased in patients with TBI and marginally decreased in patients with heart disease. Prospective studies are needed to confirm these associations temporally and to identify their underlying mechanisms.

Design of an algorithm for the diagnostic approach of patients with joint pain.

BACKGROUND: Rheumatic diseases are a reason for frequent consultation with primary care doctors. Unfortunately, there is a high percentage of misdiagnosis. OBJECTIVE: To design an algorithm to be used by primary care physicians to improve the diagnostic approach of the patient with joint pain, and thus improve the diagnostic capacity in four rheumatic diseases. METHODS: Based on the information obtained from a literature review, we identified the main symptoms, signs, and paraclinical tests related to the diagnosis of rheumatoid arthritis, spondyloarthritis with peripheral involvement, systemic lupus erythematosus with joint involvement, and osteoarthritis. We conducted 3 consultations with a group of expert rheumatologists, using the Delphi technique, to design a diagnostic algorithm that has as a starting point "joint pain" as a common symptom for the four diseases. RESULTS: Thirty-nine rheumatologists from 18 countries of Ibero-America participated in the Delphi exercise. In the first consultation, we presented 94 items to the experts (35 symptoms, 31 signs, and 28 paraclinical tests) candidates to be part of the algorithm; 74 items (25 symptoms, 27 signs, and 22 paraclinical tests) were chosen. In the second consultation, the decision nodes of the algorithm were chosen, and in the third, its final structure was defined. The Delphi exercise lasted 8 months; 100% of the experts participated in the three consultations. CONCLUSION: We present an algorithm designed through an international consensus of experts, in which Delphi methodology was used, to support primary care physicians in the clinical approach to patients with joint pain. Key Points • We developed an algorithm with the participation of rheumatologists from 18 countries of Ibero-America, which gives a global vision of the clinical context of the patient with joint pain. • We integrated four rheumatic diseases into one tool with one common symptom: joint pain. It is a novel tool, as it is the first algorithm that will support the primary care physician in the consideration of four different rheumatic diseases. • It will improve the correct diagnosis and reduce the number of paraclinical tests requested by primary care physicians, in the management of patients with joint pain. This point was verified in a recently published study in the journal Rheumatology International (reference number 31).

Differences between clinical subspecialties in the outpatient evaluation and treatment of dementia in an academic medical center.

BACKGROUND: Professional organizations have recommended guidelines for the optimal investigation and management of dementia. It is unknown whether physicians from different subspecialties investigate and treat dementia in the same manner or according to these guidelines. METHODS: We screened 1,401 charts of patients who were seen in neurology, mental health, geropsychiatry and geriatrics clinics. The charts of 410 patients who were diagnosed with dementia were reviewed in detail to determine how they were evaluated and managed. RESULTS: Overall, 40% of patients received a complete laboratory workup to rule out comorbidities, 70% of patients received neuroimaging with either computerized tomography or magnetic resonance imaging of the brain, 63% had a depression screen and 38% of patients underwent neuropsychological testing. However, the frequency with which they were obtained differed significantly across clinics (p < 0.05). The frequency with which acetylcholinesterase inhibitors (CHEIs) were used did not differ significantly (p = 0.07) for patients with Alzheimer's disease (AD), but differed significantly (p < 0.05) for dementia categories where CHEIs are thought to be useful (AD, vascular dementia and dementia with Lewy bodies). CONCLUSIONS: There were significant differences between subspecialties in the evaluation and treatment of dementia. It will be important to investigate whether these differences alter patient outcomes.

Ethnic disparities in the treatment of dementia in veterans.

OBJECTIVES: To test for ethnic disparities in the evaluation and treatment of dementia. METHODS: We reviewed 1,401 charts of patients from 4 veteran clinics that routinely evaluate dementia patients. A total of 410 patients met criteria for dementia or mild cognitive impairment (MCI) and their charts were reviewed in detail. RESULTS: Regarding their evaluation, laboratory and imaging testing did not differ between ethnic groups (p > 0.05). Depression screening was more common in African-American (AA) patients (p = 0.03). Significantly more Caucasian patients underwent neuropsychologic testing (p = 0.001). Regarding management, in a multivariate analysis, AA patients with Alzheimer's disease (AD) (odds ratio (OR) 0.09, 95% confidence interval (CI) 0.02-0.5) or 'all dementia types' (OR 0.6, 0.3-0.9) were significantly less likely to receive acetylcholinesterase inhibitors (CHEIs). Other independent predictors of CHEI use were age >or=71 years (OR 5.2, 2.8-9.6), a diagnosis of AD (OR 3.1, 1.6-6.3) or MCI (OR 0.3, 0.1-0.7), and if their evaluation included imaging (head CT or MRI; OR 1.9, 1.05-3.3). CONCLUSIONS: AA patients underwent comparable evaluations for dementia and the percentage of CHEI-responsive diagnoses rendered was similar across ethnic groups. However, dementia management differed significantly: AAs were prescribed CHEIs at considerably reduced rates. The reasons for this great disparity warrant further investigation because it may produce significantly greater cognitive impairment and hence suffering amongst AA patients.

Haemophagocytic lymphohistiocytosis presenting as liver failure following Epstein-Barr and prior hepatitis A infections.

Haemophagocytic lymphohistiocytosis (HLH) is associated with high mortality even after prompt diagnosis. We present a young man with HLH triggered by two common viral diseases, infectious mononucleosis and hepatitis A. This patient presented with fever, rapidly progressive liver failure, anasarca and cholestasis, followed by anaemia and neutropenia. His carbohydrate antigen 19-9 reached over 9000 U/mL. Initial bone marrow and liver biopsies did not show histological features of malignancy or HLH. The patient was finally diagnosed and treated almost 1 year after the initial symptoms started, and had an excellent response with etoposide and dexamethasone. This case is unusual because it was triggered following mononucleosis in a patient with positive total antibodies against hepatitis A, with rapidly developing liver failure, and also because the patient's response was excellent despite the delay in treatment. It underscores the importance of suspecting HLH when severe systemic illness develops after a viral infection, even in the absence of clear histological features.