Abstract Dedicator of Cytokinesis 8 (DOCK8) deficiency is a combined immunodeficiency that exemplifies the broad clinical features of primary immunodeficiencies (PIDs), extending beyond recurrent ...infections to include atopy, autoimmunity and cancer. It is caused by loss of function mutations in DOCK8 , encoding a guanine nucleotide exchange factor highly expressed in lymphocytes that regulates the actin cytoskeleton. Additional roles of DOCK8 have also emerged, including regulating MyD88-dependent Toll-like receptor signaling and the activation of the transcription factor STAT3. DOCK8 deficiency impairs immune cell migration, function and survival, and it impacts both innate and adaptive immune responses. Clinically, DOCK8 deficiency is characterized by allergic inflammation as well as susceptibility towards infections, autoimmunity and malignancy. This review details the pathophysiology, clinical features and management of DOCK8 deficiency. It also surveys the recently discovered combined immunodeficiency due to DOCK2 deficiency, highlighting in the process the emerging spectrum of PIDs resulting from DOCK protein family abnormalities.
Germline CBM-opathies: From immunodeficiency to atopy Lu, Henry Y.; Biggs, Catherine M.; Blanchard-Rohner, Geraldine ...
Journal of allergy and clinical immunology,
20/May , Letnik:
143, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Caspase recruitment domain (CARD) protein–B cell CLL/lymphoma 10 (BCL10)–MALT1 paracaspase (MALT1) CBM complexes are critical signaling adaptors that facilitate immune and inflammatory responses ...downstream of both cell surface and intracellular receptors. Germline mutations that alter the function of members of this complex (termed CBM-opathies) cause a broad array of clinical phenotypes, ranging from profound combined immunodeficiency to B-cell lymphocytosis. With an increasing number of patients being described in recent years, the clinical spectrum of diseases associated with CBM-opathies is rapidly expanding and becoming unexpectedly heterogeneous. Here we review major discoveries that have shaped our understanding of CBM complex biology, and we provide an overview of the clinical presentation, diagnostic approach, and treatment options for those carrying germline mutations affecting CARD9, CARD11, CARD14, BCL10, and MALT1.
A subset of patients with severe COVID-19 develop profound inflammation and multi-organ dysfunction consistent with a “Cytokine Storm Syndrome” (CSS). In this review we compare the clinical features, ...diagnosis, and pathogenesis of COVID-CSS with other hematological CSS, namely secondary hemophagocytic lymphohistiocytosis (sHLH), idiopathic multicentric Castleman disease (iMCD), and CAR-T cell therapy associated Cytokine Release Syndrome (CRS). Novel therapeutics targeting cytokines or inhibiting cell signaling pathways have now become the mainstay of treatment in these CSS. We review the evidence for cytokine blockade and attenuation in these known CSS as well as the emerging literature and clinical trials pertaining to COVID-CSS. Established markers of inflammation as well as cytokine levels are compared and contrasted between these four entities in order to establish a foundation for future diagnostic criteria of COVID-CSS.
Inborn errors of immunity manifesting as atopic disorders Vaseghi-Shanjani, Maryam; Smith, Kelsey L.; Sara, Rahnuma J. ...
Journal of allergy and clinical immunology,
November 2021, 2021-11-00, 20211101, Letnik:
148, Številka:
5
Journal Article
Recenzirano
Inborn errors of immunity are traditionally best known for enhancing susceptibility to infections. However, allergic inflammation, among other types of immune dysregulation, occurs frequently in ...patients with inborn errors of immunity. As such, the term primary atopic disorders (PADs) was recently coined to describe the group of heritable monogenic allergic disorders. It is becoming increasingly important for clinicians to recognize that allergic diseases such as food allergy, atopic dermatitis, and allergic asthma are expressions of misdirected immunity, and in patients who present with severe, early-onset, or coexisting allergic conditions, these can be indications of an underlying PAD. Identifying monogenic allergic disease through next-generation sequencing can dramatically improve outcomes by allowing the use of precision-based therapy targeting the patient’s underlying molecular defect. It is therefore imperative that clinicians recognize PADs to be able to provide informed therapeutic options and improve patient outcomes. Here, we summarize the clinical features commonly seen with each of the currently known PADs, identify clinical warning signs that warrant assessment for PADs, and lastly, discuss the benefits of timely diagnosis and management of these conditions.
Résumé
Historique
Le syndrome inflammatoire multisystémique de l’enfant (SIME) est une complication postinfectieuse de la COVID-19 qui combine des manifestations de la maladie de Kawasaki et du ...syndrome de choc toxique. En mai 2020, un groupe de travail multidisciplinaire provincial a été mis sur pied en prévision des cas émergents après la première vague de COVID-19.
Méthodologie
Le centre des auteurs a créé un groupe multidisciplinaire pour les cas de SIME en Colombie-Britannique, qui a préparé des lignes directrices inspirées de la définition de cas de SIME de l’Organisation mondiale de la Santé. Il a mis les lignes directrices à jour au moyen de méthodes d’amélioration de la qualité en fonction de la publication de nouveaux rapports et de l’évolution de l’expérience locale. Il a inclus tous les enfants évalués en personne ou dont les échantillons avaient été envoyés au centre afin de confirmer la présence du syndrome entre mai 2020 et avril 2021. Il a procédé à la collecte prospective des caractéristiques démographiques et cliniques, des caractéristiques de laboratoire et des traitements des patients.
Résultats
Au total, 52 enfants ont été évalués, et 11 ont reçu un diagnostic de SIME confirmé. Dix de ces 11 cas ont souffert d’un choc, et les atteintes gastro-intestinales et mucocutanées étaient également courantes. Les résultats de laboratoire fréquents incluaient une élévation de la protéine C-réactive, des D-dimères, de la troponine et du peptide cérébral natriurétique. Quatre des 11 cas (36 %) ont souffert d’un dysfonctionnement myocardique et trois (27 %), d’anomalies des artères coronaires. Les 11 patients ont obtenu des résultats démontrant une infection par le SRAS-CoV-2, et dix d’entre eux (91 %) ont reçu des immunoglobulines et des corticostéroïdes par voie intraveineuse.
Conclusion
La cohorte provinciale de patients atteints d’un SIME confirmé était plus susceptible de présenter un état de choc et un dysfonctionnement cardiaque, d’être admise en soins intensifs et de recevoir un traitement aux corticostéroïdes que les cas écartés. Grâce au processus évolutif privilégié par le groupe de travail, les enfants de la province possédant des caractéristiques du syndrome étaient rapidement dépistés, soumis à une évaluation standardisée et traités de manière appropriée.
Monogenic conditions that disrupt proper development and/or function of the immune system are termed inborn errors of immunity (IEIs), also known as primary immunodeficiencies. Patients with IEIs ...often suffer from other manifestations in addition to infection, and allergic inflammation is an increasingly recognized feature of these conditions.
We performed a retrospective analysis of IEIs presenting with allergic inflammation as reported in the USIDNET registry. Our inclusion criteria comprised of patients with a reported monogenic cause for IEI where reported lab eosinophil and/or IgE values were available for the patient prior to them receiving potentially curative therapy. Patients were excluded if we were unable to determine the defective gene underlying their IEI. Patients were classified as having eosinophilia or elevated IgE when their record included at least 1 eosinophil count or IgE value that was greater than the age stratified upper limit of normal. We compared the proportion of patients with eosinophilia or elevated IgE with the proportion of samples in a reference population that fall above the upper limit of normal (2.5%).
The query submitted to the USIDNET registry identified 1409 patients meeting inclusion criteria with a monogenic cause for their IEI diagnosis, of which 975 had eosinophil counts and 645 had IgE levels obtained prior to transplantation or gene therapy that were available for analysis. Overall, 18.8% (183/975) of the patients evaluated from the USIDNET registry had eosinophilia and 20.9% (135/645) had an elevated IgE. IEIs caused by defects in 32 genes were found to be significantly associated with eosinophilia and/or an elevated IgE level, spanning 7 of the 10 IEI categories according to the International Union of Immunological Societies classification.
Type 2 inflammation manifesting as eosinophilia or elevated IgE is found in a broad range of IEIs in the USIDNET registry. Our findings suggest that allergic immune dysregulation may be more widespread in IEIs than previously reported.
The decision to intervene in endangered species management is often complicated. Migratory species exemplify this difficulty because they experience diverse threats at different times and places that ...can act cumulatively and synergistically on their populations. We use population viability analysis (PVA) to compare potential conservation interventions on the critically endangered, migratory Orange-bellied Parrot
Neophema chrysogaster
. This species suffers high juvenile mortality, but it is not clear why this is so. Given uncertainty about the best recovery strategy, we compare PVA scenarios that simulate various ways of utilizing captive-bred parrots to support the wild population in the context of unresolved threatening processes. Increasing the number of juveniles entering the population each year had the greatest benefit for population growth rate and size. Directly lowering juvenile mortality rates is difficult given uncertainty about the drivers of mortality in the wild. In lieu of this, releasing 100 juveniles from captivity to the wild population each autumn (either as a stand-alone action, or in combination with other interventions) was the most feasible and straightforward intervention of the options we tested. However, our PVAs also show that unless substantial and sustainable reductions can be made to juvenile mortality rates, Orange-bellied Parrots will remain dependent on intensive conservation management. This study highlights the utility of PVAs for answering practical questions about how to implement species conservation. PVAs provide a way to incorporate the best available information in a replicable modelling framework, and to identify impacts of parameter uncertainty on demographic trends.
Background Dedicator of cytokinesis 8 (DOCK8) deficiency can be cured by allogeneic hematopoietic stem cell transplantation (HSCT). Reports of outcomes are still limited. Objective We sought to ...analyze the results of HSCT in patients with DOCK8 deficiency and report whether approaches resulting in mixed chimerism result in clinically relevant immune reconstitution. Methods We performed a retrospective chart review of 11 patients with DOCK8 deficiency and measured DOCK8 expression and cytokine production. Results Of 11 patients, 7 received HSCT from related and 4 from unrelated donors; 9 patients received busulfan-based conditioning regimens. Survival was excellent (10 91% of 11 patients alive), including a patient who had undergone liver transplantation. Patients showed significant improvements in the frequency and severity of infections. Although eczema resolved in all, food allergies and high IgE levels persisted in some patients. Lymphopenia, eosinophilia, low numbers of naive CD8+ T cells and switched memory B cells, and TH 1/TH 2 cytokine imbalance improved in most patients. Although the 8 matched related or unrelated donor recipients had full donor chimerism, all 3 recipients of mismatched unrelated donor HSCT had high levels of donor T-cell chimerism and low B-cell and myeloid cell chimerism (0% to 46%). Almost all switched memory B cells were of donor origin. All patients, including those with mixed chimerism, mounted robust antibody responses to vaccination. Conclusion Allogeneic HSCT ameliorated the infectious and atopic symptoms of patients with DOCK8 deficiency. In patients with mixed chimerism, selective advantage for donor-derived T cells and switched memory B cells promoted restoration of cellular and humoral immunity and protection against opportunistic infection.
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