Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly infectious respiratory virus which is responsible for the coronavirus disease 2019 (COVID-19) pandemic. It is increasingly ...clear that recovered individuals, even those who had mild COVID-19, can suffer from persistent symptoms for many months after infection, a condition referred to as "long COVID", post-acute sequelae of COVID-19 (PASC), post-acute COVID-19 syndrome, or post COVID-19 condition. However, despite the plethora of research on COVID-19, relatively little is known about the molecular underpinnings of these long-term effects.
We have undertaken an integrated analysis of immune responses in blood at a transcriptional, cellular, and serological level at 12, 16, and 24 weeks post-infection (wpi) in 69 patients recovering from mild, moderate, severe, or critical COVID-19 in comparison to healthy uninfected controls. Twenty-one of these patients were referred to a long COVID clinic and > 50% reported ongoing symptoms more than 6 months post-infection.
Anti-Spike and anti-RBD IgG responses were largely stable up to 24 wpi and correlated with disease severity. Deep immunophenotyping revealed significant differences in multiple innate (NK cells, LD neutrophils, CXCR3+ monocytes) and adaptive immune populations (T helper, T follicular helper, and regulatory T cells) in convalescent individuals compared to healthy controls, which were most strongly evident at 12 and 16 wpi. RNA sequencing revealed significant perturbations to gene expression in COVID-19 convalescents until at least 6 months post-infection. We also uncovered significant differences in the transcriptome at 24 wpi of convalescents who were referred to a long COVID clinic compared to those who were not.
Variation in the rate of recovery from infection at a cellular and transcriptional level may explain the persistence of symptoms associated with long COVID in some individuals.
In Australia, neuromuscular blocking agents are the leading cause of perioperative anaphylaxis. Current investigation of suspected anaphylaxis includes tryptase levels, serum immunoglobulin E (IgE) ...levels, and skin testing, including intradermal testing and skin prick testing. The gold standard for the diagnosis of a hypersensitivity reaction is a challenge test, but this poses a risk to patient safety. An alternative test, known as the basophil activation test (BAT) is a form of cellular in vitro testing using flow cytometry to measure the degree of basophil degranulation within a sample of blood following exposure to an allergen. This acts as a surrogate marker for mast cell and basophil activation, thereby identifying IgE- mediated allergy. It is most commonly used to supplement equivocal findings from initial in vitro testing to assist in confirming the diagnosis of a hypersensitivity reaction and identify the causative agent. We present a case series in which five patients with suspected anaphylaxis underwent a BAT, demonstrating its role and limitations in allergy testing within Australia.
Myopericarditis following both BNT162b2 and NVX-CoV2373 Ahmad, Saima; Yuson, Chino; Le, Adrianna ...
Allergy, asthma & clinical immunology/Allergy, asthma, and clinical immunology,
12/2022, Letnik:
18, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Myopericarditis is a well reported complication associated with SARS-Cov-2 (COVID-19) infection and vaccinations; particularly with mRNA vaccines (BNT162b2 and mRNA-1273), and in the young male ...population. The risk-to-benefit ratio in sequential vaccination dosing in young males is further clouded in the era of the omicron variant with its reported enhanced immune escape.
A case series of two cases of post vaccination myopericarditis following the NVX-CoV2373 after also developing myopericarditis with BNT162b2.
To our knowledge, we are the first to describe post vaccination myopericarditis following NVX-CoV2373 after also developing myopericarditis with BNT162b2. The similarities in presentation between the reactions of both platforms would suggest a similar pathogenesis, although the exact mechanism remains unknown. Further studies are necessary to identify these mechanisms, as well as to identify biomarkers that may identify vulnerable populations. On-going vigilance is necessary to identify those who may be at an increased risk of post-COVID vaccine myopericarditis.
Herein we report a case of sporadic inclusion‐body myositis (sIBM) occurring at an unusually young age in a patient with primary Sjögren syndrome, and use the case to explore possible shared ...mechanisms for disease susceptibility. Possible factors may include the association of both conditions with the 8.1 ancestral haplotype; the presence of anti‐cN1A antibodies, which, although considered specific for sIBM, are also seen in pSS; and the shared association with T‐cell large granular lymphocyte leukemia (T‐LGLL). Further evaluation of this patient did in fact reveal underlying T‐LGLL and mechanisms by which T cells in sIBM may escape immune regulation and contribute to disease phenotype are explored. Despite myofiber infiltration with CD8‐positive T cells in sIBM, and, although sIBM is traditionally considered treatment‐refractory, we report a significant response to the anti‐CD20 monoclonal antibody, rituximab, and discuss possible mechanisms by which this response may be mediated.
Engagement of cytokine receptors by specific ligands activate Janus kinase-signal transducer and activator of transcription (STAT) signaling pathways. The exact roles of STATs in human lymphocyte ...behavior remain incompletely defined. Interleukin (IL)-21 activates STAT1 and STAT3 and has emerged as a potent regulator of B cell differentiation. We have studied patients with inactivating mutations in STAT1 or STAT3 to dissect their contribution to B cell function in vivo and in response to IL-21 in vitro. STAT3 mutations dramatically reduced the number of functional, antigen (Ag)-specific memory B cells and abolished the ability of IL-21 to induce naive B cells to differentiate into plasma cells (PCs). This resulted from impaired activation of the molecular machinery required for PC generation. In contrast, STAT1 deficiency had no effect on memory B cell formation in vivo or IL-21-induced immunoglobulin secretion in vitro. Thus, STAT3 plays a critical role in generating effector B cells from naive precursors in humans. STAT3-activating cytokines such as IL-21 thus underpin Ag-specific humoral immune responses and provide a mechanism for the functional antibody deficit in STAT3-deficient patients.
Background
Cryopyrin‐associated periodic syndrome (CAPS) is an autoinflammatory disorder with a spectrum ranging from the milder familial cold auto‐inflammatory syndrome (FCAS) phenotype to the more ...severe Muckle–Wells Syndrome. Although headaches are the most common neurological symptoms, neuroinflammatory diseases such as multiple sclerosis (MS) have only been reported in the more severe phenotypes.
Case Presentation
We describe a 43‐year‐old male diagnosed with relapse‐remitting MS who developed cold‐induced arthralgias and urticaria. He initially presented with facial numbness and arthralgias in his late teenage years, and brain magnetic resonance imaging (MRI) demonstrated multiple lesions with periventricular white matter extension. Oligoclonal bands were detected in the cerebrospinal fluid (CSF). Symptoms gradually improved, and a decade later he presented with numbness at upper limbs and tongue. Brain and spine MRI showed new lesions, but CSF was unremarkable. He was started on interferon β‐1a with symptomatic improvement until another flare around 13 years later. Treatment was changed to dimethyl fumarate. During this hospitalization, urticaria was problematic and particularly associated with cold temperatures. This raised suspicion for possible CAPS and subsequently confirmed with an A439V mutation in the NLRP3 gene, consistent with FCAS. Anakinra was started but was not tolerated because of localized reactions despite desensitization. His serum amyloid A was mildly elevated at 9 mg/L (reference range 0–6). He remains stable from a neurological perspective, including imaging, and continues dimethyl fumarate.
Conclusions
To date, FCAS and possible association with MS has not been described. The case raises challenges in the diagnosis of concurrent disease processes. It also highlights that neurological sequelae should be considered in all spectrums of CAPS, and distinctions with MS should be made where possible.
Mevalonate kinase deficiency (MKD) is characterized by recurrent fevers and flares of systemic inflammation, caused by biallelic loss-of-function mutations in MVK. The underlying disease mechanisms ...and triggers of inflammatory flares are poorly understood because of the lack of in vivo models. We describe genetically modified mice bearing the hypomorphic mutation p.Val377Ile (the commonest variant in patients with MKD) and amorphic, frameshift mutations in Mvk. Compound heterozygous mice recapitulated the characteristic biochemical phenotype of MKD, with increased plasma mevalonic acid and clear buildup of unprenylated GTPases in PBMCs, splenocytes, and bone marrow. The inflammatory response to LPS was enhanced in compound heterozygous mice and treatment with the NLRP3 inflammasome inhibitor MCC950 prevented the elevation of circulating IL-1beta, thus identifying a potential inflammasome target for future therapeutic approaches. Furthermore, lines of mice with a range of deficiencies in mevalonate kinase and abnormal prenylation mirrored the genotype-phenotype relationship in human MKD. Importantly, these mice allowed the determination of a threshold level of residual enzyme activity, below which protein prenylation is impaired. Elevated temperature dramatically but reversibly exacerbated the deficit in the mevalonate pathway and the defective prenylation in vitro and in vivo, highlighting increased body temperature as a likely trigger of inflammatory flares.
Abstract
Kidney transplant recipients are at an increased risk of severe COVID-19-associated hospitalisation and death. Vaccination has been a key public health strategy to reduce disease severity ...and infectivity, but the effectiveness of COVID vaccines is markedly reduced in kidney transplant recipients. Urgent strategies to enhance vaccine efficacy are needed.
Methods:
RIVASTIM-rapamycin is a multicentre, randomised, controlled trial examining the effect of immunosuppression modification prior to a third dose of COVID-19 vaccine in kidney transplant recipients who have failed to develop protective immunity to a 2-dose COVID-19 vaccine schedule. Participants will be randomised 1:1 to either remain on standard of care immunosuppression with tacrolimus, mycophenolate, and prednisolone (control) or cease mycophenolate and commence sirolimus (intervention) for 4 weeks prior to and following vaccination. The primary outcome is the proportion of participants in each trial arm who develop protective serological neutralisation of live SARS-CoV-2 virus at 4–6 weeks following a third COVID-19 vaccination. Secondary outcomes include SARS-CoV-receptor binding domain IgG, vaccine-specific immune cell populations and responses, and the safety and tolerability of sirolimus switch.
Discussion:
Immunosuppression modification strategies may improve immunological vaccine response. We hypothesise that substituting the mTOR inhibitor sirolimus for mycophenolate in a triple drug regimen will enhance humoral and cell-mediated responses to COVID vaccination for kidney transplant recipients.
Trial registration:
Australia New Zealand Clinical Trials Registry ACTRN12621001412820. Registered on 20 October 2021;
https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=382891&isReview=true
The rare autoinflammatory disease mevalonate kinase deficiency (MKD, which includes HIDS and mevalonic aciduria) is caused by recessive, pathogenic variants in the
gene encoding mevalonate kinase. ...Deficiency of this enzyme decreases the synthesis of isoprenoid lipids and thus prevents the normal post-translational prenylation of small GTPase proteins, which then accumulate in their unprenylated form. We recently optimized a sensitive assay capable of detecting unprenylated Rab GTPase proteins in peripheral blood mononuclear cells (PBMCs) and showed that this assay distinguished MKD from other autoinflammatory diseases. We have now analyzed PBMCs from an additional six patients with genetically-confirmed MKD (with different compound heterozygous
genotypes), and compared these with PBMCs from three healthy volunteers and four unaffected control individuals heterozygous for the commonest pathogenic variant,
. We detected a clear accumulation of unprenylated Rab proteins, as well as unprenylated Rap1A by western blotting, in all six genetically-confirmed MKD patients compared to heterozygous controls and healthy volunteers. Furthermore, in the three subjects for whom measurements of residual mevalonate kinase activity was available, enzymatic activity inversely correlated with the extent of the defect in protein prenylation. Finally, a heterozygous
patient presenting with autoinflammatory symptoms did not have defective prenylation, indicating a different cause of disease. These findings support the notion that the extent of loss of enzyme function caused by biallelic
variants determines the severity of defective protein prenylation, and the accumulation of unprenylated proteins in PBMCs may be a sensitive and consistent biomarker that could be used to aid, or help rule out, diagnosis of MKD.
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