Druggable monogenic immune defects hidden in diverse medical specialties: Focus on overlap syndromes

In the last two decades two new paradigms changed our way of perceiving primary immunodeficiencies: An increasing number of immune defects are more associated with inflammatory or autoimmune features rather than with infections. Some primary immune defects are due to hyperactive pathways that can be targeted by specific inhibitors, providing innovative precision treatments that can change the natural history of diseases. In this article we review some of these "druggable" inborn errors of immunity and describe how they can be suspected and diagnosed in diverse pediatric and adult medicine specialties. Since the availability of precision treatments can dramatically impact the course of these diseases, preventing the development of organ damage, it is crucial to widen the awareness of these conditions and to provide practical hints for a prompt detection and cure

Prevalence of IgG antibodies against Malawi polyomavirus in patients with autoimmune diseases and lymphoproliferative disorders subjected to bone marrow transplantation

IntroductionHuman polyomaviruses (HPyVs) cause persistent/latent infections in a large fraction of the population. HPyV infections may cause severe diseases in immunocompromised patients. Malawi polyomavirus (MWPyV) is the 10th discovered human polyomavirus (HPyV 10). MWPyV was found in stool samples of healthy children. So far, the few investigations carried out on HPyV 10 did not find an association with human disease.MethodsIn this study, to verify the putative association between MWPyV and human diseases, MWPyV seroprevalence was investigated in patients affected by i) lymphoproliferative disorders (LPDs) and ii) immune system disorders, i.e., autoimmune diseases (ADs), and in iii) healthy subjects. An indirect ELISA, employing virus-like particles (VLPs) to detect serum IgG antibodies against MWPyV/HPyV 10, was carried out. The study also revealed the prevalence of another polyomavirus, Merkel cell polyomavirus (MCPyV).ResultsSera from patients with distinct autoimmune diseases (n = 44; mean age 20 years) had a prevalence of MWPyV antibodies of 68%, while in patients with lymphoproliferative disorders (n = 15; mean age 14 years), subjected to bone marrow transplantation, the prevalence was 47%. In healthy subjects (n = 66; mean age 13 years), the prevalence of MWPyV antibodies was 67%. Our immunological investigation indicates that MWPyV/HPyV 10 seroconversion occurs early in life and MWPyV/HPyV 10 appears to be another polyomavirus ubiquitous in the human population. A significantly lower MWPyV antibody reactivity together with a lower immunological profile was detected in the sera of LPD patients compared with HS2 (*p < 0.05) (Fisher’s exact test). LPD and AD patients have a similar MCPyV seroprevalence compared with healthy subjects.DiscussionMWPyV seroprevalence indicates that this HPyV is not associated with lymphoproliferative and autoimmune diseases. However, the ability to produce high levels of antibodies against MWPyV appears to be impaired in patients with lymphoproliferative disorders. Immunological investigations indicate that MWPyV seroconversion occurs early in life. MCPyV appears to be a ubiquitous polyomavirus, like other HPyVs, in the human population

Neutralizing antibodies explain the poor clinical response to Interferon beta in a small proportion of patients with Multiple Sclerosis: a retrospective study

<p>Abstract</p> <p>Background</p> <p>Neutralizing antibodies (NAbs) against Interferon beta (IFNβ) are reported to be associated with poor clinical response to therapy in multiple sclerosis (MS) patients. We aimed to quantify the contribution of NAbs to the sub-optimal response of IFNβ treatment.</p> <p>Methods</p> <p>We studied the prevalence of NAbs in MS patients grouped according to their clinical response to IFNβ during the treatment period. Patients were classified as: group A, developing ≥ 1 relapse after the first 6 months of therapy; group B, exhibiting confirmed disability progression after the first 6 months of therapy, with or without superimposed relapses; group C, presenting a stable disease course during therapy. A cytopathic effect assay tested the presence of NAbs in a cohort of ambulatory MS patients treated with one of the available IFNβ formulations for at least one year. NAbs positivity was defined as NAbs titre ≥ 20 TRU.</p> <p>Results</p> <p>Seventeen patients (12.1%) were NAbs positive. NAbs positivity correlated with poorer clinical response (<it>p </it>< 0.04). As expected, the prevalence of NAbs was significantly lower in Group C (2.1%) than in Group A (17.0%) and Group B (17.0%). However, in the groups of patients with a poor clinical response (A, B), NAbs positivity was found only in a small proportion of patients.</p> <p>Conclusion</p> <p>The majority of patients with poor clinical response are NAbs negative suggesting that NAbs explains only partially the sub-optimal response to IFNβ.</p

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Immunity and Genetics at the Revolving Doors of Diagnostics in Primary Immunodeficiencies

Primary immunodeficiencies (PIDs) are a large and growing group of disorders commonly associated with recurrent infections. However, nowadays, we know that PIDs often carry with them consequences related to organ or hematologic autoimmunity, autoinflammation, and lymphoproliferation in addition to simple susceptibility to pathogens. Alongside this conceptual development, there has been technical advancement, given by the new but already established diagnostic possibilities offered by new genetic testing (e.g., next-generation sequencing). Nevertheless, there is also the need to understand the large number of gene variants detected with these powerful methods. That means advancing beyond genetic results and resorting to the clinical phenotype and to immunological or alternative molecular tests that allow us to prove the causative role of a genetic variant of uncertain significance and/or better define the underlying pathophysiological mechanism. Furthermore, because of the rapid availability of results, laboratory immunoassays are still critical to diagnosing many PIDs, even in screening settings. Fundamental is the integration between different specialties and the development of multidisciplinary and flexible diagnostic workflows. This paper aims to tell these evolving aspects of immunodeficiencies, which are summarized in five key messages, through introducing and exemplifying five clinical cases, focusing on diseases that could benefit targeted therapy

Rheumatological complaints in H syndrome: from inflammatory profiling to target treatment in a case study

Abstract Background H Syndrome is a rare genetic condition caused by biallelic pathogenic variants in the SLC29A3 gene. It is characterized by a wide range of clinical manifestations, many of which are related to the immune-rheumatological field. These include scleroderma-like skin changes, deforming arthritis, and enlarged lymph nodes. The condition also features cardiac and endocrine defects, as well as hearing loss, for which the immune pathogenesis appears less clear. Immunomodulatory medications have been shown to improve many symptoms in recent experiences. Case presentation A 21-year-old girl was referred to our institute after being diagnosed with H syndrome. Her medical history was characterized by the development of finger and toe deformities, which developed since the first years of life and progressively worsened with clinodactyly. At 6 years of age, she was diagnosed with diabetes mellitus without typical autoantibodies and with bilateral sensorineural hearing loss. She also complained of frequent episodes of lymphadenopathy, sometimes with colliquation and growth retardation due to pancreatic insufficiency. It wasn’t until the genetic diagnosis of H syndrome that the continual increase in acute phase reactants was noticed, suggesting that an immunological pathogenesis may be the source of her problems. During her visit to our institute, she reported serious pain in both feet and hands and difficulty walking due to knee arthritis and muscle contractures. Conventional therapy with steroid injection in affected joints and methotrexate only led to partial improvement. After a thorough assessment of her inflammatory profile showing a high interferon score, the girl received treatment with baricitinib. Furthermore, based on recent data showing that SLC29A3 deficiency results in interferon production because of Toll-like Receptor 7 activation in lysosomes, hydroxychloroquine was also added. The combination of the two drugs resulted for the first time in a rapid and persistent normalization of inflammatory markers, paralleled by a dramatic improvement in symptoms. Conclusions We describe the results of inhibiting IFN inflammation in H syndrome and discuss how JAK inhibitors and antimalarials might represent a mechanistically based treatment for this orphan drug disorder

Annotated corpora and tools of the PARSEME Shared Task on Automatic Identification of Verbal Multiword Expressions (edition 1.0)

The PARSEME shared task aims at identifying verbal MWEs in running texts. Verbal MWEs include idioms (let the cat out of the bag), light verb constructions (make a decision), verb-particle constructions (give up), and inherently reflexive verbs (se suicider 'to suicide' in French). VMWEs were annotated according to the universal guidelines in 18 languages. The corpora are provided in the parsemetsv format, inspired by the CONLL-U format. For most languages, paired files in the CONLL-U format - not necessarily using UD tagsets - containing parts of speech, lemmas, morphological features and/or syntactic dependencies are also provided. Depending on the language, the information comes from treebanks (e.g., Universal Dependencies) or from automatic parsers trained on treebanks (e.g., UDPipe). This item contains training and test data, tools and the universal guidelines file

PARSEME corpora annotated for verbal multiword expressions (version 1.3)

This multilingual resource contains corpora in which verbal MWEs have been manually annotated. VMWEs include idioms (let the cat out of the bag), light-verb constructions (make a decision), verb-particle constructions (give up), inherently reflexive verbs (help oneself), and multi-verb constructions (make do). This is the first release of the corpora without an associated shared task. Previous version (1.2) was associated with the PARSEME Shared Task on semi-supervised Identification of Verbal MWEs (2020). The data covers 26 languages corresponding to the combination of the corpora for all previous three editions (1.0, 1.1 and 1.2) of the corpora. VMWEs were annotated according to the universal guidelines. The corpora are provided in the cupt format, inspired by the CONLL-U format. Morphological and syntactic information, ­­­­including parts of speech, lemmas, morphological features and/or syntactic dependencies, are also provided. Depending on the language, the information comes from treebanks (e.g., Universal Dependencies) or from automatic parsers trained on treebanks (e.g., UDPipe). All corpora are split into training, development and test data, following the splitting strategy adopted for the PARSEME Shared Task 1.2. The annotation guidelines are available online: https://parsemefr.lis-lab.fr/parseme-st-guidelines/1.3 The .cupt format is detailed here: https://multiword.sourceforge.net/cupt-format

Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study

Background Complement is likely to have a role in refractory generalised myasthenia gravis, but no approved therapies specifically target this system. Results from a phase 2 study suggested that eculizumab, a terminal complement inhibitor, produced clinically meaningful improvements in patients with anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis. We further assessed the efficacy and safety of eculizumab in this patient population in a phase 3 trial. Methods We did a phase 3, randomised, double-blind, placebo-controlled, multicentre study (REGAIN) in 76 hospitals and specialised clinics in 17 countries across North America, Latin America, Europe, and Asia. Eligible patients were aged at least 18 years, with a Myasthenia Gravis-Activities of Daily Living (MG-ADL) score of 6 or more, Myasthenia Gravis Foundation of America (MGFA) class II\ue2\u80\u93IV disease, vaccination against Neisseria meningitides, and previous treatment with at least two immunosuppressive therapies or one immunosuppressive therapy and chronic intravenous immunoglobulin or plasma exchange for 12 months without symptom control. Patients with a history of thymoma or thymic neoplasms, thymectomy within 12 months before screening, or use of intravenous immunoglobulin or plasma exchange within 4 weeks before randomisation, or rituximab within 6 months before screening, were excluded. We randomly assigned participants (1:1) to either intravenous eculizumab or intravenous matched placebo for 26 weeks. Dosing for eculizumab was 900 mg on day 1 and at weeks 1, 2, and 3; 1200 mg at week 4; and 1200 mg given every second week thereafter as maintenance dosing. Randomisation was done centrally with an interactive voice or web-response system with patients stratified to one of four groups based on MGFA disease classification. Where possible, patients were maintained on existing myasthenia gravis therapies and rescue medication was allowed at the study physician's discretion. Patients, investigators, staff, and outcome assessors were masked to treatment assignment. The primary efficacy endpoint was the change from baseline to week 26 in MG-ADL total score measured by worst-rank ANCOVA. The efficacy population set was defined as all patients randomly assigned to treatment groups who received at least one dose of study drug, had a valid baseline MG-ADL assessment, and at least one post-baseline MG-ADL assessment. The safety analyses included all randomly assigned patients who received eculizumab or placebo. This trial is registered with ClinicalTrials.gov, number NCT01997229. Findings Between April 30, 2014, and Feb 19, 2016, we randomly assigned and treated 125 patients, 62 with eculizumab and 63 with placebo. The primary analysis showed no significant difference between eculizumab and placebo (least-squares mean rank 56\uc2\ub76 [SEM 4\uc2\ub75] vs 68\uc2\ub73 [4\uc2\ub75]; rank-based treatment difference \ue2\u88\u9211\uc2\ub77, 95% CI \ue2\u88\u9224\uc2\ub73 to 0\uc2\ub796; p=0\uc2\ub70698). No deaths or cases of meningococcal infection occurred during the study. The most common adverse events in both groups were headache and upper respiratory tract infection (ten [16%] for both events in the eculizumab group and 12 [19%] for both in the placebo group). Myasthenia gravis exacerbations were reported by six (10%) patients in the eculizumab group and 15 (24%) in the placebo group. Six (10%) patients in the eculizumab group and 12 (19%) in the placebo group required rescue therapy. Interpretation The change in the MG-ADL score was not statistically significant between eculizumab and placebo, as measured by the worst-rank analysis. Eculizumab was well tolerated. The use of a worst-rank analytical approach proved to be an important limitation of this study since the secondary and sensitivity analyses results were inconsistent with the primary endpoint result; further research into the role of complement is needed. Funding Alexion Pharmaceuticals